1 Antidiabetic potential from selected Himalayan underutilized herbs: a review Exploiting

2 the role of antidiabetic potential of bioactive compounds obtained from underutilized herbs
3 of Himalayan region: A comprehensive review

5 Insha Zahoor1, Tanveer Ahmad Mir1, Tariq Ahmad Ganaie1, Wani Suhana Ayoub2, Salma
6 Farooq2,

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7 Department of Food Technology, Islamic University of Science and Technology,
8 Awantipora, India.

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9 Department of Food Technology, Desh Bhagat University, Mandi, Gobindgarh, Punjab,
10 India

12 *Corresponding author
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14 Insha Zahoor: insha.zahor@gmail.com
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34 Abstract

35 Diabetes is a metabolic condition resulting from impaired insulin synthesisDiabetes is a

36 metabolic illness caused by defective insulin production, with glucose buildup in the body
37 being the primary side effect. Many Himalayan plants have the ability to lower glucose
38 production and treat the related secondary diseases out of which,, less than 1% of these
39 plants have been pharmacologically confirmed. People frequently prefer using these
40 underutilized plants as a primary treatment or as a supplement to conventional medications due
41 to their affordability and historical use. The present analysis showed that the Himalayas employ
42 a significant number of highly valuable underutilized plant species to treat various diseases. To
43 ascertain the effectiveness of the plants against diabetes, clinical trials using the herbs need to be
44 conducted. Only a few underutilized plants of the Himalayas have been studied, despite the
45 fact that many of them can reduce glucose production. Many plants have been reported to
46 have anti-diabetic activity, but in the Himalayan region, Cichorium intybus, Dioscorea
47 dumetorum Linn., Acorus calamus, Artimisea absinthium, etc., are some of the underutilized
48 herbs that can be studied for diabetes and its complications. Since they are not subjected to
49 scientific testing and review, many herbal treatments are disregarded. Each active ingredient
50 needs to have its standardization and analysis. The scientific documentation of the
51 underutilized flora of Himalayan regions, distribution, and traditional applications may be
52 beneficial for sustainable use of such a valuable plant resource. Medical treatments made
53 from bioactive plants have been utilized for ages. The analysis showed that the chosen herbal
54 remedies held a great deal of promise as potential substitutes for diabetes medications.

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55 Additionally, every one of these plants has a unique way of bringing down blood sugar levels.
56 This is due to the basic fact that the existence of various active chemicals substantially influences
57 each herb's ability to function. This review will investigate several herbs for diabetic treatment,
58 including active compound types, potency, mechanism of action, and toxicity. The current
59 review focuses on some of the herbal plants with antidiabetic activity and the possible
60 mechanisms of their anti-hyperglycemic effects. The recent advances in extraction, isolation,
61 identification, and encapsulation of these bioactive compounds of underutilized plants of
62 the Himalayan region has also been discussed. Likewise, research is being done on
63 medicinal properties of underutilized plants of Himalayan region of Kashmir Valley.
64 .
65 Keywords: Underutilized plants; Bioactive compounds; Diabetes; Medicinal Properties.

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67 1. Introduction
68 Plants designed for medical purposes are used in herbal medicine, sometimes referedreferred to
69 as phytomedicine, or botanical medicine. Compared to traditional medicine, the use of herbal
70 medicine for medical purposes in the treatment and prevention of various illnesses, including
71 diabetes, has a long history (Choudhury et al., 2018). One of the biggest global public health
72 issues is diabetes. Hyperglycemia, often known as diabetes, is one of the frequent public health
73 hazards that is still difficult to optimally manage. Uncontrolled diabetes or persistent
74 hyperglycemia can lead to major consequences such renal disease, eyesight loss, cardiovascular
75 disease, and lower limb amputations, all of which increase the morbidity and death rate
76 associated with diabetes. Herbal medications isare one of the methods used to treat and prevent
77 diabetes and its subsequent consequences (Rawat et al., 2019).

78 The metabolic use of herbal products is not just prevalent in the food sector but also in the
79 treatment of a number of illnesses. Different plant components, such as roots, stems, bark,
80 leaves, fruits, berries, and flowers, are used in phytomedicine. , sometimes referred to as
81 botanical medicine (Rzhepakovsky et al., . 2022). The use of these medical applications dates
82 back about 5000 years, as recorded on a Sumerian clay slab. However, the first recorded use of
83 these treatments in a prescribed dosage was in Mesopotamia in 2600 B.C. (Choudhury et al., .
84 2018). Even in this new period, the World Health Organization (WHO) reports that traditional

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 85 medicines remain employed in the healthcare profession in the majority of nations, accounting
86 for about 1/4 of prescription medications derived from plants (WHO and UNICEF, 2018).

87 Complementary and alternative medicine, or CAM, therapies are the main category that includes
88 herbal medications. Patients became angry and leaned towards complementary and alternative
89 medicine (CAM) due to rising treatment costs and an expanding list of adverse effects associated
90 with conventional medications. Though less paternalistic and more patient-focused than
91 allopathy, it is also employed in conjunction with or as an alternative to allopathy.

92 According to data gathered between 2000 and 2014, there were 171-422 million more diabetic
93 patients than there were in 2000 (Choudhury et al., 2018). (Choudhury et al. 2018;.
94 Due to changes in the demographics of individuals over 65, this increase is predicted to
95 quadruple by 2030. A sedentary lifestyle, urbanization, ageing, obesity, a call for physical
96 inactivity, and rapid population expansion are further contributing factors. The number of
97 diabetes individuals rising is concerning since low blood glucose can have immediate, lethal
98 consequences. Microvascular and macrovascular disorders are among the consequences caused
99 by vascular injury. Microvascular illnesses include neuropathy and retinopathy, whereas
100 macrovascular disorders include depression, dementia, lower limb amputation, and sexual
101 dysfunction. disorder Diabetes Mellitus (DM), which affected developed and poor nations, is
102 very common. It is also regarded as a metabolic anomaly, primarily defined by insufficient
103 insulin secretion and action, followed by changes in the metabolism of lipids, carbohydrates, and
104 proteins (Naveen et al., 2021). Currently, 25 percent of people worldwide are afflicted with this
105 debilitating condition, and over 61 million people in India are diabetic (Bindu et al., 2019;
106 Suryavanshi

107 et al., 2019). Type 1 diabetes, type 2 diabetes, gestational diabetes, and prediabetes are the main
108 four types of diabetes (American Diabetes Association, 2019). The most prevalent kind of
109 diabetes among them is type 2, which shows an annual increase in patients. Type 2 diabetes is
110 defined by tissue resistance to insulin activity and a relative shortage in insulin secretion.
111 Diabetes mellitus is a serious health concern because its prevalence and fatality rates are
112 constantly rising. It is characterized by abnormal high levels of plasma glucose brought on by
113 insulin insufficiency, insulin resistance, or both, which alters the metabolism of lipids,
114 carbohydrates, and proteins. It causes a number of additional issues, such as cardiovascular

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115 disease, retinopathy, polyphagia, ketosis, and polyuria (Nisha et al., 2020). As a result, there is
116 a need for the production of more dependable and effective hypoglycemic agents. However, due
117 to their high cost, such traditional antidiabetic medications are out of reach for the average
118 person in impoverished nations.

