Metabolite profiling and biochemical investigation of the antidiabetic potential of Loranthus pulverulentus Wall n-butanol fraction in diabetic animal models.

ETHNOPHARMACOLOGICAL RELEVANCE: Globally, 537 million individuals are estimated to have diabetes. The traditional use of herbs for ameliorating diabetes symptoms is a common practice in Pakistan and use of Loranthus pulverulentus Wall (L. pulverulentus) by local people in Azad Jammu and Kashmir has been reported. AIM OF THE STUDY: In the present study, the antidiabetic potential of standardized n-butanol fraction of leaves of L. pulverulentus Wall, which is a parasite of Dalbergia sisso Roxb was assessed in both alloxan (ALX) and streptozotocin (STZ) diabetic animal models. MATERIALS AND METHODS: Chemical characterization of BF was performed using HPLC, GCMS and UHPLC-MS. The effect of the fraction (250 mg/kg) on insulin, plasma free fatty acids, L-lactate, pyruvate, MDA, HbA1c and glycogen levels in ALX and STZ animal models was determined. Liver and renal profiles were analyzed in the STZ model. Toxicological studies were performed by hemolytic, Ames mutagenicity, DNA protection, and thrombolytic assays. Histopathological analysis of the pancreas, liver, and kidney was performed. RESULTS: BF demonstrated highly significant (p < 0.001) antidiabetic potential in both diabetic models. BF significantly (p < 0.05) improved OGTT results in alloxanized diabetic mice and blocked the absorption of glucose from the gut. A significant (p < 0.001) increase in insulin levels and glycogen content in liver tissue and a decrease in plasma FFA, MDA, HbA1c, L-lactate, and pyruvate levels in STZ-diabetic mice were recorded. GC-MS and chromatographic analysis showed the presence of catechin, eugenol, longifolene, caryophyllene, Ar-tumerone and Geranyl-alpha-terpinene. Various metabolites with antidiabetic potential, including 4-hydroxycinnamyl alcohol 4-D-glucoside, zingerone glucoside, trans-trismethoxy resveratrol-d4, epigallocatechin 3-O-cinnamate, and ß-glucogallin, were identified using UHPLC-MS. Animals treated with BF showed marked improvements in cellular structures of the pancreas, liver and kidneys. This fraction is non-mutagenic and protects the DNA. CONCLUSION: The experimental fraction contained potential antidiabetic bioactive compounds responsible for alleviating diabetes-associated biochemical dysregulation. The fraction increased insulin levels and enhanced glycogen storage in muscles and the liver. It blocked glucose absorption from the intestine and substantially decreased HbA1c, lactate, pyruvate, free fatty acids, lipid, liver and kidney damage. Therefore, the use of BF for the treatment of type-2 diabetes may be beneficial.

Antidiabetic effect of Ardisia elliptica extract and its mechanisms of action in STZ-NA-induced diabetic rat model via 1H-NMR-based metabolomics.

ETHNOPHARMACOLOGICAL RELEVANCE: Ardisia elliptica Thunb. (AE) (Primulaceae) is a medicinal plant found in the Malay Peninsula and has been traditionally used to treat diabetes. However, limited studies to date in providing scientific evidence to support the antidiabetic efficacy of this plant by in-vitro and in-vivo models. AIM OF THE STUDY: To investigate the anti-hyperglycemic potential of AE through in-vitro enzymatic activities and streptozotocin-nicotinamide (STZ-NA) induced diabetic rat models using proton-nuclear magnetic resonance (1H-NMR)-based metabolomics approach. MATERIALS AND METHODS: Anti-α-amylase and anti-α-glucosidase activities of the hydroethanolic extracts of AE were evaluated. The absolute quantification of bioactive constituents, using ultra-high performance liquid chromatography (UHPLC) was performed for the most active extract. Three different dosage levels of the AE extract were orally administered for 4 weeks consecutively in STZ-NA induced diabetic rats. Physical assessments, biochemical analysis, and an untargeted 1H-NMR-based metabolomics analysis of the urine and serum were carried out on the animal model. RESULTS: Type 2 diabetes mellitus (T2DM) rat model was successfully developed based on the clear separation observed between the STZ-NA induced diabetic and normal non-diabetic groups. Discriminating biomarkers included glucose, citrate, succinate, allantoin, hippurate, 2-oxoglutarate, and 3-hydroxybutyrate, as determined through an orthogonal partial least squares-discriminant analysis (OPLS-DA) model. A treatment dosage of 250 mg/kg body weight (BW) of standardized 70% ethanolic AE extract mitigated increase in serum glucose, creatinine, and urea levels, providing treatment levels comparable to that obtained using metformin, with flavonoids primarily contribute to the anti-hyperglycemic activities. Urinary metabolomics disclosed that the following disturbed metabolism pathways: the citrate cycle (TCA cycle), butanoate metabolism, glycolysis and gluconeogenesis, pyruvate metabolism, and synthesis and degradation of ketone bodies, were ameliorated after treatment with the standardized AE extract. CONCLUSIONS: This study demonstrated the first attempt at revealing the therapeutic effect of oral treatment with 250 mg/kg BW of standardized AE extract on chemically induced T2DM rats. The present study provides scientific evidence supporting the ethnomedicinal use of Ardisia elliptica and further advances the understanding of the fundamental molecular mechanisms affected by this herbal antidote.

