PTPN11 Research Articles

Bioinformatic Analysis of Neuropeptide Related Genes in Patients Diagnosed with Invasive Breast Carcinoma

PurposeNeuropeptide receptors are expressed in many malignancies. Effectors involved in the action mechanisms of HCRTR1, HCRTR2, NPY4R (PPYR1) may be related to breast cancer (BC). Genes encoding these receptors and PPY and PTPN11 genes were aimed to examine via bioinformatics tools in the BRCA cohort. To our knowledge, this is the first study in which these receptor genes and PP, which have not found much research in BC, are examined together with PTPN11 and analyzed comprehensively in large patient cohorts from public databases. MethodscBioPortal was used for gene alteration analyses, GeneMania for association analyses with other genes, Kaplan-Meier Plotter for Overall Survival (OS) and Relapse Free Survival (RFS) analyses, UALCAN for methylation analyses, TIMER2.0 for expression analyses, The Human Protein Atlas database for expression validations, TIMER for immune infiltration analyses, WEKA 3.8.6 for diagnostic classification performances of the genes based on Random Forest Classifier and Enrichr-KG for Gene Ontology (GO) Biological Process (BP) and KEGG analysis. Results19 (1.9%) nucleotide changes were found in 996 cases. Missense mutation is most common. Decreased expression levels of the HCRTR1 gene were associated with shorter OS and RFS, but decreased expression levels of the PTPN11 gene were associated with longer OS and RFS. Decreased expression levels NPY4R (PPYR1) gene were associated with shorter RFS. Increased expression levels of HCRTR2 and PPY genes were associated with longer RFS. HCRTR1 and NPY4R (PPYR1) genes were statistically hypermethylated; conversely HCRTR2 and PPY genes were hypomethylated. There was no significant change in PTPN11 gene promoter methylation level. HCRTR1, NPY4R (PPYR1) and PTPN11 gene expressions were downregulated; conversely, HCRTR2 and PPY gene expressions upregulated. Weak correlations were observed between NPY4R (PPYR1) gene expression and CD4+ T Cell, Neutrophil, Dendritic Cell and between PTPN11 gene expression and CD8+ T Cell, Macrophage, Neutrophil, Dendritic Cell infiltrations. Area under the receiver operating characteristics curve values of the 10-fold cross-validation and by splitting the dataset in a ratio of 80:20 models were 0.930 and 0.963 respectively. HCRTR2 and HCRTR1 belong to regulation of cytosolic calcium ion concentration, cellular calcium ion homeostasis GO BPs. ConclusionIn BC patients, increases in HCRTR2 and PPY gene expressions could be considered as positive prognostic factors. Decreases in HCRTR1 and NPY4R (PPYR1) gene expressions could be considered as negative prognostic factors. Decreased expression of PTPN11 gene may have a positive prognostic factor. Changes in existing genes are likely to be both a biomarker and therapeutic target for BC. However, experimental and clinical studies are needed to elucidate the mechanisms underlying these neuropeptide receptors in terms of breast carcinogenesis.

Cigarette smoke alters calcium flux to induce PP2A membrane trafficking and endothelial cell permeability.

Alveolar capillary barrier disruption induces local edema and inflammation that impairs pulmonary function and promotes alveolar destruction in COPD. This study aimed to determine how cigarette smoke modulated the serine-threonine phosphatase protein phosphatase 2A (PP2A) to alter the barrier function of human lung microvascular endothelial cells (HLMVECs). Cigarette smoke exposure lowered overall PP2A activity and enhanced endothelial permeability in HLMVECs. However, directly decreasing PP2A activity with Fostriecin significantly reduced endothelial cell permeability. Protein fractionation studies determined that cigarette smoke diminished cytosolic PP2A activity but increased membrane and cytoskeletal activity. These changes coincided with the translocation of PP2A to the membrane, which reduced occludin phosphorylation in the membrane. Cigarette smoke decreased protein tyrosine phosphatase 1B (PTP1B) activity, a PP2A activator which also counters calcium intracellular influx. The decrease in PTP1B activity correlated with reduced calcium efflux in endothelial cells and these changes in calcium flux regulated PP2A activity. Indeed, culturing endothelial cells in low calcium medium prevented the decrease in cytosolic PP2A activity mediated by cigarette smoke. Together, these findings outline a mechanism whereby cigarette smoke acts via calcium to traffic PP2A from the cytosol to the membrane where it dephosphorylates occludin to increase endothelial cell permeability.