119 Such general shortcomings of the traditional system of medicine were primarily responsible for
120 the requirement to develop an alternative method of managing diabetes using effective
121 homegrown plant and herbal remedies. Herbal therapy has been widely approved and used to
122 treat diabetes due to its wide acceptance and minimal adverse effects as compared to
123 synthetic medications (Hasanpour et al., 2020). It is well-known that the Himalayan region
124 boasts a rich repository of medicinal and aromatic plants, which have been employed by local
125 populations for alleviating a huge range of maladies (Sonkamble et al., 2019), For), For
126 medicines and bioactive compounds like carotenoids, flavonoids, terpenoids, alkaloids, and
127 glycosides which are being effectively synthesized and used to treat diabetes, plants are
128 always regarded as reliable sources of such medications . (Aldayel et al., 2020). Many
129 plants have been reported to have anti-diabetic activity (Pandey et al., 2022), but in the
130 Himalayan region, Cichorium intybus (handh), Dioscorea dumetorum Linn. (Kreench),
131 Acorus calamus (gander), Artimisea absinthium (tethwan), etc., are some of the
132 uderutiliedunderutilized herbs the most potent and frequently studied medicinal herbs for
133 diabetes and its complications..

134 It is well-known that the Himalayan region boasts a rich repository of medicinal and aromatic
135 plants, which have been employed by local populations for alleviating a huge range of maladies.
136 (V.V. Sonkamble, N.S. Wagh, S.R. Pai, 2019)

137 Medical treatments made from bioactive plants have been utilized for ages. However,
138 traditional medicine may have its roots in the long-standing relationship that many cultures
139 worldwide have with nature and its resources, particularly plants and plant materials. Many
140 people utilize herbs to treat various illnesses, from the common cold to other infectious
141 disorders brought on by viruses, bacteria, protozoa, and fungi that are common in local
142 communities. Phumthum et al. (2020), studied the specific community-based fungal diseases
143 of important concern. The most prevalent mycoses in rural areas among these illnesses are
144 candidiasis and dermatomycosis, sometimes known as ringworm. Alternative therapies are

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145 required since these illnesses are common and frequently difficult to cure with routine available
146 medicines.
147 The phytochemicals contained in fruits, vegetables, whole grains, medicinal plants and herbs are
148 known as "bioactive molecules," and they modulate metabolic processes to improve health
149 (Chang et al., 2019). Many of the treatments that are currently in the market were produced by
150 plants, which has been a great source of pharmaceuticals since long ago. Some herbs may lower
151 blood sugar levels or be helpful for treating other illness complications (Kasole et al., 2019).
152 Various crops and plant species are the basic building blocks of the biological system and the
153 central element of metabolic pathways. The photosynthetic process, respiration, synthesis and
154 breakdown of organic substances are all considered to be part of the complex mechanism of
155 plant metabolism. (Mohanraj et al., 2018; Wieczorek et al., 2019).
156 A wide variety of herbs possess the capacity to regulate glucose metabolism and the disorders
157 associated with it as figured out in the literature (Pandey et al., 2022. However, as per the
158 pharmacological validation, more than 15-25 % of 250,000 species have been recognized.
159 Patients prefer these medications because of historical evidences and the low prices. Hence in
160 hyperglycemic condition, Himalayan herbs are playing a great role in increasing the
161 insulin production to regulate glucose metabolism. Continuity in research and development
162 is the need of the hour in order to authenticate more information from herbs and their
163 extract. The purpose of this review was to summarize the most recent research on bioactive
164 compounds found in Himalayan herbs of Kashmir Valley and their effect in diabetic
165 population.

166 2. Himalayan Plants with medicinal properties

167 The underutilized herbs of Himalayan region and the important bio actives present are
168 enlisted in Table 1. The current analysis showed that the Kashmiri Himalayas employ a
169 significant number of highly valuable indigenous medicinal plant species to treat various
170 diseases. In the hilly terrain, the local and tribal populations use these plants, the bulk of
171 which are herbaceous type. The majority among these plants are utilized to make ethno
172 medicines by utilizing their parts like foliage, rhizomes, bark, blossom, berries, and
173 kernels. The majority of medicinal species are useful in treating skin-related or
174 dermatological conditions. Several plant species are used to treat colds, coughs, fevers,
175 diarrhea, constipation (Celosia argentea, Chenopodium album), body aches (Dipsacus

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176 inermis), chest problem, and stomach aches. Some of the important Himalayan herbs with
177 medicinal properties are given below:
178 2.1 Chicory (Cichorium intybus)
179 Old Egyptian people historically cultivated chicory as a therapeutic agent, as an alternative
180 to coffee and a vegetative crop. The root of C. intybus (Local name: Handh) was found to
181 contain up to 40% inulin, which, is acceptable for diabetics (Choudhary et al., 2021).
182 Chicory plant is grown with number of uses with varying varieties. Based on its use there
183 are four major types of Chicory. The first is the rhizome or commercial intybus, primarily
184 cultivated widely in Northern Europe, Africa, Chile, and India. Its taproot finds use in
185 making inulin or a constituent instead of coffee. Second is Brussels or witloof chicory,
186 frequently grown as industrial chicory in Europe for forcing etiolated buds (chicons). Leaf
187 chicory, which may be eaten raw or cooked, comes in third place. Forage chicory is the
188 fourth one originally obtained from wild chicory, is typically found growing along
189 roadsides and in waste areas (Aldahak et al., 2021).
190 Six species of the Asteraceae genus Cichorium are found primarily in Europe and Asia.
191 Chicory, also known as Cichorium intybus L., is an herb that is upright, typically rough,
192 with large foliage. Flowers may bloom through summer (Mayer et al., 2014). Flowers have
193 radially symmetrical blooms which are head like with attractive bluish-purple coloration.
194 Flowers grow singly along the length of a fibrous and inflexible dark-green stalk. There are
195 two different types of leaves on this wildflower: huge dandelion-shaped leaves close to the
196 stem's base, and smaller lanceolate to oblong leaves that grow along the length of the stem.
197 Greek and Latin are the sources of this plant's name. Cichorium means field, and intybus
198 is a combination of the Latin tubus, which denotes the hollow stem, and the Greek verb,
199 which means to cut because of the leaves. Hindubar, Indyba in Arabic, Zral in Baluchistan,
200 and Persian, Kasni in Hindi, Gul, Hand in Punjabi, Tsikorie, are some frequent names by
201 which it is known (Katiyar, 2021).
202 2.2 Artemesia absinthium (Local name: tethwan)
203 This plant possesses a xyloid dendritic continuous growing dwarf bushy herbaceous with a
204 hairy rhizome used in herbal medicine. The plant was formerly known by the name
205 Absinthium. It is thought that its name has been derived from the Greek word
206 "absinthium," which means "undrinkable" and refers to the extremely bitter flavor (Bhat