Association of vitamin D status with redox balance and insulin resistance and its predicting ability for subclinical pregnancy toxemia in pregnant sheep.

The study aimed to evaluate the role of vitamin D on redox balance, insulin resistance and its predicting value for subclinical pregnancy toxemia (SPT) in pregnant ewes. At four weeks pre-lambing, fifteen healthy pregnant ewes were divided into two groups, ewes with sufficient vitamin D (25-hydroxy-vitamin D (25VitD) (SVD, n = 9) and ewes with insufficient 25VitD (ISVD, n = 6). Blood samples were collected at 4 weeks pre-lambing using modified frequently sampled intravenous glucose tolerance test for the estimation of various metabolites. The baseline glucose, insulin, non-esterified fatty acid (NEFA), fructosamine, beta-hydroxy butyric acid (ß-BHA), calcium, phosphorus concentration and total oxidant status (TOS) did not differ significantly between the two groups, however, total antioxidant capacity (TAC) was significantly (p = 0.031) low in ISVD ewes. Area under the curve for glucose, insulin, elimination rate of glucose and peak insulin also did not differ significantly between the two groups. Correlation analysis revealed, positive association of 25VitD with fructosamine, calcium and TAC, and negative correlation with NEFA and TOS. Subsequent blood sampling at 2 weeks pre-lambing and at lambing showed significant difference in NEFA (p = 0.001), ß-HBA (p = 0.001), and fructosamine(p = 0.012) between the two groups. A significant time x group interaction was observed in NEFA (p = 0.019), ß-HBA (p = 0.031), and fructosamine (p = 0.026) concentration. The NEFA concentrations were increased and fructosamine decreased at 2 weeks pre-lambing and at lambing along with significantly increased ß-HBA at 2 weeks pre-lambing in ISVD compared to SVD. Taking 0.8 mmol/L ß-HBA as the cut off limit for SPT, ISVD ewes had higher odds of developing SPT two weeks prior to lambing (OD 16.00; p = 0.042) and at lambing (OD 10; p = 0.077). This study concludes that 25VitD significantly influence redox balance and energy profile and serves as a valuable predictor for SPT in pregnant sheep.

Discovery of triazole tethered thymol/carvacrol-coumarin hybrids as new class of α-glucosidase inhibitors with potent in vivo antihyperglycemic activities.

Keeping in view the inhibitory potential of monoterpenes thymol and carvacrol as well as coumarin nucleus against α-glucosidase, novel series of thymol/carvacrol-coumarin hybrids was designed, synthesized and evaluated for α-glucosidase inhibitory potential. Among the series of hybrid molecules, AS14 with IC50 value of 4.32 ± 0.11 µM was selective α-glucosidase inhibitor over α-amylase (IC50 = 37.36 ± 0.84 µM). AS14 was non-toxic toward mouse normal fibroblast cells (L929: IC50 > 100 µM). Molecular docking and dynamic simulation studies confirmed desired interactions of AS14 with α-glucosidase responsible for the inhibition of its catalysis capabilities. Acute oral toxicity study confirmed AS14 as safer molecule for in vivo pharmacological investigations with LD50 value of 300 mg/kg. AS14 also showed acute hypoglycaemic effects [reduction in blood glucose levels at 1 h of administration in maltose loading test (at 10 and 20 mg/kg by 62.65 % and 70.12 %) and sucrose loading test (at 10 and 20 mg/kg by 59.65 % and 60.23 %), respectively] as well as long term (28 days) fasting blood glucose reduction (At day 28: 10 mg/kg = 54.69 % and 20 mg/kg = 62.23 % reduction in fasting blood glucose levels) capabilities in streptozotocin induced diabetic rats. Overall study represents, AS14 as potential α-glucosidase inhibitor with adequate efficacy and safety profile and act as an effective hit lead for the further development of potent and safer α-glucosidase inhibitors for the management of postprandial hyperglycemia in diabetic patients.

Acetobacter and lactobacillus alleviate the symptom of insulin resistance by blocking the JNK-JAK/STAT pathway in Drosophila melanogaster.

