Drug Metformin Research Articles

NIR-II Fluorescence/Photoacoustic Dual Ratiometric Probes with Unique Recognition Site for Quantitatively Visualizing H2S2 in Vivo.

Hydrogen persulfide (H2S2) plays a significant role in redox biology and signal transduction; therefore, quantitative visualization of H2S2 in the deep tissue of living organisms is essential for obtaining reliable information about relevant pathophysiological processes directly. However, currently reported H2S2 probes are unsuitable for this purpose because of their poor selectivity for many polysulfide species or their short wavelength, which hinders precise imaging in deep tissues. Herein, for the first time, we report a unique H2S2-mediated dithiole formation reaction. Based on this reaction, we construct the first NIR-II fluorescence (FL) and photoacoustic (PA) dual-ratiometric probe (NIR-II-H2S2) for quantitatively visualizing H2S2 in vivo. This probe shows dual-ratiometric NIR-II fluorescence (I840/I1000, 107-fold) and photoacoustic (PA800/PA900, 6.5-fold) responses towards Na2S2 species with high specificity, excellent sensitivity (1.8nM), improved water solubility, and deep-tissue penetration. More importantly, using NIR-II dual-ratiometric FL/PA imaging, we successfully demonstrated that the probe could be used to accurately quantify the fluctuating H2S2 levels in the liver-injury mouse models induced by lipopolysaccharides or metformin drugs. Overall, this study not only presents a promising tool for H2S2-related pathological research, but also provides a unique recognition site that may be generalized for designing more useful H2S2 imaging agents in the future.

NIR‐II Fluorescence/Photoacoustic Dual Ratiometric Probes with Unique Recognition Site for Quantitatively Visualizing H2S2 in Vivo

Hydrogen persulfide (H2S2) plays a significant role in redox biology and signal transduction; therefore, quantitative visualization of H2S2 in the deep tissue of living organisms is essential for obtaining reliable information about relevant pathophysiological processes directly. However, currently reported H2S2 probes are unsuitable for this purpose because of their poor selectivity for many polysulfide species or their short wavelength, which hinders precise imaging in deep tissues. Herein, for the first time, we report a unique H2S2‐mediated dithiole formation reaction. Based on this reaction, we construct the first NIR‐II fluorescence (FL) and photoacoustic (PA) dual‐ratiometric probe (NIR‐II‐H2S2) for quantitatively visualizing H2S2 in vivo. This probe shows dual‐ratiometric NIR‐II fluorescence (I840/I1000, 107‐fold) and photoacoustic (PA800/PA900, 6.5‐fold) responses towards Na2S2 species with high specificity, excellent sensitivity (1.8 nM), improved water solubility, and deep‐tissue penetration. More importantly, using NIR‐II dual‐ratiometric FL/PA imaging, we successfully demonstrated that the probe could be used to accurately quantify the fluctuating H2S2 levels in the liver‐injury mouse models induced by lipopolysaccharides or metformin drugs. Overall, this study not only presents a promising tool for H2S2‐related pathological research, but also provides a unique recognition site that may be generalized for designing more useful H2S2 imaging agents in the future.

