portrays a  chronic disease possessing considerable hyperglycemia; dysfunctional insulin liberation by pancreatic βcells is an emblem  of such disease. Recent studies have illustrated that hypoxia takes place in the pancreatic βcells of patients having T2D with hypoxia as a  result leading  to abnormalities   of insulin liberation in addition to elimination of βcell   mass via mechanistic  modes inclusive of  activation of  hypoxia inducible factor   alpha(HIF 1-α),  induction of transcriptional suppressors along with activation of 5’ AMP-activated protein kinase(AMPK) .   Earlier we  had reviewed on the aetiopathogenesis of   Type 2 diabetes mellitus(T2D) along with role of gutmicrobiota(GM),diabesity,oral health AGEs stimulated & ERand Inflammatory Stress- modulated control of the GLUT4 expression (SLC2A4) promoted  genes,;details of epigenetics, mitochondrial melatonergic pathwaysand different methods of use of various plant products ,role of extracellular vesicles ,iron&mineral metabolism  and umpteen other articles Here our  concentration is   on insight into βcell hypoxia that might result  in dysfunctional insulin liberation in T2DM .An understanding of βcell hypoxia might  aid in generation of innovative strategies for the treatment  of T2DM . Further with emerging evidence of how autophagy might be implicated in propagation  of Type 2 Diabetes,thereby targeting both hypoxia and autophagy might bethe mechanistic  modes of how separate plant products are contributing in   T2D avoidance as well as propagation.Here we have attempted to give insight regarding how βcells hypoxia aids in generation of   βcells impairment in   T2D. Achieving greater insight of βcell hypoxia might aid in generating innovative  approaches  for T2D treatment.

Diabetes mellitus( DM)  represents a chronic  disorder associated with  considerable hyperglycemia and portrays one of the commonest etiological factor of mortality along with morbidity globally  .It has been determined that 529 million  people have been  living with DM worldover of which Type2 Diabetes mellitus( T2DM)  was implicated in 96% of full patients, in addition to proportion of the patients with DM have been estimated to escalate greater than double of 1.3 billion  individuals globally by year 2050[1]. Etiological factors responsible for T2DM are complicated  crosstalking amongst numerous genetic as well as  environmental factors. The genetic makeup results in insulin resistance  (IR) along with pancreatic βcells, whereas escalated weight along with sedentary life aggravates such metabolic abnormalities[2]. Dysfunctional insulin liberation in addition to IR specialized properties of T2DM[2]. In case of IR pancreatic βcells escalate insulin liberation regarding sustenance of normal glucose tolerance; nevertheless, once βcells lose their capability of  escalating insulin liberation the plasma quantities of glucose get escalated. Continued  exposure to hyperglycemia possess inimical sequelae over βcell numbers along with working;a postulate   referred to as  gluotoxicity which results in the generation as well as propagation of T2DM[3,4]. Hyperglycemia has a  negative impacts via plethora of mechanistic  modes  toxic actions  inclusive of Oxidative   stress( OS) along with endoplasmic reticulum (ER) stress in addition to inflammation[5]. Nevertheless, recent studies have   pointed  that hyperglycemia further stimulates hypoxia in βcells[6,7]. Hypoxia in turn  aids in βcell impairment through various mechanistic modes   inclusive of hypoxia inducible factor   alpha(HIF 1-α) [8]. Earlier we   had reviewed on the aetiopathogenesis of   Type 2 diabetes mellitus(T2D) along with role of gutmicrobiota(GM),diabesity,oral health AGEs Stimulated & ERand Inflammatory Stress- Modulated Control of the GLUT4 [removed]SLC2A4 promotedgenes,;details of epigenetics, mitochondrial melatonergic pathwaysand different methods of use of various plant products ,role of ecv,iron&mineral metabolismand umpteen other articles [9-25].Here our  concentration is   on insight into βcell hypoxia that might result  in dysfunctional insulin liberation in T2DM .Aninsight of βcell hypoxia might  aid in generation of innovative strategies for the treatment  of T2DM . 

Thus a narrative review was carried out using the pubmed, Web of Science , Medline, Embase, Cochrane reviews,  and Google Scholar, Search  engine with the MeSH Terms; Type 2 diabetes mellitus(T2D); Hypoxia; the mitochondrial melatonergic pathways; oxidative   phosphorylation (OXPHOS); adenosine triphosphate(ATP); insulin exocytosis; hyperglycemia; Pancreatic βcells; prolyl hydroxylase domain(PHD) proteins ; HIFs from 1995 till date in 2024.