The dysregulation of intestinal microbiota is well-known to be one of the main causes of insulin resistance in both vertebrates and invertebrates. Specially, the acetobacter and lactobacillus have been identified as potentially capable of alleviating insulin resistance. However, the molecular mechanism underlying this effect requires further elucidation. In this study, we employed Drosophila melanogaster (fruit fly) as a model organism to delineate how intestinal microbiota disrupts the host intestinal signaling pathway, contributing to insulin resistance. Our findings demonstrate that a long-term high-sugar diet lead to a reduction in the general diversity of intestinal microbiota in flies, as well as a marked decrease in the abundances of acetobacter and lactobacillus. Furthermore, we observed that symptoms of insulin resistance were alleviated by feeding flies with acetobacter or lactobacillus, indicating that these microorganisms play an essential role in maintaining blood sugar homeostasis in flies. Conversely, when all intestinal microbiota was removed, flies show severe symptoms of insulin resistance, confirming that the critical role of intestinal microbiota in maintaining host blood sugar homeostasis. Our studies suggested that the intestinal but not fat body JNK pathway mediates the communication of intestinal microbiota and host insulin pathway. In flies, downregulation of JNK activity alleviates symptoms of insulin resistance by decreasing the activity of the JAK/STAT pathway. However, this offsets the therapeutic effects of supplying flies with acetobacter or lactobacillus, suggesting that the therapeutic function of these microorganisms is based on their interaction with JNK-JAK/STAT axis. Taken together, our study reveals that acetobacter and lactobacillus alleviate insulin resistance symptoms in a JNK-JAK/STAT pathway-dependent manner, indicating the therapeutic potential of probiotic supplementation and regulation of the activities of JNK-JAK/STAT pathway for diabetes control.

Black mulberry extract inhibits hepatic adipogenesis through AMPK/mTOR signaling pathway in T2DM mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Black mulberry (Morus nigra L.) is an ancient dual-use plant resource for medicine and food. It is widely used in Uyghur folklore for hypoglycemic treatment and is a folkloric plant medicine with regional characteristics. However, the mechanism of Morus nigra L. treatment in diabetes mellitus has not been fully understood, especially from the perspective of hepatic lipid accumulation is less reported. OBJECTIVE OF THIS STUDY: This study was to explore the potential of Morus nigra L. fruit ethyl acetate extract (MNF-EA) to reduce blood sugar levels by preventing the production of hepatic lipogenesis and to provide more evidence for the use of MNF-EA as an adjuvant therapy for type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: In this study, the chemical composition of MNF-EA was first analyzed and characterized using UPLC-Q-TOF-MS technique. A series of in vitro studies were performed with HepG2-IR cells and oleic acid (OA)-induced HepG2 cells, including MTT assay, glucose uptake assay, oil red O staining and Western blot analysis. The STZ-HFD co-induced T2DM mice were employed for in vivo research, including physical indices, biochemical analysis, histopathological examination, and Western blot analysis. RESULTS: The 19 compounds in MNF-EA were identified by UPLC-Q-TOF-MS technique. Insulin resistance (IR) and lipid droplet accumulation in HepG2 cells were greatly improved by MNF-EA treatment, which had no appreciable side effects at the dosage used. In T2DM mice, MNF-EA decreased fasting blood glucose (FBG), saved body weight, and significantly improved oral glucose tolerance (OGTT) and IR status. In addition, MNF-EA treatment also improved lipid metabolism disorders and liver function in T2DM mice. Histopathological sections showed that MNF-EA treatment reduced hepatic steatosis. Mechanistic studies suggest that MNF-EA acted through the AMPK/mTOR pathway. CONCLUSIONS: These results suggest that MNF-EA has great potential to reverse the metabolic abnormalities associated with T2DM by regulating the AMPK/mTOR signaling pathway. Therefore, we believe that MNF is a promising medicinal and food-homologous agent to improve T2DM.

Biohybrid tongue based on hypothalamic neuronal network-on-a-chip for real-time blood glucose sensing and assessment.

The expression of sweet receptors in the hypothalamus has been implicated in energy homeostasis control and the pathogenesis of obesity and diabetes. However, the exact mechanism by which hypothalamic glucose-sensing neurons function remains unclear. Conventional detection methods, such as fiber photometry, optogenetics, brain-machine interfaces, patch clamp and calcium imaging, pose limitations for real-time glucose perception due to their complexity, cytotoxicity and so on. Therefore, this study proposes a biohybrid tongue based on hypothalamic neuronal network (HNN)-on-a-chip coupling with microelectrode array (MEA) for real-time glucose perception. Hypothalamic neuronal cultures were cultivated on a two-dimensional "brain-on-chip" device, enabling the formation of neuronal networks and electrophysiological signal detection. Additionally, we investigated the endogenous expression of sweet taste receptors (T1R2/T1R3) in hypothalamic neuronal cells, providing the basis for the biohybrid tongue based on HNN-on-a-chip's sweetness detection capabilities. The spike signal response to sucrose and glucose stimulation was detected, and concentration-dependent responses were explored with glucose concentrations ranging from 0.01 mM to 8 mM. MEAs allow for real-time recordings, enabling the observation of dynamic changes in neuronal responses to glucose fluctuations over time. The biohybrid tongue based on HNN-on-a-chip can measure various parameters, including spike frequency and amplitude, providing insights into neuronal firing patterns and excitability. Moreover, hypothalamic glucoregulatory neurons that sense and respond to changes in blood glucose was identified, including glucose-excited neurons (GE-Neurons) and glucose-inhibited neurons (GI-Neurons). The detection range for GE-Neurons spans from 0.4 to 6 mM, while GI-Neurons demonstrate sensitivity within the range of 1-8 mM. And the glucose detection limit was firmly established at 0.01 mM. Through non-linear regression analysis, the IC50 for GI-Neurons' spike firing was determined to be 4.18 mM. In conclusion, the biohybrid tongue based on HNN-on-a-chip offers a valuable in vitro tool for studying hypothalamic neurons, elucidating glucose sensing mechanisms, and understanding hypothalamic neuronal function.