CSIG-13. TARGETING GENETIC DEPENDENCIES EXPOSES DIFFUSE MIDLINE GLIOMA CELL OF ORIGIN VULNERABILITIES

Abstract Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG), are uniformly fatal brain cancers affecting children, adolescents, and young adults. These tumors are characterized by ‘oncohistone’ mutations in histone H3 genes (H3F3A, HIST1H3B, HIST1H3C), resulting in the substitution of lysine 27 to methionine (H3K27M), resulting in dominant negative hypomethylation at lysine 27 (H3K27) and a global loss of gene silencing. CRISPR-Cas9 loss-of-function gene deletion screens identified mutation-independent dependencies on PIK3CA and MTOR genes for tumor growth and proliferation, highlighting a targetable molecular dependency across DMG patient-derived models (n=38). However, systemic PI3K/mTOR inhibition increased blood glucose and insulin levels, promoting hyperinsulinemia/hyperglycemia and reduced efficacy in vivo. To exploit genetic dependencies while maintaining compliance and therapeutic benefit, we optimized combinations of clinically relevant PI3K inhibitors (paxalisib, GCT007, everolimus) with the antiglycemic drug metformin to restore glucose homeostasis and decrease DMG insulin receptor activity in vivo, extending the survival of DIPG xenograft models. Phosphoproteomic profiling of DIPG models treated with PI3K/mTOR inhibitors promoted calcium-activated PKC signaling. The brain-penetrant PKC inhibitor enzastaurin in combination with paxalisib, synergistically extended the survival of DIPG xenograft models, including those mimicking disease progression, with further benefits potentiated using metformin in a multimodality approach. Combined PI3K-PKC inhibition in vivo promoted differentiation of OPC-like DMG to more OC-like cells, enhancing PDGFRA-JAK/STAT proinflammatory signaling, showing features of demyelination and MHC-II+ antigen expression, including PD1/PDL1. In parallel, combined PI3K/mTOR and PDGFRA inhibition using paxalisib and avapritinib synergistically extended the survival of patient-derived xenograft models, showing the preclinical relevance of simultaneously targeting these vulnerabilities. Together, we reveal that therapeutic inhibition of PI3K/mTOR and compensatory PKC signaling, while mitigating side effects with metformin, altered the chromatin architecture, leading to cellular differentiation and opening the door for clinically relevant checkpoint inhibitors. This combination strategy addresses DMG genetic dependencies, cellular and systemic responses to precision therapies, while harnessing the immune system for potential clinical translation.

Efficient PEGylated magnetic nanoniosomes for co-delivery of artemisinin and metformin: a new frontier in chemotherapeutic efficacy and cancer therapy

Two strategies were employed to modify the performance of the nano-niosome drug delivery system. Initially, the surface of the nano-niosomes underwent modification through the inclusion of polyethylene glycol, thereby altering its properties. Additionally, the core of the nano-niosomes was equipped with Fe3O4 magnetic nanoparticles to impart magnetic characteristics to the system. This study presents the development of PEGylated magnetic nanoniosomes (PMNios) for the co-delivery of artemisinin (ART) and metformin (MET) in cancer therapy, highlighting significant advancements in chemotherapeutic efficacy. The magnetization of the nano-niosomes facilitated the targeted delivery of drugs to specific tissues, while PEGylation improved the bioavailability of the nano-niosomes. These PEGylated magnetic niosomes (PMNios) were then loaded with artemisinin and metformin drugs. The synthesized PMNios were thoroughly evaluated in terms of zeta potential, size, morphology, and entrapment efficiency. The PMNios achieved a drug loading efficiency of 88%. They exhibited an average size of 298 nm, a polydispersity index of 0.32, and a zeta potential of − 19 mV, indicating the complete stability. SEM and TEM images of the PMNios revealed a spherical morphology. Subsequently, the PMNios were compared with other forms of nano-niosomes, including empty niosomes, non-magnetic niosomes, and non-PEGylated niosomes. The encapsulation of the nano-niosomes with magnetic nanoparticles allows for faster delivery of the encapsulated drugs to the tumor site, while PEGylation improved the stability, bioavailability, and controlled release of the PMNios. Furthermore, the in-vitro effectiveness of various formulations of the PMNios against A549, a lung cancer cell line, demonstrated that the PMNios exhibited appropriate toxicity towards cancer cell lines in the presence of an external magnetic field. Gene expression level of Bcl2 were lower for the PMNios-ART-MET system, whereas the level of Bax were higher than the other group. The PMNios-ART-MET system also demonstrated well internalization into the A549 cells and preponderant endocytosis. These findings underscore the novelty and potential of PMNios as a robust platform for the targeted co-delivery of hydrophilic and hydrophobic drugs, promising a new frontier in cancer therapy by enhancing the therapeutic index and minimizing side effects.

A headspace GC-MS method to quantify nitrosamine impurities and precursors in drug products: Method validation and product testing.

Pharmaceutical manufacturers are working to mitigate the formation of nitrosamine impurities in drug products. The work herein describes the development and validation of a headspace GC-MS method according to ICH Q2(R1) guidelines for the detection and quantification of NDMA, NDEA, NDIPA, and NEIPA in drug products. The analytical procedure was further modified to include detection and quantitation of DMF due to the potential decomposition pathway of DMF to form dimethylamine, a known precursor for NDMA formation. The NDMA impurity was detected in the "sartan" class of drug products between 0.1 and 113 ppm. The validated analytical procedure was applied in an investigation of approaches to mitigate nitrosamine formation in metformin drug products. The developed analytical procedures provide another tool for pharmaceutical manufacturers to evaluate drug products for nitrosamine impurities.