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207 et al., 2019). The name of the plant may have come from its potential to represent chastity
208 because it was used to encourage menstruation. It naturally grows on rocky slopes,
209 uncultivated, arid land, the edges of trails, and fields. The silver-green leaves of Artemisia
210 species are grown for their fragrant, gastronomic, and therapeutic qualities. They have
211 silver or grey alternating leaves that are occasionally sharply splitted. Blooms do not show
212 any attraction. Such herbs make a habitat around sunny, dry landscape locations such as
213 rock gardens. Plants begin to flower in mid-summer, drooping heads of amber and tube
214 shaped bloom appear on the foliage axis.
215 The therapeutic value of Artemisia absinthium was previously recognized for its ability
216 against pests like rodents, bookworms, bedbugs, and fabric moths. Due to the presence of
217 multiple active components that function in various ways, important oil components often
218 possess a wide range of phytochemical activity. From an ethno-pharmacological
219 perspective, this herb is being in use traditionally also possess a number of
220 pharmacological effects including liver protection, anti-anxiety, anti-spasmodic, enhances
221 bile movement, reduces menstrual problems, purgative, bile production response, soothing,
222 defensive stimulant (Msaada et al., 2015).
223 In both healthy and diabetic mice, Artemisia absinthium was found to provide considerable
224 hypoglycemic action comparable to 10 mg/kg. Diabetic rats given Artemisia absinthium
225 showed increased food intake and body weight. After receiving Artemisia absinthium
226 treatment, diabetic rats levels of lipids, sterol, were seen dramatically reduced, while their
227 high-density lipoprotein (HDL) levels got raised. The amount of hepatic glycogen has also
228 significantly increased (Shafi and Tabassum, 2013).
229 Human lifestyle and eating habits have changed significantly over the past century,
230 resulted in several chronic ailments. Diabetes is a chronic condition caused by unchecked
231 protein, lipid, and glucose metabolism in the body. Depending on one’s point of view,
232 diabetes has just become somewhat more complicated or more understandable. According
233 to a recent study, Scandinavian researchers have suggested to divide diabetes into five
234 distinct disease subtypes rather than the current two. An expert in the endocrine system
235 from Lund University, Sweden, stated that modified distribution system defines "paradigm
236 change" so every condition might be regarded with respect to it. He added that this is the
237 first step toward customized therapy for diabetes (Ahlqvist et al., 2018). The endogenous

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238 insulin hormone insufficiency or impaired efficacy leads to the lifelong illness known as
239 diabetes mellitus, which can either be genetic or adaptive. Elevated urine levels, high thirst,
240 high appetite, also exhaustion are all signs of diabetes (Mukhtar et al., 2020). Diabetes
241 disorder is associated with severe problems like, raised level of blood sugar, declined level
242 of blood sugar, irreparable harm, disability, and organ failure. The condition and its
243 complications cannot be effectively treated with allopathic medications. As a result,
244 attention is now being paid to traditional medicine. As a result of higher levels of
245 triglycerides (TG), low-density lipids (LDL), and lower levels of high-density lipids (HDL),
246 diabetes has been associated with a greater risk of developing atherosclerosis early in life.
247 Acetyl choline esterase enzyme activity in the brain and RBC membrane decreased under
248 diabetes conditions (Shaban et al., 2021). With its high concentration of flavonoids and
249 essential oils, Artemisia is regarded as a significant medicinal variety and functions as a
250 main ingredient in alcoholic beverages (Behbahani et al., 2017). Absinthe is the perennial
251 shrubby plant (Artemisia absinthium), found throughout the Kashmir valley and has a
252 widespread distribution from Europe to North Asia.
253 2.3 Acorus calamus
254 For more than a century, Acorus calamus (Local name: vai gander), popularly known as
255 "Vacha" or either "Sweet flag," is a key plant with respect to the Indian system of
256 Medicine which also have inborn therapeutic framework. The Indian Ayurvedic medical
257 system has used AC rhizomes as a solo sedative or a component of some compound sedative
258 combinations to treat psychoneurosis, sleeping problem, mania, epilepsy, and memory loss
259 (Akers et al., 2019). Additionally, it is used to cure tumors, haemorrhoids, skin conditions,
260 deadness, and general debility. It is also used to treat hacks, fever, bronchitis, irritability,
261 sorrow, and other mental clutters, and as a remedy for a few harmful conditions like
262 stimulant, emetic, carminative, stomachic (Laidaw et al., 2016). This plant presently
263 flourishes in Central Asia, India, Central Europe and North America. It is typical in
264 mountains including the Himalayas of India. Triploid and tetraploid AC species are found
265 in Jammu (India) zone while diploid ones in Europe and America (Rana et al., 2013).
266 Since ancient Greek and Roman times, the Acorus calamus has been utilized for a variety of
267 medical conditions (Khwairakpam et al., 2018). It is a well-known folk remedy used for
268 over a century in India and China to treat edema, constipation, fever, asthma, and other

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269 conditions. Numerous native American cultures utilize this and acts as opiate for pain in
270 the head, teeth, and it is recognized to be a possible sedative agent. Dehydrated roots
271 possess widespread phytochemicals which can cure disorders like bronchitis, digestive
272 system problems, ortho-disorders, heart problems and nervous system disorders
273 (Khwairakpam et al., 2018). In addition, Merak, Banten, and Indonesian traditional folk
274 medicine have all employed this plant's roots extensively to cure diabetes. An effective
275 Indian traditional medicine called the Acorus calamus has been used to treat urinary and
276 hepatic problems, dermatitis, pansinusitis, choking, pyrexias, respiratory disorder, and
277 many more conditions (Khwairakpam et al., 2018). It was noted that rats administered
278 alcoholic or aqueous extract for 30 days at a specific dosage while consuming an
279 atherogenic diet showed a drop in cholesterol and triglyceride levels and increase in HDL
280 levels. Rats that ingested saponins from isolated alcoholic extract experienced the same
281 effects. A study determined that herbal extracts had a concentration-dependent influence
282 on the activation of peroxisome proliferator-activated receptors (Sharma et al., 2020).
283 2.4 Dioscorea dumetorum Linn.
284 A perennial herb, yam (Dioscorea spp.) is mostly grown in equatorial and semi-equatorial
285 areas lying on the globe. Only six out of more than one hundred fifty species of yam
286 worldwide D. dumenterum (Local name: Kashmiri Kreench) are of much importance. The
287 organic acid, and phenolic extracts that Dioscoreacea contain have phytochemical
288 properties. It also contains phenolic compounds with low toxicity. Antioxidant activity,
289 anticancer, antimutagenic, and antibacterial activities of phenolic compounds have also
290 been reported.
291 According to Raju et al. (2012), diosgenin, a phytochemical is found in yam which elevated
292 the bulk among Wistar rats that were given food containing diosgenin extract.
293 Streptozotocin-prompted rats with diabetes were given feed containing saponin extract,
294 which is a feed of commercial importance. This was accomplished by lowering blood
295 glucose levels. D. dumetorum produces a high yield in terms of agronomy, with yields of 40
296 tons/hectare being seen in agricultural stations (Mumo et al., 2018). Dioscorea dumetorum
297 is renowned for its medicinal qualities as well. D. dumetorum contains the unique bioactive
298 chemical dioscoretine, which is effectively used as a hypoglycemic agent in antidiabetic
299 drugs.