SiJunZi decoction ameliorates bone quality and redox homeostasis and regulates advanced glycation end products/receptor for advanced glycation end products and WNT/ß-catenin signaling pathways in diabetic mice.

ETHNOPHARMACOLOGICAL RELEVANCE: SiJunZi decoction (SJZD), one of the traditional Chinese medicine formulas, has been clinically and traditionally used to improve glucose and lipid metabolism and promote bone remodeling. AIM OF THE STUDY: To study the actions and mechanisms of SJZD on bone remodeling in a type 2 diabetes mouse model. MATERIALS AND METHODS: Diabetic mice generated with a high-fat diet (HFD) and streptozotocin (STZ) were subjected to SJZD treatment for 8 weeks. Blood glucose and lipid profile, redox status and bone metabolism were determined by ELISA or biochemical assays. Bone quality was evaluated by micro-CT, three-point bending assay and Fourier transform infrared spectrum (FTIR). Bone histomorphometry alterations were evaluated by Hematoxylin-Eosin (H&E), tartrate resistant acid phosphatase (TRAP) staining and Safranin O-fast green staining. The expressions of superoxide dismutase 1 (SOD1), advanced glycation end products (AGEs), receptor for advanced glycosylation end products (RAGE), phosphorylated nuclear factor kappa-B (p-NF-κB), NF-κB, cathepsin K, semaphorin 3A (Sema3A), insulin-like growth factor 1 (IGF1), p-GSK-3ß, (p)-ß-catenin, Runt-related transcription factor 2 (Runx2) and Cyclin D1 in the femurs and/or tibias were examined by Western blot or immunohistochemical staining. The main constituents in the SJZD aqueous extract were characterized by a HPLC/MS. RESULTS: SJZD intervention improved glucose and lipid metabolism and preserved bone quality in the diabetic mice, in particular glucose tolerance, lipid profile, bone microarchitecture, strength and material composition. SJZD administration to diabetic mice preserved redox homeostasis in serum and bone marrow, and prevented an increase in AGEs, RAGE, p-NF-κB/NF-κB, cathepsin K, p-GSK-3ß, p-ß-catenin expressions and a decrease in Sema3A, IGF1, ß-catenin, Runx2 and Cyclin D1 expressions in tibias and/or femurs. Thirteen compounds were identified in SJZD aqueous extract, including astilbin, liquiritin apioside, ononin, ginsenoside Re, Rg1, Rb1, Rb2, Ro, Rb3, Rd, notoginsenoside R2, glycyrrhizic acid, and licoricesaponin B2. CONCLUSIONS: SJZD ameliorates bone quality in diabetic mice possibly via maintaining redox homeostasis. The mechanism governing these alterations are possibly related to effects on the AGEs/RAGE and Wnt/ß-catenin signaling pathways. SJZD may offer a novel source of drug candidates for the prevention and treatment of type 2 diabetes and osteoporosis.

A long lifetime and highly sensitive wearable microneedle sensor for the continuous real-time monitoring of glucose in interstitial fluid.

The short lifetime and low sensitivity of the current glucose electrochemical sensors are two major issues for implementing continuous real-time monitoring of glucose in vivo. Here we show that a unique microneedle-based glucose monitoring skin patch (termed here MGMSP) can continuously measure glucose in real time in live animals with micromolar sensitivity and over 14 days of service life. This MGMSP employs a glucose oxidase (GOD) and carbon nanotube (CNT) modified hollow syringe as electrochemical sensor for glucose monitoring, an integrated circuit for signal processing and transmission, and the real-time glucose levels are displayed on smartphone via Bluetooth. The designed microneedle device protects the stability of the sensing molecules immobilized within the inner surface of hollow syringe and simultaneously the interior space of hollow syringe substantially increases the amount of immobilized sensing molecules. This microneedle design thus extends the lifetime as well as improves the detection sensitivity. The final MGMSP enables the continuous real-time monitoring of glucose in the interstitial fluid of live rats. This innovative microneedle-based MGMSP could potentially provide the public with high-accuracy continual glucose monitoring.