Multifunctional mesoporous nanoselenium delivery of metformin breaks the vicious cycle of neuroinflammation and ROS, promotes microglia regulation and alleviates Alzheimer's disease

Clinical trials based on a single molecular target continue to fail, and the adverse effects of Aβ protein aggregation and neuroinflammation need to be solved and treatment of Alzheimer's disease. Herein, by designed a nano-sized flower mesoporous selenium transport carrier (Met@MSe@Tf) with high enzyme-like activity, metformin (Met) was loaded, and transferrin (Tf) was modified to bind to transferrin receptor to promote receptor-mediated transport across the BBB. In the AD lesion environment, with the acidic environment response dissociation, promote the release of metformin by nanoflower to achieve therapeutic effect in the brain lesion site. Metformin, a major anti-diabetic drug in diabetic metabolism, has been found to be a promising new therapeutic target in neurodegenerative diseases. Further studies showed that the metformin drug release from the designed and synthesized transport nanoparticles showed high intrinsic activity and the ability to degrade the substrate involved, especially the degradation of Aβ deposition in the cortex and hippocampus, increased the phagocytosis of microglia, thus relieving neuroinflammation simultaneously. Collectively, in vivo experiments demonstrated that Met@MSe@Tf significantly increased the number of NeuN-positive neurons in the hippocampus of AD mice, promoted neurovascular normalization in the brain, and improved cognitive dysfunction in AD transgenic AD mice. Thus, it provides a preclinical proof of concept for the construction of a highly modular accurate drug delivery platform for Alzheimer's disease.

Application of Fabric Phase Sorptive Extraction as a Green Method for the Analysis of 10 Anti-Diabetic Drugs in Environmental Water Samples

Due to the increased prevalence of diabetes, the consumption of anti-diabetic drugs for its treatment has likewise increased. Metformin is an anti-diabetic drug that is commonly prescribed for patients with type 2 diabetes and has been frequently detected in surface water and wastewaters, thus representing an emerging contaminant. Metformin can be prescribed in combination with other classes of anti-diabetic drugs; however, these drugs are not sufficiently investigated in environmental samples. Fabric phase sorptive extraction (FPSE) has emerged as a simple and green method for the extraction of analytes in environmental samples. In this study, FPSE coupled with a high-performance liquid chromatography diode array detector (HPLC-DAD) was employed for the simultaneous analysis of different classes of anti-diabetic drugs (metformin, dapagliflozin, liraglutide, pioglitazone, gliclazide, glimepiride, glargine, repaglinide, sitagliptin, and vildagliptin) in environmental water samples. Four different fabric membranes were synthesized but the microfiber glass filter coated with sol-gel polyethylene glycol (PEG 300) was observed to be the best FPSE membrane. The parameters affecting the FPSE process were optimized using a combination of one-factor-at-a-time processes and the design of experiments. The FPSE was evaluated as a green extraction method, based on green sample preparation criteria. The FPSE-HPLC-DAD method achieved acceptable validation results and was applied for the simultaneous analysis of anti-diabetic drugs in surface and wastewater samples. Glimepiride was detected below the quantification limit in both lake and river water samples. Dapagliflozin, liraglutide, and glimepiride were detected at 69.0 ± 1.0 μg·L−1, 71.9 ± 0.4 μg·L−1, and 93.9 ± 1.3 μg·L−1, respectively, in the city wastewater influent. Dapagliflozin and glimepiride were still detected below the quantification limit in city wastewater effluent. For the hospital wastewater influent, metformin and glimepiride were detected at 1158 ± 21 μg·L−1 and 28 ± 0.8 μg·L−1, respectively, while only metformin (392.6 ± 7.7 μg·L−1) was detected in hospital wastewater effluent.

Multilayer patch functionalized microfibrillated cellulosic paper sensor for sweat glucose monitoring.