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300 It has a hypoglycemic impact and is used in conventional medicine to treat diabetes. The
301 scientific name for D. dumetorum Linn. is bitter yam in Africa. Dioscoretine, is an alkaloid
302 compound found whose extract possesses an antihyperglycemic effect. Aqueous extract of
303 the D. dumetorum tuber has been said to control hyperlipidemia, hypercholesterolemia, and
304 hyperketonemia. The herb primarily treats diabetes problems by acting as an active
305 hypoglycemic agent (Gupta et al., 2017).
306 One of the herbs in the Dioscoreaceae family used to treat DM is called Dioscorea
307 dumetorum (bitter yam). It has been widely utilized in the Nigerian traditional system of
308 medicine like a painkiller against swelling (Ukwueze et al., 2015), antioxidant against-
309 cholinesterase (Salawu et al., 2017), and in managing high lipidemic, high cholesterol and
310 hyperketoacidosis (Obidiegwu et al., 2020). D. dumetorum starch is reportedly being used
311 in the manufacturing of chloroquine tablets having strong mechanically resistance with
312 prolonged release.
313 2.5 Saussurea costus
314 Saussurea costus ethanol extract significantly boosted HDL-C levels in both serum and
315 tissue while reducing triglycerides (Kilani et al., 2022). Aqueous extract of S. costus was
316 found to lower blood triglycerides and cholesterol in rabbits, according to Ansari et al.
317 (2019). S. simpsoniana, another species in the genus, is also known to lower cholesterol
318 levels and the risk of stroke (Rathore et al., 2021). Due to their antioxidant properties, the
319 primary active ingredients in S. costus have existed as hypolipidemic and hypoglycemic
320 therapeutic agents. When isoproterenol was administered to rats at a dose of 85 mg/kg,
321 myocardial disease and scarring were developed, the cardioprotective effects of costus root
322 aqueous extract were detected in the diseased rats. Three doses of costus aqueous extract
323 (100, 200, and 300 mg/kg) were administered orally in rats. Oxidative stress was
324 significantly reduced at a dose of 200 mg/kg of costus. The myocardial complications that
325 results from AESL's acute verbal administration of the drug mediates oxidative stress by
326 causing a drop in the levels of TBARS. At absorption of 100, 200 , and 250 mg/kg
327 hydroalcoholic root extract in terms of costus was examined to explore immunomodulatory
328 activity, but no significant effects on humoral immunity or any quantity of antibodies
329 produced by spleen cells were found. Higher concentrations of costus extract suggested the

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330 possibility of immunomodulatory activity in the immune system, both humoral and
331 cellular.
332 3. Herbal plants with antidiabetic activity and the possible mechanisms of their anti-
333 hyperglycemic effects.
334 Diabetes is a chronic endocrine condition that is becoming more and more prevalent in the
335 world. Nowadays, diabetes is a serious health problem that affects people of all ages
336 because of its multi organ system involvement and severe repercussions. Worldwide
337 research is concentrated on identifying alternative modalities because diabetes treatment is
338 still difficult to achieve despite pharmacological development and therapeutic measures.
339 Numerous conventional treatments for diabetes have been discovered after extensive
340 analytical research. For treating health problems and complications resulting from
341 polygenic illnesses, compounds and extracts obtained from various natural resources,
342 notably plants, have always been popular tools (Mukhtar et al., 2020). Numerous
343 therapeutic plants have positive results with experimental research done on animals that
344 can be applied to human beings.
345 The various herbal plants such as Aegle marmelos Corr. (Rutaceae), Azadirachta indica
346 Juss. (Maliaceae), Capparis deciduas (Capparaceae), Catharanthus roseus L. (Apocynaceae),
347 and Gymnema slyvestra Roxb. (Asclepiadaceae) are shown in Fig 1. These herbal plants
348 have significant antidiabetic activity. It was discovered that A. marmelos restored blood
349 sugar and body weight to normal levels just as effectively as insulin (Tiwari et al., 2014).
350 Malate dehydrogenase, a metabolic enzyme, was considerably predominant in STZ-
351 induced diabetic rats than in control rats. The K m values of these enzymes were reversed to
352 levels that were close to normal by the use of insulin and the leaf extract from A. marmelos.
353 The Azadirachta indica Juss. (Maliaceae) seed (Neem seed) kernel powder showed notably
354 show antidiabetic and antihyperlipidemic activity in alloxan diabetic rats (Das et al., 2012).
355 Neem leaf extract's potential mechanism of action against hyperglycemia was investigated
356 in healthy and diabetic rabbits produced with STZ. To minimize oxidative stress in alloxan
357 diabetic rats, antidiabetic treatment with powdered fruit of Capparis decidua
358 (Capparaceae) decreased alloxan-induced lipid peroxidation and alteration of erythrocyte
359 superoxide dismutase and catalase enzymes (Maqbool et al., 2019). Catharanthus roseus L.
360 (Apocynaceae) leaves, and twigs exhibit antidiabetic and anti-lipid peroxidative properties

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361 when extracted with dichloromethane-methanol (DCMM). Extra glucose utilization is the
362 mechanism of antidiabetic activity (Patel et al., 2012). Humans urine glucose levels are
363 decreased by Gymnema slyvestra Roxb. (Asclepiadaceae) leaf powder or decoction.
364 Diabetes-prone rabbits (Oyenihi et al., 2016), diabetic dogs (Singhal et al., 2014, 2014), and
365 diabetic people all were found to lower blood sugar levels after ingesting an aqueous or
366 alcoholic extract of leaves. Research studies of in vitro and in vivo types have illustrated as
367 it stimulates insulin secretion or release. The possible antihyperglycemic mechanism of
368 herbal plants in organ specific manner is illustrated in Fig. 2
369 The findings of earlier studies clearly demonstrate the ability of herbal treatments to
370 suppress glucosidase and amylase during the management of diabetes mellitus. These
371 medicinal herbs slow down the intestinal absorption of carbohydrates, which helps them
372 treat post-annual hyperglycemia as well. When it comes to regulating glucose, certain
373 plants have numerous effects. Some of these herbs are being studied for their potential to
374 regenerate pancreatic B cells, boost insulin sensitivity, increase glucose utilization, and act
375 as antioxidants. Due to excessive production of reactive oxygen species (ROS), decreased
376 endogenous antioxidant potential, including superoxide dismutase (SOD) and catalase
377 (CAT), and impaired patient antioxidant status, long-term diabetic conditions also put
378 patients at risk for developing vascular complications.
379 4. Identification, characterization and extraction of bioactive compounds of Himalayan
380 herbs
381 Bioactive compounds have a wide variety of varied effects when interacting with elements
382 of live tissue. The primary and secondary metabolites are of two categories produced by
383 therapeutic plants. Breathing, photosynthesis, and growth are all processes in which
384 primary metabolites are involved. Primary metabolites are necessary for synthesizing
385 secondary metabolites because they are involved in various cellular processes, including
386 growth, regulation and maintenance
387 The unprocessed plant extract is a mixture of many bioactive compounds with varying
388 polarity. As a result, one of the key tasks in identifying and classifying bioactive
389 compounds is extracting plant extract. To identify and categorise these bioactive
390 compounds, a variety of distinct segregation techniques are used, including

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391 chromatography methods and various spectroscopic techniques. Fig. 3 shows isolation and
392 identification and extraction of bioactive compounds from herbal plants.