Efficacy and safety of isotonic versus hypotonic intravenous maintenance fluids in hospitalized children: an updated systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Iatrogenic hyponatremia is a common complication following intravenous maintenance fluid therapy (IV-MFT) in hospitalized children. Despite the American Academy of Pediatrics' 2018 recommendations, IV-MFT prescribing practices still vary considerably. OBJECTIVES: This meta-analysis aimed to compare the safety and efficacy of isotonic versus hypotonic IV-MFT in hospitalized children. DATA SOURCES: We searched PubMed, Scopus, Web of Science, and Cochrane Central from inception to October 1, 2022. STUDY ELIGIBILITY CRITERIA: We included randomized controlled trials (RCTs) comparing isotonic versus hypotonic IV-MFT in hospitalized children, either with medical or surgical conditions. Our primary outcome was hyponatremia following IV-MFT. Secondary outcomes included hypernatremia, serum sodium, serum potassium, serum osmolarity, blood pH, blood sugar, serum creatinine, serum chloride, urinary sodium, length of hospital stay, and adverse outcomes. STUDY APPRAISAL AND SYNTHESIS METHODS: Random-effects models were used to pool the extracted data. We performed our analysis based on the duration of fluid administration (i.e., ≤ 24 and > 24 h). The Grades of Recommendations Assessment Development and Evaluation (GRADE) scale was used to evaluate the strength and level of evidence for recommendations. RESULTS: A total of 33 RCTs, comprising 5049 patients were included. Isotonic IV-MFT significantly reduced the risk of mild hyponatremia at both ≤ 24 h (RR = 0.38, 95% CI [0.30, 0.48], P < 0.00001; high quality of evidence) and > 24 h (RR = 0.47, 95% CI [0.37, 0.62], P < 0.00001; high quality of evidence). This protective effect of isotonic fluid was maintained in most examined subgroups. Isotonic IV-MFT significantly increased the risk of hypernatremia in neonates (RR = 3.74, 95% CI [1.42, 9.85], P = 0.008). In addition, it significantly increased serum creatinine at ≤ 24 h (MD = 0.89, 95% CI [0.84, 0.94], P < 0.00001) and decreased blood pH (MD = -0.05, 95% CI [-0.08 to -0.02], P = 0.0006). Mean serum sodium, serum osmolarity, and serum chloride were lower in the hypotonic group at ≤ 24 h. The two fluids were comparable in terms of serum potassium, length of hospital stay, blood sugar, and the risk of adverse outcomes. LIMITATIONS: The main limitation of our study was the heterogeneity of the included studies. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Isotonic IV-MFT was superior to the hypotonic one in reducing the risk of iatrogenic hyponatremia in hospitalized children. However, it increases the risk of hypernatremia in neonates and may lead to renal dysfunction. Given that the risk of hypernatremia is not important even in the neonates, we propose to use balanced isotonic IV-MFT in hospitalized children as it is better tolerated by the kidneys than 0.9% saline. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42022372359. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information.

Continuous glucose monitoring has an increasing role in pre-symptomatic type 1 diabetes: advantages, limitations, and comparisons with laboratory-based testing.

Type 1 diabetes (T1D) is well-recognised as a continuum heralded by the development of islet autoantibodies, progression to islet autoimmunity causing beta cell destruction, culminating in insulin deficiency and clinical disease. Abnormalities of glucose homeostasis are known to exist well before the onset of typical symptoms. Laboratory-based tests such as the oral glucose tolerance test (OGTT) and glycated haemoglobin (HbA1c) have been used to stage T1D and assess the risk of progression to clinical T1D. Continuous glucose monitoring (CGM) can detect early glycaemic abnormalities and can therefore be used to monitor for metabolic deterioration in pre-symptomatic, islet autoantibody positive, at-risk individuals. Early identification of these children can not only reduce the risk of presentation with diabetic ketoacidosis (DKA), but also determine eligibility for prevention trials, which aim to prevent or delay progression to clinical T1D. Here, we describe the current state with regard to the use of the OGTT, HbA1c, fructosamine and glycated albumin in pre-symptomatic T1D. Using illustrative cases, we present our clinical experience with the use of CGM, and advocate for an increased role of this diabetes technology, for monitoring metabolic deterioration and disease progression in children with pre-symptomatic T1D.

Engineering superstable islets-laden chitosan microgels with carboxymethyl cellulose coating for long-term blood glucose regulation in vivo.

Islet transplantation to restore endogenous insulin secretion is a promising therapy for type 1 diabetes in clinic. However, host immune rejection seriously limits the survival of transplanted islets. Despite of the various encapsulation strategies and materials developed so far to provide immune isolation for transplanted islets, long-term blood glucose regulation is still difficult due to the inherent defects of the encapsulation materials. Herein, a novel islet-encapsulation composite material with low immunogenicity, good biocompatibility and excellent stability is reported. Specifically, chitosan (CS) microgels (diameter: ∼302 µm) are prepared via Michael addition reaction between maleimide grafted chitosan (CS-Mal) and thiol grafted chitosan (CS-NAC) in droplet-based microfluidic device, and then zwitterionic surface layer is constructed on CS microgel surface by covalent binding between maleimide groups on CS and thiol groups on thiol modified carboxymethyl cellulose (CMC-SH). The as-formed carboxymethyl cellulose coated chitosan (CS@CMC) microgels show not only long-term stability in vivo owing to the non-biodegradability of CMC, but also fantastic anti-adsorption and antifibrosis because of the stable zwitterionic surface layer. As a result, islets encapsulated in the CS@CMC microgels exhibit high viability and good insulin secretion function in vivo, and long-term blood glucose regulation is achieved for 180 days in diabetic mice post-transplantation.