Electrochemical analysis of glucose monitoring without painful blood collection provides a new noninvasive route for monitoring glucose levels. Thus, in this study, biobased cellulosic papers (methylated and phosphorylated one) based glucose monitoring sensor is developed. To achieve high hydrophilicity, microfibrillated cellulose (MFC) were functionalized using hexokinase mediated phosphorylation (-OH to -[Formula: see text]). The instinctive increased surface charge density from 36.2 ± 3.4 to 118.4 ± 1.2 µmol/g and decrease contact angle (45°-22°) confirms the increased hydrophilicity of paper. Furthermore, functionalized phos-MFC paper increase the capillary flow of sweat, required low quantity (1µl) of sweat for accurate analysis of glucose level. Additionally, chemically induced methyl groups (-CH3) make the sensor more barrier to other chemicals. In addition, a multilayer patch design combined with sensor miniaturization was used to lead to an increase in the efficiency of the sweat collection and sensing processes. Besides, this paper sensor integrated with artificial transdermal drug delivery unit (agarose gel as skin) for monitoring glucose levels in sweat. The patch monitoring system increase the accuracy of sensing with fluctuation in sweat vol. (1-4µl), temperature (20-70 °C), and pH (4.0-7.0). In addition, temperature dependency artificial transdermal delivery (within agarose gel) of drug metformin agrees the measurement accuracy of sensor, called "switch system" without any error. As a result, the reported MFC paper based multi-patch disposable sensing system provides a novel closed-loop solution for the noninvasive sweat-based management of diabetes mellitus.

Antidiabetic, antihyperlipidemic effects and quantification of bioactive compounds by HPLC from Crassula ovata leaves extracts on streptozotocin induced diabetic Wistar rats

Background: Crassula ovata have been recommended in ethno medicines for the treatment of diabetes. In this research the scientific claim is studied and validated. Objective: Objective of the current study has been focused to assess the traditional use of Crassula ovata to heal diabetes, hyperlipidemia and to check the presence of constituents responsible for these actions. Methods: The approved plant's ethanol, acetone, and chloroform extracts were prepared by maceration. For in vivo activity, the model of streptozotocin induced diabetes mellitus in rats was chosen, wherein antidiabetic parameters such as body weight, urine volume, blood glucose level, and lipid profile parameters were evaluated. Quantification of bioactive compounds was done by a high-performance liquid chromatographic technique using diode-array detection. Results: The ethanolic extract noticeably depleted increased blood glucose levels and has positive effects on altered lipid profile after administering a dose of 200 mg/kg orally compared with oral hypoglycemic drug metformin. HPLC analysis of ethanolic extract identified several secondary metabolites in Crassula ovata, including Gallic acid, Rutin, Luteolin, Caffeic acid, Catechin, Kaempferol and Quercetin. These compounds have been reported for their potential antidiabetic effects. The analytical data on the chemical composition supported its traditional use in diabetes management. Conclusion: From the results, it can be concluded that, Crassula ovata ethanolic extract can be ideal for the treatment of diabetes and hyperlipidemia. Further studies are required to locate the active pharmaceutical ingredient for the said actions.

The Antidiabetic Drug Metformin Attenuated Depressive and Anxietylike Behaviors and Oxidative Stress in the Brain in a Rodent Model of Inflammation Induced by Lipopolysaccharide in Male Rats.

Inflammation is considered to be a link between diabetes and central nervous system (CNS) disorders, including depression and anxiety. Metformin is suggested to have antioxidant, anti-inflammatory, and mood-improving effects. The aim of the current research was to investigate the effects of the antidiabetic drug metformin on depressive- and anxiety- like behaviors and oxidative stress in the brain in a rodent model of inflammation induced by lipopolysaccharide (LPS) in male rats. The rats were treated as follows: (1) Vehicle instead of metformin and lipopolysaccharide, (2) Lipopolysaccharide (1 mg/ kg) + vehicle instead of metformin, (3-5) Lipopolysaccharide + 50, 100, or 150 mg/ kg of metformin. After the behavioral tests, including open field (OF), elevated pulse maze (EPM), and force swimming (FS) tests, the brains were removed, and malondialdehyde (MDA), nitric oxide (NO) metabolites, total thiol, catalase (CAT) activity, interleukin-6 (IL-6) and superoxide dismutase (SOD) activity were determined. In the EPM, metformin increased the open arm time and entry and decreased closed arm time and entry. In the FS test, metformin lowered the immobility and increased active time compared to lipopolysaccharide. In the OF test, metformin increased total crossing and total distance, time spent, traveled distance, and crossing number in the central zone. As a result of metformin administration, IL-6, MDA, and NO metabolites were decreased while thiol content, SOD, and CAT activity were increased. The results indicated that the well-known antidiabetic drug metformin attenuated depressive- and anxiety-like behaviors induced by inflammation in rats. These beneficial effects are suggested to be due to their attenuating effects on neuroinflammation, oxidative stress, and NO in the brain.