Mapping Protein Conformational Landscapes from Crystallographic Drug Fragment Screens.

Proteins are dynamic macromolecules. Knowledge of a protein's thermally accessible conformations is critical to determining important transitions and designing therapeutics. Accessible conformations are highly constrained by a protein's structure such that concerted structural changes due to external perturbations likely track intrinsic conformational transitions. These transitions can be thought of as paths through a conformational landscape. Crystallographic drug fragment screens are high-throughput perturbation experiments, in which thousands of crystals of a drug target are soaked with small-molecule drug precursors (fragments) and examined for fragment binding, mapping potential drug binding sites on the target protein. Here, we describe an open-source Python package, COnformational LAndscape Visualization (COLAV), to infer conformational landscapes from such large-scale crystallographic perturbation studies. We apply COLAV to drug fragment screens of two medically important systems: protein tyrosine phosphatase 1B (PTP1B), which regulates insulin signaling, and the SARS CoV-2 Main Protease (MPro). With enough fragment-bound structures, we find that such drug screens enable detailed mapping of proteins' conformational landscapes.

CSIG-06. BRAF GERMLINE MUTATIONS AND PREDISPOSITION TO BRAIN TUMORS

Abstract We report on two BRAF-mutated children and discuss genetic counseling regarding predisposition to brain tumors. Molecular analysis of the PTPN11 gene and twelve other genes in the RAS-MAPK pathway was carried out in a series of 54 dysmorphic patients with suspected Rasopathies. Two heterozygous BRAF germline mutations were detected in two 7-year-old girls, at exon 6 and 12 respectively. Both patients had the distinctive facial appearance of cardio-facio-cutaneous syndrome (CFC) type 1. Patients with CFC are rare and characterized by phenotypic and genetic heterogeneity, with overlaps with Noonan syndrome. While nearly 75% of CFC cases have germline BRAF mutations, the frequency of BRAF mutations is inferior in Noonan and LEOPARD syndromes. BRAF mutations in CFC are often found in the cysteine-rich domain of the BRAF protein (exons 6, 11, 12, 13, 14, 15 and 16). Conversely, somatic BRAF mutations are more common, grouped into classes according to their kinase activity level, and have been associated with a variety of malignancies, including pediatric and adult brain tumors (low- and high-grade gliomas, glioblastomas and low-grade astrocytomas). BRAF V600E is the most common somatic mutation, but other mutations are currently being identified. Many of these mutations are within the kinase domain, while others are located across the gene and have less well-understood functional consequences. Germinal V600E mutation has been described once, in a CFC patient having a severe phenotype. Nevertheless, it seems that patients with germline BRAF mutations and gliomas have not yet been reported. Given the rarity of CFC, it is unclear whether there is a high risk of brain tumors. Further molecular studies will enable us to refine recommendations for the prevention, monitoring and care of people with germline BRAF mutations, given the success of BRAF inhibitors in certain cancers, with encouraging results in gliomas.

Rational design and synthesis of novel N-benzylindole-based epalrestat analogs as selective aldose reductase inhibitors: An unexpected discovery of a new glucose-lowering agent (AK-4) acting as a mitochondrial uncoupler

Diabetes mellitus is one of the most frequent metabolic diseases associated with hyperglycemia. Although antidiabetic drugs reduce hyperglycemia, diabetic patients suffer from abnormal fluctuations in blood glucose levels leading to the onset of long-term complications. Aldose reductase inhibitors are considered a promising strategy for regulating the occurrence of diabetic-specific comorbidities. So far, epalrestat is the only drug being approved in Asian countries. In this paper, we ground our research in discovering novel epalrestat analogs that prevent chronic complications and normalize hyperglycemia. Herein, we describe the rational design and synthesis of four novel 4-thiazolidinone acetic acid derivatives (AK-1-4) being evaluated for their efficacy against aldose reductase from rat lenses and their specificity over the homologous enzyme from rat kidneys. AK-1-4 were also tested against human recombinant protein tyrosine phosphatase 1B as a key target in insulin sensitization and towards the closely related T-cell-derived enzyme. Docking analyses suggested possible binding modes on examined targets. The promising inhibitory profile of AK-4 sparked our interest in exploring its effect on the insulin-receptor signaling pathway and its ability to stimulate glucose uptake under ex vivo conditions. We further investigated the ability of AK-4 to target mitochondria acting as an uncoupling agent and impairing mitochondrial membrane potential. Herein, we report for the first time a new glucose-lowering agent (AK-4) that can combine alleviation for chronic diabetic complications without off-target adverse effects and antihyperglycemic efficacy through controlled mitochondrial uncoupling activity. Pharmacokinetic and toxicity studies in silico revealed optimal properties of AK-4 for oral administration without potential side effects.