Association between insulin resistance and serum insulin-like growth factor 1 levels in patients with non-remitting major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is linked to an increased risk of diabetes; however, the underlying pathomechanism remains unknown. Although insulin-like growth factor 1 (IGF-1) is involved in the pathogenesis of both insulin resistance (IR) and MDD, no studies have investigated the relationship between IGF-1 and IR in patients with MDD. METHODS: We recruited 120 patients with MDD (84 non-remitting patients and 36 remitting patients) and 99 control participants. Blood samples were collected after overnight fasting to investigate associations between serum and clinical factors, such as serum IGF-1 levels and homeostasis model assessment-insulin resistance (HOMA-IR). RESULTS: Serum IGF-1 levels were higher in patients with non-remitting MDD than in control participants and patients with remitting MDD (P = 0.001 and P = 0.007, respectively). There were no significant differences in HOMA-IR between the three groups. HOMA-IR was positively correlated with serum IGF-1 levels in patients with non-remitting MDD (R = 0.355; P= 0.001) but not in control participants or patients with remitting MDD. A stepwise multiple regression analysis with various clinical factors revealed a positive association of serum IGF-1 levels and body mass index with HOMA-IR in patients with non-remitting MDD. LIMITATIONS: This is a cross-sectional study and therefore we cannot draw firm conclusions about causal associations. CONCLUSIONS: Serum IGF-1 levels may play a role in IR in patients with MDD who fail to achieve remission. Further studies, including longitudinal studies, are needed to determine the relationship between high serum IGF-1 levels and subsequent IR and diabetes risk.

Huayuwendan decoction ameliorates inflammation via IL-17/NF-κB signaling pathway in diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Huayuwendan decoction (HYWD) is a broad used traditional Chinese medicine and therapeutic effects against type 2 diabetes mellitus (T2DM). The mechanism of HYWD on the treatment of T2DM is still unclear. AIM OF THE STUDY: For this reason, this study was performed to uncover the effects and mechanism of action of HYWD on T2DM. MATERIALS AND METHODS: Male Wistar rats were chosen to set up the T2DM model. This study was randomly divided into six groups: CON (control), MOD (model), HYWDL (Huayuwendan decoction Low Dose), HYWDM (Huayuwendan decoction Middle Dose), HYWDH (Huayuwendan decoction High Dose), and MET (Metformin). Body weight gains were estimated. Using H&E staining, pathological alterations was explored. The serums of fasting plasma glucose (FPG), 2-h postprandial plasma glucose (2 h PG) were detected by Roche blood glucose meter. LDL-C and HDL-C were analyzed by automatic biochemical analyzer. Network pharmacology analyzed the active ingredients, drug targets, and key pathways of HYWD in T2DM treatment. The islet function and inflammation related factors were determined by ELISA. NF-κB signaling pathway or IL-17 signaling pathway related proteins were analyzed by Western blotting. IL-17RA were determined by immunohistochemistry analyze. RESULTS: HYWD inhibited weight gain in T2DM rats. Histopathological results showed that HYWD inhibits liver injury. HYWD suppressed LDL-C and enhanced HDL-C in serum of T2DM rats. HYWD reduce FPG and 2 h PG, inhibit Fins, GSP and IRI, but enhance IAI in serum of T2DM rats. In addition, the network pharmacology results identified 292 chemical compounds in HYWD. 279 candidate targets were recognized, including IL-17A, IL-1ß, NFкB, stats, mmp3, and cxcl2. The pathways revealed that the possible target of HYWD related with the regulation of IL-17 signaling pathway and NF-κB pathway. Then in vivo study, HYWD reduced the levels of IL-6, TNF-α, IL-17 and IL-1ß in serum and inhibit the protein expression involved in IL-17/NF-κB signaling pathway. CONCLUSIONS: The study demonstrates that HYWD may improve T2DM by repressing with the IL-17/NF-κB signaling pathway, which offer encouraging support for using alternative medicine of type 2 diabetes mellitus.

Hyperglycemia effect of Pinctada martensii hydrolysate in diabetic db/db mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Pinctada martensii (Dunker) and other marine shellfish flesh have been traditionally used in China as folk remedies regulate blood sugar. AIM OF THE STUDY: To investigate the main active constituents and the pharmacological mechanism of Pinctada martensii flesh enzymatic hydrolysate (PMH) against T2DM. MATERIALS AND METHODS: The hypoglycemic activity of enzymolysis peptides from Pinctada martensii was evaluated by using db/db mice, through the influence of glycemic index, blood lipid and key protein expression of PI3K-Akt pathway. In addition, label-free quantitative proteomics was used to screen the key proteins for Pinctada martensii hydrolysate (PMH) to improve T2DM, and Western blot and qRT-PCR were used to verify the expression difference of differential proteins at protein and mRNA levels between different groups. RESULTS: PMH were prepared and characterized. In vivo investigations revealed that the PMH could regulate blood glucose and improve glucose tolerance and insulin tolerance, reduced serum total cholesterol, triglyceride, low-density lipoprotein cholesterol levels and increase high-density lipoprotein cholesterol levels in db/db mice. Western blot results showed that PMH could up-regulate IRS-1, P-PI3K/PI3K and P-Akt/Akt levels in db/db mice. Label-free quantitative proteomic approach was used to analyze the proteome in db/db mouse liver, 231 proteins were reversed significantly (p < 0.05), and these proteins were involved in oxidative phosphorylation, glycolysis/gluconeogenesis and other pathways. Further screened 15 proteins with FC > 1.2 could be enriched in the retinol metabolic pathway, and the proteins in this pathway were also verified. CONCLUSIONS: PMH has hypoglycemic effect and can be used as a potential natural T2DM intervener. The hypoglycemic activity of PMH is related to its regulation of the PI3K/AKT pathway. The PI3K/AKT pathway and the retinol pathway are considered as another potential pathway for PMH to exert hypoglycemic effects.