We found a total of 250 articles ,out of which we selected 68 articles for this review.No meta-analysis was done. 

2. Stimulation of Hypoxia in pancreatic βcells by hyperglycemia 

In case of normoxic IR pancreatic βcells, glucose gets metabolized into pyruvate   through    glycolysis in addition to its further oxidation takes place for  generation of  adenosine triphosphate(ATP) through oxidative   phosphorylation (OXPHOS).An  escalation of ATP results in the  closing of ATP sensitive potassium  (KATP ) channels In pancreatic βcells resulting in membrane  depolarization, Calcium(Ca2+ ) influx as well as insulin  vesicle exocytosis[26]. Cellular   oxygen  quantities are  controlled  by the harmony amongst supply along with requirement of oxygen in addition to once hypoxia takes place oxygen utilization is greater than its supply . Acknowledged the considerable requirement of mitochondrial OXPHOS at the time of insulin liberation, βcells  utilize considerable oxygen  quantities . Actually  it has been revealed by  the group of Yamagata  et al.[  [6,7,27], along with others that pancreatic islets of Langerhans    as well as  βcells lines become  hypoxic [6,7],  with ease under escalated  glucose situation [6,7,27]. Such  studies have further illustrated that islets in animal models  of T2DM are hypoxic[28]. Thereby inadequate oxygen supply might further be implicated in βcells hypoxia in vivo.

The oxygen tension in   maximum mammalian cells is   varying amongst the  values of 20-65 mmHg(parallel to 3-9%O2) [29], as well as the  average tissue oxygen tension at the surface of the normal mouse islets varying amongst the  values  of44.7-45.7mmHg (parallel to 6.3-6.4%O2) [30]. Hypoxic reactions have been illustrated to take place in culture situations in vitro [31]. Continuous exposure of MIN6 βcells to 5%O2 tension result in cellular hypoxia with dysfunctional insulin liberation along with hampers βcells growth ; 3%O2 tension resulted in apoptosis with ease in addition to diminished  βcells numbers as well as working [32,33]. Thereby hypoxic stress represents the mechanistic   mode behind βcells failure in case of T2DM[32,34]., [32reviewed in ref 35].(Figure1)

3. Part of HIFs in Pancreatic βcells 

The sustenance of oxygen homeostasis  is significant  in reference to ATP generation in addition to energy  accessiblity in cells .Thereby all mammals possess the  capacity of sensing, reacting to as well as rectifyingy hypoxia .HIFs portray crucial members of the  basic-loop-helix PerArntSim  transcription factor family along with are comprised of oxygen sensitive HIF 1-α subunit in addition to  a HIF 1β/ aryl hydrocarbon receptor nuclear translocator (ARNT) subunit which gets constitutively  expressed  [31,36,].Three  kinds of HIFs are existent (HIF 1-α, HIF 2-α, in addition to HIF 3-α); nevertheless, maximum of the transcriptional reactions are apparently secondary to HIF 1-α, along with HIF 2-α[37].At the time of normoxic situations, HIF 1-α undergoes hydroxylation at the 2proline residues amongst the oxygen based breakdown  domain by the prolyl hydroxylase domain(PHD) proteins in the existence of oxygen,2 oxoglutarate as well as iron . Hydroxylated, HIF 1-α subunits get poly ubiquitinated by the vonHippel-Lindau protein in addition to are targeted for  proteasomal breakdown. Hydroxylation by the PHD proteins gets avoided along with  following breakdown in case of hypoxic situations . In view of  this  stabilized HIF 1-α undergoes dimerization with HIF 1β along with activation of a substantially greater quantities of target genes inclusive of those implicated in glycolysis ,erythropoiesis , in addition to angiogenesis by binding to the hypoxia response element in  their promoter areas.