393 Alkaloids, tannins, flavonoids, and phenolic compounds are the most significant bioactive
394 compoundsbioactive compounds of plants. Many of these native medicinal herbs are also
395 utilized as food plants and spices (Sun et al., 2019). The herbal medicine makes considerable
396 use of the plants mentioned in Table 2.
397 The bioactive compounds of Himalayan plants are prepared with different solvents
398 (aqueous, ethanol, and methanol). The extraction yield of a selected plant extract can be
399 compared using an aqueous solvent system along with two organic solvents (methanol and
400 ethanol). The solvent choice for extraction of bioactive compounds depends on the
401 physicochemical characteristics and their capacity to dissolve molecules since they can
402 create intermolecular interactions with many targeted compounds. According to Poole et
403 al. (2020), better extraction can be observed in methanol solvent because methanol has a
404 better penetration across the plant plasma membranes, which facilitates the quick
405 liberation of cellular contents into the solvent and hence net yield of crude extract is in
406 increased quantity.
407 Fruits, nuts, roots, vegetables, herbs, and spices are rich in bioactive components,
408 particularly polyphenols and non-starch polysaccharides (Saeed et al., 2021). Because
409 bioactive compounds are so important, the manufacturing industry is seeking for eco-
410 innovative methods to reduce a bioactive compound loss (Gomes-Arajo et al., 2021).
411 Antioxidants, anti-tumour, anti-swelling, anti-hyperglycemic, anti-hyperlipidemic, also
412 anti-anxiety characteristics are all present in these compounds (Saeed et al., 2021; Ben-
413 othman et al., 2020). Many researchers have used various current approaches to extract
414 bioactive compounds chemicals. Several extracting procedures are applied to isolate such
415 important phytochemicals from various origins. The type, preparation technique, and
416 energy usage all influence the extraction method used. It must be chosen to minimize loss
417 and energy consumption while obtaining the highest possible extraction yield of target
418 chemicals. Many researchers, like (Koçak et al., 2018), have indicated that the sample
419 preparation stage takes up about 60% of the entire time. The last analysis, which involves a
420 spectroscopic or chromatographic approach, takes around 7% of the overall time. Failure
421 to select an appropriate extraction process might result in the loss of the targeted
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422 component, and a mis-understanding among results. The present study identified multiple
423 extraction procedures that may be classified as traditional or environmentally friendly.
424 Many classic extraction procedures are utilised, including solid-liquid extraction technique
425 (SLE), liquid-liquid extraction technique also solid-phase microextraction. Traditional
426 techniques are now outdated and have a number of disadvantages, including nutrient loss,
427 low extraction yield and extended extraction times, increased energy use, and inefficiency.
428 Sasidharan et al. (2011) reviewed a variety of extraction procedures and explored their
429 benefits, including lower solvent usage, shorter extraction times, lower energy
430 consumption, and high extract output. In the present scenario, environment-friendly and
431 novel methods are at maximum applied to obtain phytochemicals from various essential
432 origins. Ultrasound extraction, supercritical fluid extraction, microwave extraction,
433 pressurised liquid extraction, membrane ultra-filtration extraction, instant controlled
434 pressure drop extraction, surfactant extraction, and enzyme-based extraction are some of
435 the high-yielding and efficient extraction techniques. In addition, numerous food industries
436 have employed ultrasonic, microwave, and high-pressure technologies to extend the shelf
437 life of foods (Li et al., 2021).
438 4.14.1 Various technologies used in extraction of bioactive compounds from Himalayan
439 plants
440 Extraction is the primary step in isolating and extracting plant phytochemicals. This
441 changes an actual suspension grid to specimen that can be used in further analysis. Many
442 ethnic groups have used elixir, undertone, admixture, digesting, also infiltration processes
443 to prepare extract prepare samples and use therapeuticuse therapeutic properties of plants.
444 The first known extraction methods are said to have been discovered in the eleventh
445 century, and serve as the foundation for more sophisticated extraction methods today
446 (Bitwell et al., 2023). . The 18th century reveals thereveals the introduction of the
447 advancedthe advanced extraction process known as "Soxhlet Extraction," which is a more
448 advanced version of the digesting and decoction methods. This is in keeping with the
449 modernization and industrial expansion era. However, these conventional methods of
450 extraction, like the Soxhlet method, show some shortfalls, for example, the solvent
451 requirement is high and takes much time with less output. Requirement for growing
452 population which comprises an increasing desire of natural products or their extracts for

15
453 the broad and safe applications, and well-time availability about best quality products
454 having less formulation charges and increased yield (Stéphane et al., 2021).. There is a rising
455 need for alternative and unconventional extraction strategies, which have been developed
456 from time to time to address these issues. Fig. 4 shows preferred cutting-edge extraction
457 methods and plant parts for various compound extraction. These include enzyme-aided
458 extraction (EAE), pressurized liquid extraction (PLE), ultrasound assisted extraction,(UAE),
459 (PEF), microwave assisted extraction technique (MAE). These methods are called "Green
460 Extraction" methods because they achieve a higher extraction yield while using less energy
461 and are noted as having quick excavation times, less volumes about biological, least toxic
462 liquids, with ease of use. As a result, extraction methods are said to be green when
463 compared with other solvents, consume less power, guarantee the safety and high quality of
464 the extract. All of these extraction methods have demonstrated their efficacy in the
465 extraction of different phytochemicals out of plantof plant source which can adhere to
466 fundamental ideas that maximize extraction output, adapt to industry needs, clarify
467 debasements also the poisonous substances, prevent dropdown in performance at
468 extraction time and ensure safety of food products. Selecting the best method for the
469 extraction process is essential. As a result, one should pay close attention to a few crucial
470 areas while extracting. For instance, the extraction output and quality of the extract may
471 be influenced by factors such as the use ofuse of a known matrix of plant, the accurate time
472 at which plant material parts completely dry, grind, becomegrind, become powder from
473 which particle size and the identification of the specific constituents, the extraction cycle
474 number, the type of extractor its design and process temperature. (Al-Mansoub et al., 2014;
475 Azwanida, 2015).

476 4.1.1 Ultra Sound-Assisted Extraction (UAE) of Bioactive Compounds. from plants.

477 Ultrasound-assisted extraction (UAE) is a frequently used extraction technique based on the
478 generation of high-frequency ultrasonic waves (20–1000 kHz) that generate cavitation due to the
479 material's expansion and contraction cycles (Dzah et al., ; 2020; Fu et al., ; 2020 ). The roots of
480 research in this field. The UAE's application in bioactive chemical extraction can be traced back
481 to the 1980s (Vinatoru et al., ; 2017). When the approach was presented as a way for greatly
482 increasing the extraction yields of target molecules for which ordinary laboratory equipment

16
483 (e.g., ultrasonic) can simply be used a bath for cleansing. However, the UAE method's
484 optimization for the many applications remains a work in progress., iIndicates a "challenge" that
485 should consider the following factors: extraction, temperature, the length of time, the intensity of
486 the ultrasound, the frequency of the ultrasound, and the type of ultrasound (Dzah et al., ; 2020).
487 In general, increasing the temperature during the extraction process has a positive effect on the
488 viscosity and surface tension of the solvents utilisedutilized, which leads to an increase in the
489 overall extraction yield. Temperatures in the UAE, on the other hand, often vary between RT to
490 70 °C, with higher temperatures being more common. With regard to the extraction time, a
491 compromise should be made between increasing the total extraction yield and reducing the
492 energy input. On the basis of the studied literature, an extraction time of about 30 min was
493 presented by many authors as the optimal (Setyaningsih et al., ; 2019 and Chen et a.,l; 2018). All
494 advantages and benefits of the UAE technique for the extraction of bioactive compounds have
495 already been described in numerous reviews and are partly listed here (Chemat et al., l; 2017;
496 Dzah et ., al; 2020). Consequently, the combination of the advantages of UEA with the proven
497 extractability of green DES/NADES for the various bioactive compounds certainly represents a
498 promising alternative to classical long-term extraction protocols.