Combined Administration of Metformin and Amprolium to Rats Affects Metabolism of Free Amino Acids in the Brain, Altering Behavior, and Heart Rate.

The risk of developing diabetes and cardiometabolic disorders is associated with increased levels of alpha-aminoadipic acid and disturbances in the metabolism of branched-chain amino acids. The side effects of the widely used antidiabetic drug metformin include impaired degradation of branched-chain amino acids and inhibition of intracellular thiamin transport. These effects may be interconnected, as thiamine deficiency impairs the functioning of thiamine diphosphate (ThDP)-dependent dehydrogenases of 2-oxo acids involved in amino acids degradation, while diabetes is often associated with perturbed thiamine status. In this work, we investigate the action of metformin in rats with impaired thiamine availability. The reduction in the thiamine influx is induced by simultaneous administration of the thiamine transporters inhibitors metformin and amprolium. After 24 days of combined metformin/amprolium administration, no significant changes in the total brain levels of ThDP or activities of ThDP-dependent enzymes of central metabolism are observed, but the affinities of transketolase and 2-oxoglutarate dehydrogenase to ThDP increase. The treatment also significantly elevates the brain levels of free amino acids and ammonia, reduces the antioxidant defense, and alters the sympathetic/parasympathetic regulation, which is evident from changes in the ECG and behavioral parameters. Strong positive correlations between brain ThDP levels and contents of ammonia, glutathione disulfide, alpha-aminoadipate, glycine, citrulline, and ethanolamine are observed in the metformin/amprolium-treated rats, but not in the control animals. Analysis of the obtained data points to a switch in the metabolic impact of ThDP from the antioxidant and nitrogen-sparing in the control rats to the pro-oxidant and hyperammonemic in the metformin/amprolium-treated rats. As a result, metformin administration along with the amprolium-reduced thiamine supply significantly perturb the metabolism of amino acids in the rat brain, altering behavioral and ECG parameters.

Metformin hydrolase is a recently evolved nickel-dependent heteromeric ureohydrolase

The anti-diabetic drug metformin is one of the most widely prescribed medicines in the world. Together with its degradation product guanylurea, it is a major pharmaceutical pollutant in wastewater treatment plants and surface waters. An operon comprising two genes of the ureohydrolase family in Pseudomonas and Aminobacter species has recently been implicated in metformin degradation. However, the corresponding proteins have not been characterized. Here we show that these genes encode a Ni2+-dependent enzyme that efficiently and specifically hydrolyzes metformin to guanylurea and dimethylamine. The active enzyme is a heteromeric complex of α- and β- subunits in which only the α-subunits contain the conserved His and Asp residues for the coordination of two Ni2+ ions in the active site. A crystal structure of metformin hydrolase reveals an α2β4 stoichiometry of the hexameric complex, which is unprecedented in the ureohydrolase family. By studying a closely related but more widely distributed enzyme, we find that the putative predecessor specifically hydrolyzes dimethylguanidine instead of metformin. Our findings establish the molecular basis for metformin hydrolysis to guanylurea as the primary pathway for metformin biodegradation and provide insight into the recent evolution of ureohydrolase family proteins in response to an anthropogenic compound.

In-Vitro and In-Silico Studies of Brevifoliol Ester Analogues against Insulin Resistance Condition.