Three kinds of PHD proteins(PHD1, PHD2 in addition to PHD 3)get  expressed in βcells[38], as well as HIF 1-α gets brokendown pacily in case of normal oxygen situations .Nevertheless, HIF 1-α is existent in normoxic  βcells[39]. Glucose  transporter 2  (GLUT2) portrays a lesser affinity glucose  transporter whose requirement is for sustenance of normal glucose stimulated insulin liberation in βcells[40]. Glucokinase,that is a rate  restricting glycolytic enzyme,  works in the form of a sensor for the physiological insulin liberation in βcells[41]. Intriguingly elimination of  Hif-α gene in βcells results in dysfunctional insulin liberation in addition to glucose intolerance in   mice having a diminished expression of soluble  carrier family  2 member 2 (Slc2a2)gene that encodes GLUT2 along with Gck  gene( that encoded glucokinase) [39]. Frequently HIF 1-α knockout (KO) diminished expression quantities of Slc2a2 in addition to  Gck are considerably  repressedin case of  insulin liberation in   MIN6 βcells at the time of  normoxic situations [39].  Thereby HIF 1 expression  at basal   quantities for  insulin liberation is necessary, despite mechanistic  modes behind this diminished  expression quantities of Slc2a2 in addition to GckbyHIF1-αinsufficiencyareuncharted(Figure2A,B).

Legend for Figure 2. 

Courtesy ref no-35-Roles of hypoxia-inducible factor (HIF)-1 in insulin secretion by β-cells. (A) Glucose is metabolized via the glycolytic pathway and mitochondrial oxidative phosphorylation, resulting in the generation of adenosine triphosphate (ATP), KATP channel closure, Ca2+ entry, and insulin exocytosis. Under normoxic conditions, HIF-1α is degraded by von Hippel–Lindau (VHL) proteins. (B) HIF-1α is degraded under normal oxygen conditions, but remains present in normoxic β-cells. HIF-1α deficiency causes impaired insulin secretion with a decreased expression of glucose transporter type 2 (GLUT2) and glucokinase (GCK). (C) HIF-1α overexpression switches glucose metabolism from mitochondrial oxidation to glycolysis, thereby leading to the attenuation of mitochondrial activity and impaired insulin secretion. (D) Treatment with the HIF-1α inhibitor PX-478 prevents the upregulation of HIF-1α targets (GLUT1, HK2, LDHA, and PDK1) and restores insulin secretion in metabolic workload. HK2, hexokinase 2; LDHA, lactate dehydrogenase A; MCT4, monocarboxylate transporter 4; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1.

Additionally,    HIF 1-α confers protection against βcells damage  in type 1 diabetes mellitus(the autoimmune kinds of diabetes) [42]. Furthermore HIF 1-α/ ARNT insufficiency further repressed insulin liberation in βcells[43]. Interestingly, declined HIF 1-α in addition to ARNT /HIF1β have been found in T2DM patients [39,43]. Moreover HIF 1-α signaling gets repressed in a complicated  manner by hyperglycemia via PHD) proteins based mechanistic modes[8,44].  Such findings robustly portray that HIF 1-α proteins possess a significant   part in sustenance of βcells working as well as the manner  dysfunctional HIF 1 signaling is  responsible for βcells impairment in type2 diabetics . 

Compared to that it have further been illustrated that HIF 1-α expression is escalated in the βcells   of various diabetic animals, inclusive of ob/ob   mice, mice which received high  fat diet(HFD), in addition to db/db mice [7,45]. Maintainance of HIF 1-α overexpression by the elimination of  Vhl gene(implicated in encoding   vonHippel-Lindau protein ) results  in dysfunctional insulin   liberation along with glucose intolerance in   mice[46], pointing that  the upregulation   of HIF 1-α is inimical for the working of βcells as well as aids in T2DM generation. HIF 1-α results  in the activation   of the transcription of the genes  encoding   GLUT 1, glycolytic enzymes(glucose-6- phosphatase  isomerase, and phosphoglycerate mutase)ii) pyruvate dehydrogenase kinase (PDK) iii) lactate dehydrogenase A(LDHA) in addition to iv) monocarboxylase transporter 1(MCT4) [47], PDK 1 is involved in the inactivation of the  enzyme pyruvate dehydrogenase which  is responsible for the transformation  of   pyruvate to acetylCoA for the mitochondrial tricarboxylic acid(TCA)/Krebs Cycle. LDHA prevents pyruvate from gaining entry in to TCA by   transforming pyruvate to lactate  in addition to MCT4 facilitates extrusion   of  lactate from cells. Sequentially, the major influence of HIF 1-α on glucose metabolism is switching energy metabolism from mitochondrial respiration to glycolysis. Nevertheless, mitochondrial oxidative metabolism possesses key  part in the regulation of insulin   liberation[48]. the main exposition for the inimical actions in reference to HIF 1-α on insulin   liberation is amelioration of mitochondrial actions(Figure2C). Interestingly,  therapy of  diabetic mice by utility of HIF 1 hampering agent PX-478 results  in improvement  of insulin  liberation along with glucose intolerance[45], indicating that hampering HIF 1-α might be  a plausible treatment for type2 diabetics(Figure2D). Overall such outcomes point that a harmonious in addition to sufficient quantities of HIF 1-α actions  is imperative for the normal insulin   liberation by pancreatic βcells. 