499 Most authors have identified choline chloride:lactic acid-based DES (molar ratio usually 1:2) to
500 be the most promising solvent for extraction of phenolic acids using the UAE-DES/NADES
501 techniques. When choline chloride is combined with other organic acids, such as its’s also worth
502 looking at p-toluenesulfonic acid, oxalic acid, and citric acid (Zhou et al.,; 2018). When
503 polyalcohol-based DES is utilised, however, the combination of DES and UAE for the extraction
504 of different flavonoid subclasses is most optimal (Mansur et al., l; 2019; Fanali et al.,; 2020 ). As
505 an example, UAE-DES extraction of flavonoids in ordinary buckwheat sprouts has been
506 improved by Mansur et al. (2019). There are nine different DES based on choline chloride and
507 different HBD (acetamide, triethylene glycol, etc.). The following substances were used: 1,2-
508 propanediol, 1,4-butanediol, urea, ethylene glycpol, glycerol, oxalic acid, and malonic acid was
509 evaluated. Among the DES tested, a choline chloride solution in 80 percent water: Ethylene
510 glycol (DES) is a kind of ethylene glycol. The most promising solvent was chosen, and the
511 following conditions were proven to be ideal: an extraction temperature of 56 °C and a period of
512 40 minutes in the UAE (Mansur et al., ; 2019). In addition, Jeong et al.;( 2018). suggested a
513 UAE-DES one-step approach for extracting and analysing polar bioactive chemicals and volatile

17
514 monoterpenes from peppermint leaves (Jeong et al.,; 2018). The most promising solvent in this
515 investigation was choline chloride:glucose (molar ratio 5:2) NADES. The volatile monoterpenes
516 were determined directly using a newly developed and fully optimised method based on
517 headspace solid-phase microextraction coupled to gas chromatography (HS-SPME-GC-MS),
518 while the main polyphenol indices (TPC and TFC) and antioxidant values were determined using
519 the same extract (without further dilution with organic solvents) (FRAP, DPPH and ABTS).
520 These findings appear to be quite promising from both an economic and environmental
521 standpoint. However, the proposed method is likely to be confined to chemical evaluation of
522 peppermint samples from various origins, with little potential for usage in large-scale procedures.

523 Alkaloids, with an estimated 12,000 molecules, are one of the biggest classes of secondary
524 metabolites of microbial, plant, and animal origin. Alkaloids are nitrogenous chemicals that are
525 soluble in organic solvents but not in water and can be used in a variety of industries. Takla et al.
526 (2018) compared and assessed the potential and efficacy of NADES and non-ionic surfactants
527 for the extraction of amaryllidaceae alkaloids from Crinum powellii bulbs for the first time. They
528 showed that the extraction was substantially better than previously utilised procedures, which
529 required the use of organic solvents and water. The best solvent was water-based choline
530 chloride:fructose NADES, and the other RSM-optimized parameters were a temperature of 50 °C
531 and a sonification time of 1 h. NADES based on choline chloride and lactic acid proven to be the
532 optimum choice for the morphinan alkaloids (from Jiang et al., 2019).
533 Some studies also mentioned that sonication increased the yields of bioactive compounds
534 significantly in the process of extraction and decreased extraction time. As the effects mentioned
535 above, the use of ultrasound could be a promising way to introduce innovation into extraction
536 processes.
537
538 We can conclude that, given the diversity and complexity of cash crops and medicinal plants, as
539 well as their inherent variances in nature and structure, the multiple physical mechanisms
540 (fragmentation, erosion, sonocapillary effect, sonoporation, local shear stress, and detexturation)
541 combine to extract bioactive chemicals from cash crops using ultrasound. These physical
542 mechanisms may play a continuous or simultaneous function in time and space during the
543 ultrasonic extraction of bioactive chemicals.

18
544 4.1.2 Microwave-Assisted Extraction (MAE) of Bioactive Compounds from Himalayan
545 plants
546 Microwave-assisted extraction (MAE), which operates at frequencies ranging from 0.3 to 300
547 GHz, has recently been proposed as a potential green method for extracting diverse bioactive
548 chemicals from various natural sources (Panja, 2018). The MAE procedure can be carried out in
549 either a "“closed-vessel"” or a "“open-vessel"” system (Ameer et al., 2017). In both
550 circumstances, the MAE system rapidly raises the temperature, resulting in a shorter extraction
551 time and a higher target analyte extraction yield. When compared to traditional Soxhlet
552 extraction, MAE has the added benefit of being able to evaluate many samples at the same time.
553 Because many solvents, particularly non-polar ones (toluene, hexane, and dichloromethane), are
554 transparent to microwave energy, choosing the right one is critical for maximal process
555 utilisationutilization (Panja, 2018). Polar solvents, such as MeOH, EtOH, and ethyl acetate,
556 absorb microwave radiation, convert it to heat, and cause the cell wall to crack, allowing the
557 analytes to enter the solvent matrix. Given that DES/NADES can efficiently absorb microwave
558 energy, using DES/NADES as a solvent or co-solvent in the MAE for the effective extraction of
559 several kinds of bioactive chemicals is an intriguing approach. The extraction efficiency of MAE
560 is also influenced by a number of other factors, including the sample particle size, the
561 solvent/solid ratio, the microwave power used, the irradiation time, and so on (Panja, 2018). In
562 this context, Wei et al. (2015). Submitted the first study report describing the use of DES in
563 combination with MAE for the extraction of four key bioactive components of Radix
564 Scutellariae. Chen et al. (2016) developed the MAE-DES method for isolating bioactive
565 chemicals from Radix Salviae miltiorrhizae a year later. The scientists used an RSM to
566 optimiseptimize the extraction process, and the following extraction settings were considered
567 optimal: a temperature of 70 °C, an irradiation time of 11.11 minutes, a microwave power of 800
568 W, and a solid–liquid ratio of 0.007 g/Ml. They also found a statistically significant increase in
569 extraction yields of five analytes when compared to hot reflux extraction and UAE findings. For
570 the extraction of 48 different bioactive compounds from olive leaves, Zhao et al. (2019)
571 developed a technology based on MAE-DES pre-treatment combined with microwave
572 hydrodistillation of essential oils from cumin seed in a recently published publication .
573 According to the findings, after MAE-DES pre-treatment of the sample, a greater number of
574 compounds were extracted, resulting in a higher overall extraction yield. The high operating

19
575 costs and high impurity concentration of the extracts obtained are two of the most significant
576 drawbacks of using MAE in industrial-scale procedures. Different analytes could be extracted
577 simultaneously due to the intensive extraction conditions, necessitating additional purification
578 processes to generate "“ready-to-use"” extracts.

579 4.1.3. Supercritical Fluid Extraction of Bioactive Compounds from Himalayan plants.