Enzyme (α-Glucosidase, α-Amylase, PTP1B & VEGFR-2) Inhibition and Cytotoxicity of Fluorinated Benzenesulfonic Ester Derivatives of the 5-Substituted 2-Hydroxy-3-nitroacetophenones

The prevalence of small multi-target drugs containing a fluorinated aromatic moiety among approved drugs in the market is due to the unique properties of this halogen atom. With the aim to develop potent antidiabetic agents, a series of phenylsulfonic esters based on the conjugation of the 5-substituted 2-hydroxy-3-nitroacetophenones 1a–d with phenylsulfonyl chloride derivatives substituted with a fluorine atom or fluorine-containing (-CF3 or -OCF3) group were prepared. Their structures were characterized using a combination of spectroscopic techniques complemented with a single-crystal X-ray diffraction (XRD) analysis on a representative example. The compounds were, in turn, assayed for inhibitory effect against α-glucosidase, α-amylase, protein tyrosine phosphatase 1 B (PTP1B) and the vascular endothelial growth factor receptor-2 (VEGFR-2) all of which are associated with the pathogenesis and progression of type 2 diabetes mellitus (T2DM). The antigrowth effect of selected compounds was evaluated on the human breast (MCF-7) and lung (A549) cancer cell lines. The compounds were also evaluated for cytotoxicity against the African Green Monkey kidney (Vero) cell line. The results of an in vitro enzymatic study were augmented by molecular docking (in silico) analysis. Their ADME (absorption, distribution, metabolism and excretion) properties have been evaluated on the most active compounds against α-glucosidase and/or α-amylase to predict their drug likeness.

A novel fluorescent probe with Aggregation-Induced emission characteristics for PTP1B activity sensing and inhibitor screening

Protein tyrosine phosphatase 1B (PTP1B) is an attractive target for the treatment of metabolic diseases such as type 2 diabetes and obesity. In this study, a novel fluorescent probe with aggregation-induced emission (AIE) characteristics was designed and synthesized. Within the fluorescent probe, a tetraphenylethene core is connected to a peptide sequence that can be specifically recognized and hydrolysed by PTP1B. Due to the dephosphorylation of PTP1B, the fluorescent probe exhibited AIE in a turn-on manner, indicating PTP1B activity. This probe was successfully used to detect PTP1B activity in HepG2 cell lysates. Then, a probe-based method was applied to screen for potential PTP1B inhibitors from a natural product library, and three novel PTP1B inhibitors were discovered. These findings indicated that the proposed approach offered a new avenue for discovering potential PTP1B inhibitors.

PTP1B Modulates Carotid Plaque Vulnerability in Atherosclerosis Through Rab5-PDGFRβ-Mediated Endocytosis Disruption and Apoptosis.