Compared to that  HIF 2-α a paralog(created by gene duplication) of HIF 1-α further undergoes dimerization with HIF 1β for the activation of target genes  in reaction  to hypoxia. Nevertheless, HIF 1-α as well as HIF 2-α possess unique Part in βcells .The manner described earlier, βcells particular Hif 1-α KO  mice  illustrate dysfunctional  insulin  liberation along with glucose intolerance[39] Compared to that HIF 2-α insufficiency in βcells does not lead to dysfunctional  insulin  liberation along with glucose intolerance in mice  getting normal chow diet[48]. A chronic escalation in mitochondrial metabolism   escalates electron flux in the electron transport chain(ETC) leading to escalated generation of reactive oxygen species(ROS) [49]. HIF 2-α possesses significant part in the controlling of the cellular redox status   by activation of the antioxidant gene expression Sod2 (encoding superoxide dismutase), as well as Cat(encoding catalase) in addition to confers protection against mitochondrial injury by ROS[50]. Frequently there is  reduced expression of the antioxidant genes  in the islets of βcells particular Hif 1-α KO mice along with such mice form dysfunctional  insulin liberation along with glucose intolerance on getting HFD[49]. Such outcomes point that HIF 2-α  is involved in preservation of βcells working  in situations of metabolic excess by stimulating  generation of antioxidant genes expression. 

4. Part of Transcriptional Suppressors in Hypoxic βcells 

Working of the HIFs   is basically in the form of activators of transcription ; nevertheless, suppression of transcription further takes place for hampering events which possess considerable energy requirement in case of hypoxic situations[51]. Actually, 5% of genes inclusive of certain genes implicated in insulin liberation  caused downregulation in hypoxic islets along with MIN6 βcells [32,33,52], pointing that genes suppression portrays one more adaptive reaction to hypoxia in βcells. Global  gene expression  evaluation displayed that basic- helix -loop-helix family  member E40 (BHLHE40) in addition to activating transcription factor 3(ATF3) represent hypoxia stimulated transcriptional suppressors in Hypoxic βcells (Figure3) [33].

Legend for Figure 3. 

Courtesy ref no-35-The transcriptional repressor basic helix-loop-helix family member E40 (BHLHE40) is highly induced in hypoxic β-cells. BHLHE40 inhibits insulin secretion by suppressing the expression of musculoaponeurotic fibrosarcoma oncogene family A (MAFA), a transcription factor that regulates insulin exocytosis, and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), which plays important roles in mitochondrial biogenesis and adenosine triphosphate (ATP) production.

BHLHE40(alias DEC1/SHARP2/STRA13) portrays  a member of basic- helix -loop-helix family  in addition to works by binding to DNA at the   Class EB motifs[53]. The  transcription factor musculoaponeurotic fibrosarcoma oncogene(MAFA) which possesses a key part  in glucose stimulated insulin liberation,by  controlling gene implicated in insulin exocytosis inclusive of Stxbp1( encoding MUNC 18-1) as well as  Stx1a ( encoding syntaxin A) [55]. Peroxisome Proliferator Activated Receptor γ Coactivator -1α(PGC-1α) whose encoding gets done by  Ppargc1α controls mitochondrial biogeneration as well as ATP generation[55]. Remarkable induction of the  transcriptional suppressor BHLHE40 expression in βcells by hypoxia along with   suppresses insulin liberation by suppressing  expression of Mafa in addition to Ppargc1α.. Persistently βcells particular Bhlhe40 insufficiency results  in improvement of insulin   liberation along with glucose intolerance in ob/ob mice. 