Brevifoliol is a diterpenoid that occurs naturally in the plants of Taxus genus and is widely used as chemotherapy agent for the management of cancer. A series of semisynthetic esters analogues of brevifoliol were prepared by Steglich esterification and attempted for their pharmacological potential against insulin resistance conditions using in-vitro and in-silico assays. The aim of this study is to understand the pharmacological potential of eighteen semisynthetic analogs through Steglich esterification of Brevifoliol against insulin resistance condition Methods: In the in-vitro study, insulin resistance condition was induced in skeletal muscle cells using TNF-α, pro-inflammatory cytokine and these cells were treated with brevifoliol analogues. The most potent analouge was further validated using in-silico docking study against the tumor necrosis factor (TNF-α) (PDB ID: 2AZ5) and Human Insulin Receptor (PDB ID: 1IR3), using the Auto dock Vina v0.8 program. Although, all the analogues of Brevifoliol significantly exhibited the pharmacological potential. Among all, analogue 17 was most potent in reversing the TNF-α induced insulin resistance condition in skeletal muscle cells and also to inhibit the production of TNF-α in LPSinduced inflammation in macrophage cells in a dose-dependent manner. Similarly, in-silico molecular docking studies revealed that analogue 17 possesses a more promising binding affinity than the selected control drug metformin toward the TNF-α and insulin receptor. These findings suggested the suitability of analogue 17 as a drug-like candidate for further investigation toward the management of insulin resistance conditions.

Unveiling the role of solubilization of metformin hydrochloride assimilated in nonionic surfactants mediated mixed micellar assemblies

This study examines the distribution of an antidiabetic drug metformin hydrochloride (MNH) between water and mixed micellar environments produced by nonionic surfactants Tween 80 (TW-80) and Triton X-100 (TX-100). In our research, we described the UV–visible absorption spectra of a drug at various surfactant concentrations above and below critical micelle concentration (CMC). When employing TX-100, the absorbance spectra appeared to shift towards shorter wavelengths (blue shift) and there was an increase in absorbance intensity (hyperchromic shift), while using Tween 80, absorbance intensity increased (hyperchromic shift). We estimated the partition coefficient (Kx) from differential absorption data and utilized it to derive the free energy of partition (∆Gp). The partition coefficient in a single micellar system was found to be 7.82×106 and 1.79×106 in the presence of TW-80 and TX-100, respectively. The partition coefficient for the MNH/TW-80 system in a mixed micellar system reaches its maximum value of 1.08×107 when TX-100 is present at 1.26×106 M, indicating a considerable increase in the solubilizing power of micelles. The results showed that mixed micelles of TX-100/TW-80 were more effective for the solubilization of MNH than their individual micelles. It was crystal clear from the negative values of ∆Gb that binding is also spontaneous.

Protective effect and mechanism of Zuogui Jiangtang Jieyu Formula on damage to hippocampal synaptic microenvironment in rats with diabetes-related depression based on microglia-neuron crosstalk signal CD300f/TLR4

This study aims to reveal the protective effect and mechanism of Zuogui Jiangtang Jieyu Formula on the damage to hippo-campal synaptic microenvironment in rats with diabetes-related depression(DD) via regulating microglia immune receptor molecule-like family member f(CD300f)/Toll-like receptor 4(TLR4) signal. Firstly, the model of DD rats was established by a two-week high-fat diet+STZ injection+chronic mild and unpredictable stress plus isolation for 28 days. The rats were randomly divided into normal group, model group, CD300f blocker(CLM1, 2 μg·kg~(-1)) group, CD300f agonist(Fcγ, 5 μg·kg~(-1)) group, positive drug(0.18 g·kg~(-1) metformin+1.8 mg·kg~(-1) fluoxetine) group, and high-dose and low-dose(20.52 and 10.26 g·kg~(-1)) Zuogui Jiangtang Jieyu Formula groups. Depression-like behavior of rats was evaluated by open field and forced swimming experiments. The levels of blood glucose and insulin were detected by biochemical analysis. The levels of tumor necrosis factor α(TNF-α), interleukin-1β(IL-1β), indoleamine 2, 3-dioxygenase(IDO), 5-hydroxytryptamine(5-HT), and dopamine(DA) in the hippocampus were detected by enzyme-linked immunosorbent assay. The changes in the synaptic ultrastructure in hippocampal neurons of rats were observed by transmission electron microscopy. The protein expressions of CD300f, TLR4, synaptophysin(SYN), and postsynaptic density protein 95(PSD-95) in microglial cells of the hippocampus were detected by immunofluorescence and Western blot. The results indicated that compared with that in the normal group, the total movement distance in open field experiments was reduced in the model group, and the immobility time in forced swimming experiments increased, with an elevated insulin level in serum, as well as TNF-α, IL-1β, and IDO levels in the hippocampus. The 5-HT and DA levels in the hippocampus were reduced. In addition, the CD300f expression was down-regulated in microglial cells of the hippocampus, and the TLR4 expression was up-regulated. Moreover, the expression of synapse-related proteins SYN and PSD-95 in hippocampal neurons decreased, and the synaptic ultrastructure of hippocampal neurons was significantly damaged. Compared with the model group, the CD300f blocker and agonist aggravated and alleviated the above abnormal changes, respectively. High-dose and low-dose Zuogui Jiangtang Jieyu Formula could significantly improve the above depression-like beha-vior in rats, inhibit the abnormal increase of TNF-α, IL-1β, and IDO and the decrease of 5-HT and DA, effectively increase the expression of CD300f in microglial cells, and decrease the expression of TLR4. They could up-regulate the protein expression of presyna-ptic membrane SYN and postsynaptic membrane PSD-95 in hippocampal neurons and finally improve the damage to the hippocampal synaptic microenvironment. In conclusion, this research confirmed that Zuogui Jiangtang Jieyu Formula effectively alleviated the depression-like behavior and inhibited inflammatory activation of microglial cells in the hippocampus of rats with DD, and the mechanism might be related to the regulation of CD300f/TLR4 signal to alleviate the damage to hippocampal synaptic microenvironment.