Protein tyrosine phosphatase 1B (PTP1B) is a protein tyrosine phosphatase and modulates platelet-derived growth factor (PDGF)/platelet-derived growth factor receptor (PDGFR) signaling in vascular smooth muscle cells (VSMCs) via endocytosis. However, the related molecular pathways that participated in the interaction of endo-lysosome and the trafficking of PDGFR are largely unknown. This study aims to determine the subcellular regulating mechanism of PTP1B to the endo-lysosome degradation of PDGFR in atherosclerotic carotid plaques, thereby offering a potential therapeutic target for the stabilization of carotid plaques. The immunohistochemical staining technique was employed to assess the expression levels of both PDGFR-β and Caspase 3 in stable and vulnerable carotid plaques. Tunnel staining was utilized to quantify the apoptosis of carotid plaques. Live-cell imaging was employed to observe endocytic motility, while cell apoptosis was evaluated through Propidium Iodide staining. In an invivo experiment, ApoE-/- mice were administered a PTP1B inhibitor to investigate the impact of PTP1B on atherosclerosis. The heightened expression of PDGFR-β correlates with apoptosis in patients with vulnerable carotid plaques. At the subcellular level of VSMCs, PDGFR-β plays a pivotal role in sustaining a balanced endocytosis system motility, regulated by the expression of Rab5, a key regulator of endocytic motility. And PTP1B modulates PDGFR-β signaling via Rab5-mediated endocytosis. Additionally, disrupted endocytic motility influences the interplay between endosomes and lysosomes, which is crucial for controlling PDGFR-β trafficking. Elevated PTP1B expression induces cellular apoptosis and impedes migration and proliferation of carotid VSMCs. Ultimately, mice with PTP1B deficiency exhibit a reduction in atherosclerosis. Our results illustrate that PTP1B induces disruption in endocytosis and apoptosis of VSMCs through the Rab5-PDGFRβ pathway, suggesting a potential association with the heightened vulnerability of carotid plaques.

A switch from lysosomal degradation to secretory autophagy initiates osteogenic bone metastasis in prostate cancer.

The identification of both autophagy-related material degradation and unconventional secretion has paved the way for significant breakthroughs linking autophagy to a plethora of physiological processes and disease conditions. However, the mechanisms that coordinate these two pathways remain elusive. Here, we demonstrate that a switch from the lysosomal degradation to a secretory autophagy pathway is governed by protein tyrosine phosphatase 1B (PTP1B, encoded by PTPN1). Dephosphorylation at two tyrosine residues of syntaxin17 (STX17) by PTP1B reduces autophagosome-lysosome fusion while switching the cells to a secretory autophagy pathway. Both PTP1B overexpression and tumour-derived extracellular vesicles (EVs) can activate the secretory autophagy pathway in osteoblasts. Moreover, we demonstrate that osteoblastic LC3+ EVs, generated via the secretory autophagy pathway, are the primary contributor to tumour-associated bone remodelling in prostate cancer. Depletion of tumour-derived EVs secretion or genetic ablation of osteoblastic PTP1B rescues aberrant bone remodelling and lesions, highlighting the relevance between LC3+ EVs and the formation of bone metastatic niche. Our results reveal the significance of tumour-regulated PTP1B in the fate decision of autophagosomes, and propose a role ofLC3+ EVs in shaping the bone metastatic niche.

Multioxidized polyketides from an endophytic Penicillium sp. YUD17006 associated with Gastrodia elata

Three novel, highly oxygenated polyketides, multioketides A−C (1−3), and three previously described multioxidized aromatic polyketides (4−6), were isolated from an endophytic Penicillium sp. YUD17006 associated with Gastrodia elata. Their chemical structures were elucidated using extensive spectroscopic data, electronic circular dichroism calculations, and single X-ray diffraction analysis. All metabolites were characterized by a typical α,β-unsaturated ketone fragment and exhibited a high degree of oxidation. Multioketides A and B were identified as a pair of epimers featuring a rare dihydroisobenzofuranone core. Multioketide C possessed a novel 5/6/6/6 heterotetracyclic chemical architecture with unusual 1,4-dioxin functionalities. Plausible biosynthetic pathways for 1−6 were proposed. Additionally, compound 3 demonstrated weak inhibitory activities against both acetylcholinesterase and protein tyrosine phosphatase 1B.

Refractory Chylothorax and Ventricular Hypertrophy Treated with Trametinib in a Patient with Noonan Syndrome: 18-Month Follow-Up