580 The majority of physiologically active molecules in plant materials are found inside cells that are
581 contained by the pectocellulosic cell wall, which is made up of a well-organized cellulosic
582 structure made up of sugar-alcohols and ether bonds (between carbohydrates-proteins). Puri et al
583 (2012) have found that strong lignin strengthens and protects this complex. Furthermore, many
584 chemicals (phenolics) are linked to the cell wall through hydrogen and hydrophobic bonding
585 (polysaccharides). As a result, it is's challenging to remove bounded bioactive chemicals. In
586 recent years, there has been an increasing focus on green chemical extraction. Sub- and
587 supercritical fluids (ScF) can be used in the extraction process to achieve this. ScF can be
588 employed as a reaction medium, a precipitation and micronization solvent, a chromatography
589 mobile phase, and an extraction solvent, among other things. With a high feed to solvent ratio, it
590 is reasonable to employ the ScF to perform the supercritical fluid extraction (SFE) method at an
591 industrial scale for the separation of components with significant commercial value, such as
592 nutraceuticals, medicines, and food additives (Belwal et al., 2018). The SFE method is an
593 alternate sample preparation method that uses less organic solvents and produces more. The
594 extraction process in SFE requires the use of gases, most commonly CO₂CO2. The critical point,
595 or the ideal temperature and pressure at which the chemical can evaporate, is crucial in SFE,
596 which is more environmentally friendly than traditional extraction processes. It is the most
597 technologically advanced extraction method and has a wide range of applications in the
598 chemical, food, agriculture, pharmaceutical, and nutraceutical industries. Supercritical anti
599 solvent fractionation (SAF) is another ScF method that uses CO₂CO2 as an anti solvent because
600 polar and high molecular weight molecules that are insoluble in CO22 can be recovered in a
601 separator chamber and separated from non-polar matrix components. Under pressured
602 conditions, SAF maintains a constant contact between Sce CO₂CO2 and a polar liquid
603 combination. This will allow polar components that are insoluble in Sce CO₂CO2 to precipitate
604 from the liquid mixture, while non-polar components that are dissolved in Sce CO₂CO2 will flow

20
605 and be collected by the downstream pressure reduction system (Catchpole et al., ; 2009). The
606 lipophilic nature of CO₂CO2 facilitates separation and concentration of polar molecules from
607 organic extracts, which is the main benefit of SAF. SAF enables work at low temperatures and in
608 the absence of oxygen and light,. CO₂CO2 is also affordable, recyclable, and non-toxic.
609 4.1.4. Pressurised liquid extraction of Bioactive Compounds
610 Many uses of pressurised liquid extraction (PLE) for the extraction of bioactive chemicals from
611 plants have been developed in recent years as well as comparisons of PLE extracts prepared
612 according to pharmacopoeia monographs. This method, which uses water as a solvent, is
613 particularly appropriate for the recovery of bioactive chemicals and appears to be milder than
614 previous techniques, with no artefacts produced. This study strategy answers to our society's
615 need for trash reduction as well as waste valorisation, transforming waste into a resource (Belwal
616 et al., 2018).
617 The use of more sophisticated procedures that employ the idea of green extraction has caused a
618 change in extraction technique trends. These methods have the enormous advantage of producing
619 good quality yield, using less energy and solvent, and taking less time to extract. Advanced
620 extraction techniques, however, cannot be scaled up for pilot or industrial applications. The
621 laboratory-based experimentation conditions and value modifications are typically not designed
622 for industrial application. Therefore, the creation of commercially viable industrial extraction
623 techniques and tools is urgently required. The primary goal of contemporary analytical research
624 is the development of environmentally friendly and cost-effective extraction techniques for
625 increased recovery of bioactive chemicals at shorter process times from natural sources. But no
626 single extraction method was discovered to be efficient for the extraction of all chemicals.
627 Therefore, the best extraction method relies on the plant matrix and the kind of compound, and
628 specific selection criteria should be followed (Belwal et al., 2018).
629 .
630 Additionally, mixing extraction techniques frequently has advantages to get around a technique's
631 drawbacks. On the other hand, high-efficiency extraction techniques and the requirement for
632 solvent recycling or reuse are invariably linked to high operational costs and energy usage.
633 Therefore, the quest for alternative green extraction techniques is crucial for a productive and
634 affordable compound output.
635

21
636 The various extraction technology for extraction of bioactive compounds from various
637 plants is shown in Table 23. Processing plant sources in an effective, affordable, and eco-
638 friendly manner is required for the recovery of high-value biomolecules. According to
639 various studies, bioactive compounds of edible and agri-industrial origin have enticing
640 medicinal characteristics. Polyphenols are one of the many groups of bioactives, which
641 have a variety of uses in food, flavouring, beautifying products and medicinal industries
642 (Chhikara et al., 2018). Numerous therapeutic functions of these active ingredients could
643 effectively find use in medical field (Rengasamy et al., 2020). Processing plant sources in an
644 effective, affordable, and environmental friendly manner is required to recover high-value
645 biomolecules. Traditionally, the food industry has extracted nutritionally significant food
646 additives using hydro-thermal techniques based on organic solvents. Hence, during past
647 some decades, efforts were focused to create new procedures that could minimize
648 extraction constraints, thereby increasing extract effectively. A maximum of these
649 unconventional extract collection methods enable the release about the bioactive molecules
650 bound in a complicated system comprising long chain carbohydrate molecules and
651 proteins. Nevertheless, each among such approaches must be used separately taking into
652 account the benefits they have while resolving the challenges that impede their
653 development. Because of generation of heat and force of air the ultrasonication and
654 microwave techniques are unable to extract the heat and oxygen affected phytochemicals.
655 However, in SFE, the intricate cell wall structure makes it difficult for supercritical carbon
656 dioxide (SC-CO₂CO2) to permeate, significantly impacting the overall extraction efficiency.

657 5. Nanoencapsulation of bioactive Compounds

658 In the world of food science, nanoencapsulation has become more commonplace recently. It
659 is an encapsulation technology in which a bioactive molecule serves as the core matrix and
660 is contained inside a wall matrix resistant to enzymatic and environmental degradation.
661 Utilizing a stable sized surface material that offers defense to phytochemical substances
662 that can be particularly susceptible to high temperature and digestion promoting chemicals
663 found within the human digestive system. Additionally, these wall materials assist in
664 sustaining the active compound's nutritional function and in disguising some compound’s
665 unpleasant tastes (Pateiro et al., 2021). Since they preserve the substances as prolonged