ATF3 further represses the expression of genes implicated in glucose metabolism inclusive of Ins1( encoding insulin1) Ins2( encoding insulin2) in addition to Irs2( encoding insulin Receptor  substrate-1(IRS-2)] [33,56]. Additionally, the hypoxia stimulated upregulation of the proinflammatory  II1b as well as proapoptotic  Noxa genes along with activation of caspase-3 get suppressed  by Atf3 insufficiency in MIN6 βcells [33,56,57].Such observations further point that the transcriptional suppressor ATF3 is implicated in hypoxia stimulated βcells impairment in addition to elimination.

5. Controlling of Various Stress Pathways in βcells by Hypoxia 

5’ adenosine mono phosphate (AMP)-activated protein kinase(AMPK) portrays an evolutionary preserved  serine /threonine kinase. Activation of AMPK takes place in reaction to energy stresses for instance hypoxia  by  sensing escalated quantities of AMP as well as/or adenosine  di phosphate: ATP ratio by hampering anabolic events which generate ATP[58]. Hepatocyte nuclear  factor 4 alpha (HNF-4α) represents a  transcription factor from the nuclear receptor super family   which possesses  significant key part in insulin liberation[59]. It was observed by  the group of  Yamagataet al.[60], that hypoxia stimulated AMPK activation diminished insulin liberation by diminishing the  stability of HNF-4α [60]. Thereby downregulation of HNF-4α by activation of AMPK might be responsible for the dysfunctional insulin liberation in  case of hypoxic  situations.

Dysfunctional protein homeostasis(alias  proteostasis) in the ER  results  in accrual of unfolded along with aberrantly  folded  protein alias ER stress, resulting in   activation of the ER unfolded   protein responses(UPRER) for the the   amelioration of proteostasic stress[61]. Hypoxia escalates βcells demise by hampering the expression of  adaptive UPRER genes inclusive of Hspa5( encoding heat shock protein family A member 5) Hsp90b1 (encoding heat shock protein90 beta  family member1)Fkbp11 ( encoding FKBP prolyl isomerase 11) in addition to spliced Xbp1(encoding X-box binding protein 1). Such hampering actions of  hypoxia  modulated by the activation of c-Jun-N-terminal kinase  (JNK) as well as DNA damage  inducible transcripts3 however are autonomous of HIF 1-α[62]. UPRER getting inactivated  might be the   cellular mechanistic  mode behind escalated   cell demise by hypoxic stress .

OS gets stimulated in tissue in case of escalated glucose situations. Noticeably, βcells possess considerable susceptibility  specifically  to ROS in view of their expression  of minimal quantities   of antioxidant   enzymes  inclusive of glutathione peroxidase(GPx), catalase(CAT) , as well as mitochondrial  manganese SOD along with ROS formed  in βcells decline insulin  genes expression reducing the expression in addition to /or DNA binding actions of pancreatic as well as  duodenal homeobox 1 (PDX1) transcription facto[63]. Interestingly, hypoxia further escalates ROS  generation at the mitochondrial ETC[64]. Such outcomes robustly point that hypoxia  stimulated ROS generation further  is implicated in βcell impairment .

From these findings documented above it is clear that hypoxia impacts a plethora of  events cascade of  at the time of glucose stimulated insulin liberation . Particularly hypoxia ameliorated insulin liberation by switching glucose metabolism from mitochondrial respiration to glycolysis via the activation of HIF 1. Hypoxia further hampered insulin liberation by repressing the expression of MAFA(exocytosis) as well as Peroxisome Proliferator Activated Receptor γCoactivator -1α(PGC-1α)via the activation of transcriptional suppressor BHLHE40 . Additionally, the hypoxia stimulated activation of AMPK resulted   in downregulation of the  expression of HNF-4α   resulting in aberrant insulin liberation. Moreover, hypoxia  stimulated ROS generation  hamper insulin gene expression  via the decontrolling of PDX1(seeFigure4) .