Safety and antidiabetic activity of Lagenaria siceraria (Molina) Standl. juice in streptozotocin -induced diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes and its complications have overwhelmed India's healthcare system. Current therapies are expensive and have adverse side effects, thus dietary changes and alternative treatments are needed. Lagenaria siceraria (Molina) Standl. Juice is used mainly for its nutritional and medicinal values, however toxicity of the juice and antidiabetic effects have been poorly characterized. AIM OF THE STUDY: To investigate the toxicity, anti-diabetic and anti-inflammatory efficacy of Lagenaria siceraria (Molina) Standl. (LS) juice. MATERIALS AND METHODS: In vitro antidiabetic (α-glucosidase, α-amylase and DPP-4 inhibitory) activities were screened using standard procedures. The glucose uptake test was carried out by using L6 rat skeletal muscle cell line. In vivo sub-acute toxicity of LS juice was assessed on Wistar rats. Wistar rats were induced with diabetes by a single intraperitoneal (I.P) injection of freshly prepared streptozotocin (55 mg/kg body weight). The animals were randomly divided into 6 groups: normal control, untreated diabetic control, diabetic rats. Different dose of 200 mg/kg, 400 mg/kg and 600 mg/kg body weight of LS juice were administered, one group of diabetic rats were administered with 2 IU/mL insulin. The rats were sacrificed on the 31st day of the experiment and various in vivo biochemical parameters were evaluated in the serum and tissue homogenates of diabetic rats. RESULTS: Significant dose-dependent inhibition of α-amylase (22.6%), α-glucosidase (50.13%), and DPP-4 (61.50%) activity was observed by LS juice. LS juice (10 µg/mL) increased insulin-mediated 2NBDG (2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl) Amino)-2-Deoxyglucose) absorption in L6 cells. Animals treated with LS juice showed no toxicity or unfavorable pharmacological effects. Lagenaria siceraria (Molina) Standl. Juice improved glucose tolerance in diabetic rats with reduced fasting blood glucose. Lipopolysaccharide induced NF-κB, TNF-α and IL-1ß production was also decreased in rats fed with LS juice. CONCLUSION: Lagenaria siceraria (Molina) Standl. Juice has demonstrated promising anti-inflammatory properties as well as the capacity to inhibit the digestion enzymes glucosidase and amylase. Our findings thus open new avenues for further research into the antidiabetic potential of LS juice.

Antidiabetic effects of polyherbal mixture made of Centaurium erythraea, Cichorium intybus and Potentilla erecta.

ETHNOPHARMACOLOGICAL RELEVANCE: The polyherbal mixture made of Centaurium erythraea aerial parts and Cichorium intybus roots and Potentilla erecta rhizomes has been used for centuries to treat both the primary and secondary complications of diabetes. AIM OF THE STUDY: As a continuation of our search for the most effective herbal mixture used as an ethnopharmacological remedy for diabetes, this study aimed to compare the in vitro biological activities of this polyherbal mixture and its individual ingredients, and, most importantly, to validate the ethnopharmacological value of the herbal mixture through evaluation of its phytochemical composition, its potential in vivo toxicity and its effect on diabetes complications. MATERIALS AND METHODS: Phytochemical analysis was performed using HPLC-UV. Antioxidant activity was estimated via the DPPH test. Potential cytotoxicity/anticytotoxicity was assessed using an in vitro RBCs antihemolytic assay and an in vivo sub-chronic oral toxicity method. Antidiabetic activity was evaluated using an in vitro α-amylase inhibition assay and in vivo using a chemically induced diabetic rat model. RESULTS: The HPLC-UV analysis revealed the presence of p-hydroxybenzoic acid, p-hydroxybenzoic acid derivative, catechin, five catechin derivatives, epicatechin, isoquercetin, hyperoside, rutin, four quercetin derivatives, caffeic acid, and four caffeic acid derivatives in the polyherbal mixture decoction. Treatment with the decoction has shown no toxic effects. The antioxidant and cytoprotective activities of the polyherbal mixture were higher than the reference's ones. Its antidiabetic activity was high in both in vitro and in vivo studies. Fourteen days of treatment with the decoction (15 g/kg) completely normalized blood glucose levels of diabetic animals, while treatments with insulin and glimepiride only slightly lowered glycemic values. In addition, lipid status of treated animals as well as levels of serum AST, ALT, ALP, creatinine, urea and MDA were completely normalized. In addition, the polyherbal mixture completely restored the histopathological changes of the liver, kidneys and all four Cornu ammonis regions of the hippocampus. CONCLUSIONS: The polyherbal mixture was effective in the prevention of both primary and secondary diabetic complications such as hyperlipidemia, increased lipid peroxidation, non-alcoholic fatty liver disease, nephropathy and neurodegeneration.