22
666 periods than alternative kinds of nano materials. Liposomes or lipid bilayer shells are
667 thought to be the finest for encapsulating and delivering bioactive molecules. Also, casein
668 micelles are thought to have the potential for encapsulating minerals like calcium and
669 phosphate (Sadiq et al., 2021). The particle size of nano-capsules typically ranges from 1 to
670 100 nm. In addition to it the food business, the packaging sector uses nanoencapsulation to
671 package flesh, berry harvest to increase keeping quality while maintaining their dietary
672 value (Nile et al., 2020). For encapsulation, a variety of nano-carriers are utilized because
673 these aid in maintaining molecule prolonged energetic, chitosan-based glycolipid nano-
674 carriers have tendency to enhance antitumor property close to active xanthin that is., 25.8-
675 times (Paramanick et al., 2017). Rutin was encapsulated in several experiments however
676 the delivery rate of rutin to the desired region in the body was only 25% after 60 hours
677 (Grgic et al., 2020). Currently, scientists employed polysaccharide based phytochemical
678 components originating out of grape un-used portion, interestingly, the encapsulation
679 protected the chemical from degradation in the gastrointestinal system and increased the
680 bioactivity of the targeted compound (Nowsheen et al., 2015). Also, biomolecules such as
681 peptides are enclosed utilizing fatty nano-materials comprising two layers of surface active
682 ingredient also a flowing liquid for protection (Amoabediny et al., 2018). Additionally,
683 hybrid nano-carriers with chitosan and liposomes are used in encapsulating compounds
684 increases enclosing coherence. Depending on how much energy is used to encapsulate these
685 molecules, several methods are used, such as top-down and bottom-down procedures as
686 well as their combination (Al-Kassas et al., 2017). In contrast to the bottom-up method,
687 which uses different techniques, the top-down method of encapsulation uses equipments,
688 which results in high power consumption. When compared to the micro-encapsulation
689 method, the nanoencapsulation of bioactive substances is substantially more complicated.
690 It is broken down into three primary categories such as, top-down, bottom-up, and a
691 combination of both. Bottom-up techniques are confined to less kinetic methods. Bottom-
692 up methods demand raised kinetic efficient apparatus (Noorie et al., 2021). Delivery
693 motivation, release, speed of delivery, dissolution, stoutness with respect to micro emulsion,
694 and the manufacturing price are some variables that affect the choice of a specific method
695 for designing nano-capsules.

696

23
697 6. Side effects of underutilized herbs for medicinal purposes

698 Plant medications have the potential to be dangerous, have unfavorable effects, and in severe
699 situations, even be fatal. These can arise from the side effects of active chemicals, overdosing,
700 improper prescriptions, adulteration, or contamination. While some of these impacts are well
701 recognised, there are still those that need further scientific investigation. Because it contains the
702 alkaloid atropine, the Thornapple Datura stramonium is used as a treatment for asthma.
703 However, it is also a dangerous and potentially lethal hallucinogen. Given the availability of
704 potent naturally occurring poisons like nicotine and atropine, there is absolutely no reason to
705 assume that a product derived from nature is safe (Peduruhewa et al., 2021). Furthermore, plant
706 medicines are frequently not subject to the same strict quality standards as conventional
707 medicines, and their dosages can vary greatly depending on the growth conditions of the plants.
708 For example, older plants can be far more toxic than younger ones, and plants grown in
709 contaminated or toxic environments typically contain more toxic substances than plants grown in
710 safe, organic environments. The pharmacologically active plant extracts have the potential to
711 interact with conventional drugs in two ways: first, by increasing the dose of related compounds;
712 second, by delaying and interfering with the body's systems that metabolisemetabolize drugs in
713 the liver, such as the cytochrome P450 system, which prolongs the half-life of the drugs and
714 increases their potential cumulative effect. Pregnancy may be hazardous while using plant-based
715 medications (Nirmala et al., 2022).). Plant extracts can have a variety of complex impacts on the
716 human body since plants typically contain multiple distinct chemicals.
717

718 7. Future Perspective

719 The increasing global population has sparked a renewed interest in underutilized herbs of
720 Himalayan region among researchers and food professionals worldwide. The breadth of research
721 and development (R&D) was increased in tandem with underutilized herbs diversification and an
722 assessment of their applicability for various agro-ecosystems, particularly those with harsh
723 agroclimatic conditions. Through a number of international platforms, attention has been drawn
724 to the needs of rural farmers in marginal agro-habitats with few options for sustaining their
725 livelihoods and the adoption of policies to secure their basic needs. Herbal treatments are used
726 for their antidiabetic potential, which is used to improve insulin sensitivity, glucose absorption,

24
727 and insulin secretion mechanism regulation. To dispel any uncertainties and substantiate the
728 pharmacological effects of both the herb and its preparations, further study is required.
729 Commercialized formulations are guaranteed to pass clinical trials prior to implementation;
730 nonetheless, given the current state of the disease, prompt protocol validation and testing are
731 required to ascertain the status of particular herbs as active ingredients in extract formulations.
732 Each active ingredient must have its characterization, toxicity, efficacy status, long-term role and
733 effect on the body, and standardization thoroughly addressed before it can proceed to
734 manufacture. In addition, following the trials, the relevant regulatory agencies will be contacted
735 to further verify the created mixture's effectiveness and safety.

736 8
737

738 8.
739 76. Conclusion
740 The analysis showed that the chosen herbal remedies held a great deal of promise as potential
741 substitutes for diabetes medications. Additionally, every one of these plants has a unique way of
742 bringing down blood sugar levels. This is due to the basic fact that the existence of various active
743 chemicals substantially influences each herb's ability to function. From ancient times to modern
744 culture, herbal remedies have been proven to be successful against medical therapies. The
745 pathway of response mechanisms with distinct pharmacological activities and related benefits
746 have been assessed by upgraded study. Even in contemporary medicine, a sizable percentage of
747 currently marketed medications are derived from plants, such as digitalis, anti-malarials, aspirin,
748 and others. Diabetes is a metabolic disease mostly caused by defective insulin synthesis or
749 resistance to the insulin's action mechanism. One of the main adverse effects of diabetes on the
750 body is glucose accumulation. Many plants have the potential to lower glucose production and
751 treat related secondary illnesses, however fewer than 1% of the 250,000 species have been
752 pharmacologically isolated. In addition to treating diabetes, other benefits of using herbs include
753 lowering blood pressure, controlling cholesterol, controlling body mass index, and preventing
754 cardiovascular disease.
755 Due to its historical use and cost, patients frequently choose herbal treatments either as a primary
756 treatment or as a supplement to conventional therapy.

25
757 Human resource has to develop a robust immune system due to the exponential rise in dangerous
758 diseases. The only way to do this is by ingesting bioactive substances of botanical origin. Such a
759 situation prompted scientists to look towards a traditional and eco-friendly extraction technique
760 to capture bioactive compounds from plant matrixes. Plant-based natural products have been and
761 will continue be a source of potential pharmaceuticals and nutraceuticals. Underutilized plants
762 provide primary bioactive extracts to manufacture pure medicines. The majority of medicinal
763 plants are, however, taken from the wild, and because of the rising demand for them on both
764 national and global trade, an extraordinarily increasing collection and exploration related to such
765 indigenous genus is seen. The Indian pharmaceutical industry receives several underutilized
766 plants from the Himalayan Valley. This emphasizes necessity with respect to domestication and
767 cultivation of valuable therapeutic plants for trade. Each active ingredient in these plants needs to
768 have its standardization, characterization, long-term role and impact on the human body, efficacy
769 status, and toxicity profile completely addressed before it is advanced for manufacture.
770 Moreover, further study is required to dispel any uncertainties and confirm the antidiabetic and
771 other pharmacological effect of the plant itself and its extraction forms.

772 Funding: This research received no external funding.

773 Data Availability Statement: Data is contained within the article.

774 Conflicts of Interest: The authors declare no conflict of interest

775 Author contributions: All authors listed have made a substantial, direct, and intellectual
776 contribution to the work and approved it for publication.
777 Acknowledgements: The first author would like to thank Indian Council of Medical Research
778 (ICMR) for providing ICMR Research Associate fellowship.
779
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