Legend for Figure 4

Courtesy ref no-35-Roles of hypoxia in insulin secretion. Hypoxia affects multiple steps during the processes of glucose-stimulated insulin secretion, including dysregulation of transcription factors (e.g., MAFA, PDX1, and HNF4α), attenuation of mitochondrial activities, activation of AMPK, and inhibition of exocytosis 

6.Conclusions

Diabetes implicates a clinical scenario where pancreatic βcells are engulfed in a vicious cycle which leads to a dysfunctional insulin reaction to glucose generated hyperglycemia that  sees to it that βcells lose their efficacy in reference to insulin liberation that leads to a improvement   of hyperglycemia that  causes a minimum of  part restoration of βcell working [3]. Hypoxia  guarantees proneness of  βcells to impairment along with failure in addition to hampering of HIF 1-α actions as well as repression  of BHLHE40 leads to  improvement of insulin liberation along with hyperglycemia in case of animal models of diabetes, pointing that hypoxia might work in the  form of an innovative therapeutic target for type2diabetes in addition to improvement   of hypoxia might work  as advantageous  for the propagation of  βcells impairment in T2D.  Nevertheless, hypoxia further stimulates ATF3 expression, activation of AMPK inactivation of UPRER  along with ROS generation (seeFigure5) .

Legend for Figure 5. 

Courtesy ref no-35-Roles of hypoxia in β-cell function and number. Hypoxia causes impaired insulin secretion through the induction of hypoxia-inducible factor 1 (HIF-1) and basic helix-loop-helix family member E40 (BHLHE40). Hypoxia also suppresses insulin secretion through the activation of adenosine monophosphate-activated protein kinase (AMPK) and the induction of reactive oxygen species (ROS), whereas, it promotes β-cell death via the induction of activating transcription factor 3 (ATF3) and the inhibition of the endoplasmic reticulum unfolded protein response (UPRER).

Moreover, HIF 1-α basically guides the  reaction to acute hypoxia as well as its expression gets diminished at the time of continuous hypoxia[65]. Thereby the robustness along with time period   of  hypoxia may result  in activation of  adaptive reaction in βcells in a differential manner. Further  work  would yield greater insight in the germane aiding of influence of  every adaptive pathway in the event of manner  βcell hypoxia would be  essential for buttressing our understanding regarding pathophysiological mechanistic  modes of T2 diabetes mellitus . Greater work would aid  in   provision of influence regarding innovative information in    reference to influence of  hypoxic stress over βcells impairment in addition to the efficacy  of βcells hypoxia in the  form of   antidiabetic therapeutic  target. 

Moreover the impairment of β cells possess the  capacity of generating via different mechanistic  modes, inclusive of OS/ER or hypoxic stress, in addition to through inducing cytokines; such events result  in apoptosis, unregulated autophagy as well as and do not proliferate. Transdifferentiation amongst β cells along with α cells takes place in some pathological situations, in addition to and upcoming  corroboration pointing that the β-cell dedifferentiation or transdifferentiation might be responsible for the diminished β-cell mass found in patients with robust T2DM. FOXO1,portrays  a crucial transcription factor in insulin signalling(rev in detail by us in ref 20and23,63],. Liang et el. [66],further documented HIF 1-α/ FOXO1axis regulated autophagy conferred  protection  for βcell survival in case of  hypoxia in human  islet by utility of CoCl2 escalating β-cell apoptosis as well as choloroquine aggravated autophagy hampering in case of FOXO1KO accelerated apoptosis   with immunofluorescent staining  reported that significant reduction  in LC3 in addition to  p62/SQSTMW expression quantities which  were negatively  associated with glycated haemoglobin A1c (HbA1c ) inpatients with robust  T2DM. Thereby HIF 1-α/ FOXO1   axis controlled autophagy which is  of  advantage  for βcells survival under hypoxia in human  islets. Furthermore,emerging reports  have displayed advantage  of restoration of autophagy  in pancreatic βcells  as a therapeutic target for type2Diabetes as   displayed by  Zhao etal. [67], as well as we had  detailed autophagy comprehensively previously [68]. Thereby targeting hypoxia as well as autophagy might be the  next line of treatment for preventing robust T2DM   the way illustrated in figure 6  by different plant extracts and tradional Chinese medicines[rev in det inref no67]  . 

Legend for Figure 6

Courtesy ref no-67-Role of autophagy in pancreatic islet β cells in the diabetic state. Yellow rectangle: Traditional Chinese compounds; Blue rectangle: Chemical drugs; Pink rectangle: Monomers from Chinese Herbal; Gray rectangle: Experimental Chemicals. →: activate: ⟞: inhibit.