Potential hepato-protective effect of Salvia hispanica (chia) and Chenopodium quinoa (quinoa) in diabetic male albino rats

Chia and quinoa seeds are novel sources of bioactive compounds that may improve lipid profile, blood glucose homeostasis, and body weight in diabetic rats. This work aims to study the effect of different percentages of chia and quinoa consumption, alone or in a mixture, compared to Metformin drug on regulating lipid profile, blood glucose level, and weight of male diabetic rats. The consumption of quinoa and chia seeds showed a significant decline in fasting blood glucose (FBG), fasting insulin level, Hemoglobin A1C (HbA1c), and Homeostatic Model Assessment for Insulin (HOMA-IR), while the best results were obtained with Metformin and chia seeds. A decrease in mean body weight, triglycerides, total cholesterol, low density lipoprotein (LDL-C), and very low-density lipoprotein (VLDL-C), and an increase in high density lipoprotein (HDL-C) occurred, which was significant when consuming chia and quinoa seeds rather than treatment with metformin. Chia and quinoa seeds could improve blood glucose homeostasis and lipid profile in diabetic rats. These research findings could promote the daily consumption of quinoa and chia as great functional foods that could improve blood glucose homeostasis and lipid profile.

Study of the Effect of Fresh Green Asparagus officinalis L. Stems Extract and Metformin Drug on Induced Polycystic Ovary Syndrome (PCOS) in Female Albino Rats

During this research, Polycystic Ovary Syndrome (PCOS) was studied and the effect of Metformin Drug and an extract of fresh Asparagus officinalis L. stems on it was studied. The study involved 20 adult female albino rats divided into four groups, each containing five female rats. The first group received a physiological saline solution, while the second group was induced with Polycystic Ovary Syndrome (PCOS) by being dosed with Letrozole. The third group, after the induction of PCOS, was treated with Metformin, and the fourth group was dosed with Fresh Asparagus officinalis L. stems extract. The study focused on hormonal and Histological changes. The results showed that the group of rats with PCOS induced by Letrozole had a significant decrease in the levels of Progesterone (Prog.) and Oestradiol (E2) hormones, and a significant increase in Testosterone (Testo.) compared to the control group. Dosing rats with Fresh Asparagus officinalis L. stems extract led to a significant decrease in (E2) hormone level and a significant increase in Progesterone (Prog.) hormone level compared with the control group. Dosing rats with Metformin led to a significant decrease in (E2) hormone level and a significant increase in Progesterone (Prog.) and Testosterone (Testo.) hormone levels compared to the control group. The results also indicated significant changes in hormone levels between Treatment groups and PCOS induction group. The histological study revealed changes in the shape of the ovary, the appearance of cystic structures, congestion of blood vessels, and increased ovarian cellularity. Metformin showed fewer Histological changes, while Asparagus officinalis L. stems extract had a therapeutic effect with moderate severity, leading to the disappearance of cystic vesicles and the appearance of corpus luteum and primary vesicles. In conclusion, we conclude that both the therapeutic agents Metformin and the extract of Fresh Asparagus officinalis L. stems showed a therapeutic effect on Polycystic Ovary Syndrome, as Metformin drug showed a treatment for this Syndrome, but it requires a long period to show this result, meaning we need more than 28 days, which is the duration of the study, but Asparagus officinalis L. stems extract had Faster healing effect within just 28 days. Fresh Green, tender Asparagus officinalis L. stems is one of the significant medicinal plants that is used to treat or prevent polycystic ovarian syndrome. Research has shown that it is an effective treatment for the condition. Future researchers studying polycystic ovarian syndrome will find this article useful.