Panax Quinquefolium Saponins enhances angiogenesis in rats with diabetes and myocardial infarction.

ETHNOPHARMACOLOGICAL RELEVANCE: Xi Yang Shen (Panax quinquefolium L.) was originally recorded in "Ben Cao Cong Xin" edited by Wu Yiluo during the Qing Dynasty. Panax Quinquefolium Saponins (PQS) is the main component derived from Panax quinquefolium L, and has been wildly used in the treatment of coronary heart disease. AIM OF THE STUDY: This study aims to explore the potential role and underlying mechanisms of PQS in promoting angiogenesis in rats with diabetes and myocardial infarction. MATERIALS AND METHODS: Echocardiograms were used to assess cardiac function, while the heart weight to tibia length ratio was calculated to determine cardiac hypertrophy. Hematoxylin and eosin, periodic acid-Schiff and Masson's trichrome staining were used to examine cardiac morphology, myocyte diameter, and myocardial fibrosis. Immunofluorescence staining was employed to evaluate arteriolar density. The transcriptomes were analyzed and bioinformatic analyses were conducted to predict the potential angiogenesis-promoting mechanism of PQS. In addition, RT-PCR and western blotting was utilized to examine the expression of genes and proteins influenced by PQS. RESULTS: PQS improved blood glucose, ameliorated cardiac function, reduced cardiac hypertrophy, and enhanced myocardial morphology in diabetic rats with myocardial infarction. PQS was also found to decrease myocyte diameter, curtail myocardial fibrosis, and increase arteriolar density. However, the effects of PQS were abolished following the deletion of protein kinase C δ (PKCδ). Molecular docking predicted strong interactions between the major blood components of PQS and PKCδ. Transcriptomic and bioinformatic analyses indicated that PQS may bolster angiogenesis by activating the VEGF/PI3K-Akt/eNOS pathway in rats with diabetes and myocardial infarction. Finally, the study demonstrated that PQS could inhibit the expression of PKCδ and stimulate the activation of the VEGF/PI3K-Akt/eNOS pathway. CONCLUSIONS: PQS improves blood glucose, enhances cardiac function, mitigates cardiac damage, and boosts arteriolar density. The angiogenic impact of PQS appears to be, at least partially, due to its modulation of the PKCδ-mediated VEGF/PI3K-Akt/eNOS signaling pathway in rats with diabetes and myocardial infarction.

Revealing the improvement of diabetes by Si Wei Jiang Huang Tang San through ERK/HIF1α signaling pathway via network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Si Wei Jiang Huang Tang San (SWJHTS) is a traditional Tibetan medicine prescription for the treatment of urethritis, frequent urination, and urgency, composed of four traditional Chinese medicines: Curcumae longae rhizoma, Berberidis cortex, Tribuli fructus, and Phyllanthi fructus. However, whether SWJHTS exhibits hypoglycemic efficacy and its specific mechanism remain unclear. AIM OF THE STUDY: In this study, we aimed to investigate the anti-diabetic effects of SWJHTS and elucidate the underlying mechanism. MATERIALS AND METHODS: HPLC-MS method was used to identify the key components of four kinds of traditional Chinese medicine (Curcumae longae rhizoma, Berberidis cortex., Tribuli fructus, and Phyllanthi fructus) which composed SWJHTS and determine their structure. Normal mice and 145 mg/kg STZ-induced type 1 diabetic mice were treated with three doses of SWJTHS by oral gavage. Body weight, 24h food and water intake, fasting blood glucose, glucose tolerance and other indicators were measured to evaluate the hypoglycemic effect of SWJHTS. OMIM, Genecards and other databases were used to collect targets of diabetes, and HPLC-MS results and TCMSP database information were used to collect drug component targets. Bioinformatics methods such as pathway enrichment analysis and molecular docking were used to predict the key targets of SWJHTS. The gene and protein expressions of HIF1α and ERK signaling pathways in HepG2 cells treated with SWJHTS were detected by RT-PCR and Western blot. RESULTS: A total of 181 components were identified, including curcumin, palmatine, and berberine, etc. The in vivo studies showed that SWJHTS could significantly lower fasting blood glucose levels and improve the symptoms of polydipsia, polyphagia, and polyuria in diabetic mice. Furthermore, we identified HIF1α as the potential key target of SWJHTS against diabetes utilizing network pharmacology approach and in silico molecular docking. Subsequently, we experimentally confirmed that SWJHTS could suppress the high glucose-induced upregulation of HIF1α expression, which mediated the glucose consumption in HepG2 cells. The ERK signaling pathway was further found to be activated by the SWJHTS as the upstream of HIF1α. CONCLUSIONS: SWJHTS can improve glucose metabolism by targeting the ERK/HIF1α signaling pathway; hence might be a prospective anti-diabetic drug for diabetic patients as traditional Tibetan medicine.