Organismal metabolism regulates the expansion of oncogenic PIK3CA mutant clones in normal esophagus.

Oncogenic PIK3CA mutations generate large clones in aging human esophagus. Here we investigate the behavior of Pik3ca mutant clones in the normal esophageal epithelium of transgenic mice. Expression of a heterozygous Pik3caH1047R mutation drives clonal expansion by tilting cell fate toward proliferation. CRISPR screening and inhibitor treatment of primary esophageal keratinocytes confirmed the PI3K-mTOR pathway increased mutant cell competitive fitness. The antidiabetic drug metformin reduced mutant cell advantage in vivo and in vitro. Conversely, metabolic conditions such as type 1 diabetes or diet-induced obesity enhanced the competitive fitness of Pik3caH1047R cells. Consistently, we found a higher density of PIK3CA gain-of-function mutations in the esophagus of individuals with high body mass index compared with those with normal weight. We conclude that the metabolic environment selectively influences the evolution of the normal epithelial mutational landscape. Clinically feasible interventions to even out signaling imbalances between wild-type and mutant cells may limit the expansion of oncogenic mutants in normal tissues.

Pharmacological characterization of the antidiabetic drug metformin in atherosclerosis inhibition: A comprehensive insight.

Atherosclerosis (AS) is a progressive disease that interferes with blood flow, leading to cardiovascular complications such as hypertension, ischemic heart disease, ischemic stroke, and vascular ischemia. The progression of AS is correlated with inflammation, oxidative stress, and endothelial dysfunction. Various signaling pathways, like nuclear erythroid-related factor 2 (Nrf2) and Kruppel-like factor 2 (KLF2), are involved in the pathogenesis of AS. Nrf2 and KLF2 have anti-inflammatory and antioxidant properties. Thus, activation of these pathways may reduce the development of AS. Metformin, an insulin-sensitizing drug used in the management of type 2 diabetes mellitus (T2DM), increases the expression of Nrf2 and KLF2. AS is a common long-term macrovascular complication of T2DM. Thus, metformin, through its pleiotropic anti-inflammatory effect, may attenuate the development and progression of AS. Therefore, this review aims to investigate the possible role of metformin in AS concerning its effect on Nrf2 and KLF2 and inhibition of reactive oxygen species (ROS) formation. In addition to its antidiabetic effect, metformin can reduce cardiovascular morbidities and mortalities compared to other antidiabetic agents, even with similar blood glucose control by the Nrf2/KLF2 pathway activation. In conclusion, metformin is an effective therapeutic strategy against the development and progression of AS, mainly through activation of the KLF2/Nrf2 axis.

Kynurenine pathway in type 2 diabetes: Role of metformin.

The Kynurenine pathway (KP) which is involved in the synthesis of nicotinamide adenine dinucleotide (NAD) from tryptophan (Trp) is intricate in the development of insulin resistance (IR) and type 2 diabetes (T2D). Inflammatory reactions in response to cardiometabolic disorders can induce the development of IR through the augmentation of KP. However, kynurenine (KYN), a precursor of kynurenic acid (KA) is increased following physical exercise and involved in the reduction of IR. Consequently, KP metabolites KA and KYN have anti-diabetogenic effects while other metabolites have diabetogenic effects. KP modulators, either inhibitors or activators, affect glucose homeostasis and insulin sensitivity in T2D in a bidirectional way, either protective or detrimental, that is not related to the KP effect. However, metformin through inhibition of inflammatory signaling pathways can reduce the activation of KP in T2D. These findings indicated a strong controversy regarding the role of KP in T2D. Therefore, the objectives of this mini review were to clarify how KP induces the development of IR and T2D. In addition, this review aimed to find the mechanistic role of antidiabetic drug metformin on the KP, and how KP modulators affect the pathogenesis of T2D.