RASopathies are a group of genetic syndromes caused by germline mutations in genes involved in the RAS/Mitogen-Activated Protein Kinase signaling pathway, which regulates cellular proliferation, differentiation, and angiogenesis. Despite their involvement at different levels of this pathway, RASopathies share overlapping clinical phenotypes. Noonan syndrome is the most prevalent RASopathy, with an estimated incidence of 1 in 2500 live births, and it is typically inherited in an autosomal dominant manner, with 50% of cases involving gain-of-function mutations in the PTPN11 gene. De novo mutations are common, accounting for 60% of cases. The phenotype of Noonan syndrome includes characteristic facial and physical features, congenital cardiac defects, lymphatic and cerebrovascular anomalies, renal malformations, hematological abnormalities, developmental issues, and an increased risk of cancer. Severe congenital cardiac defects and lymphatic abnormalities significantly impact prognosis, contributing to increased morbidity and mortality. Recent therapeutic advancements have introduced trametinib, an MEK1/2 inhibitor, for treating Noonan syndrome patients with severe cardiac and lymphatic complications. To assess its efficacy, here, we present a case of a newborn with Noonan syndrome who exhibited refractory chylothorax, ventricular hypertrophy, and pulmonary stenosis who was treated with trametinib. The patient demonstrated significant improvement in chylothorax and left ventricular hypertrophy, though pulmonary stenosis persisted. This case further confirms trametinib’s potential as a therapeutic option for severe Noonan syndrome complications, emphasizing the need for further clinical trials to optimize treatment protocols and evaluate long-term outcomes.

Co-Crystallized Ligand Based Designing and Synthesis of Some Heterocyclic Derivatives of Chalcone as “Protein-tyrosine phosphatase 1B” Inhibitors

Co-Crystallized Ligand Based Designing and Synthesis of Some Heterocyclic Derivatives of Chalcone as “Protein-tyrosine phosphatase 1B” Inhibitors

Variants of the PTPN11 Gene in Mexican Patients with Noonan Syndrome

Background/Objectives: Noonan syndrome (NS) is a genetic multisystem disease characterized by distinctive facial features, short stature, chest deformity, and congenital heart defects. NS is caused by gene variants of the RAS/MAPK pathway, with PTPN11 accounting for about 50% of cases. This study aimed to identify PTPN11 pathogenic variants in Mexican patients with NS to enhance our understanding of the disease in this population. Methods: This study included 91 probands and 60 relatives, all of which were clinically evaluated by a geneticist. Sanger sequencing was used to screen the entire PTPN11 gene. Results: Twenty-one previously reported pathogenic variants were identified in 47.3% of the probands. The most frequently occurring were p.Asn308Asp (16.3%) and p.Met504Val (16.3%). Variants p.Tyr279Cys and p.Thr468Met were found exclusively in patients with lentiginosis. Eighty-three percent of patients carried a variant in one of the three exons (3, 8, or 13) where the greatest genetic diversity was observed. Common clinical findings identified in probands included short stature (82%), cardiac anomalies (70.7%), short neck (68.4%), and pectus excavatum (63.2%), although features represented by only one patient each were also detected. Conclusions: This study confirmed the clinical diagnosis of NS in 43 probands and 11 relatives, and further genetic analysis of the remaining 48 probands is required to identify the causal variant. The genetic and clinical variability observed in our cohort was consistent with reports from other populations, underscoring the importance of comprehensive care for all patients. This research provides the most extensive clinical and molecular characterization of NS in Mexican patients, identifying pathogenic variants of PTPN11.

Exploring cutting-edge approaches in diabetes care: from nanotechnology to personalized therapeutics.

Diabetes mellitus (DM) is a persistent condition characterized by high levels of glucose in the blood due to irregularities in the secretion of insulin, its action, or both. The disease was believed to be incurable until insulin was extracted, refined, and produced for sale. In DM, insulin delivery devices and insulin analogs have improved glycemic management even further. Sulfonylureas, biguanides, alpha-glucosidase inhibitors, and thiazolidinediones are examples of newer-generation medications having high efficacy in decreasing hyperglycemia as a result of scientific and technological advancements. Incretin mimetics, dual glucose-dependent insulinotropic polypeptide, GLP-1 agonists, PPARs, dipeptidyl peptidase-4 inhibitors, anti-CD3 mAbs, glucokinase activators, and glimins as targets have all performed well in recent clinical studies. Considerable focus was placed on free FA receptor 1 agonist, protein tyrosine phosphatase-1B inhibitors, and Sparc-related modular calcium-binding protein 1 which are still being studied. Theranostics, stem cell therapy, gene therapy, siRNA, and nanotechnology are some of the new therapeutic techniques. Traditional Chinese medicinal plants will also be discussed. This study seeks to present a comprehensive analysis of the latest research advancements, the emerging trends in medication therapy, and the utilization of delivery systems in treating DM. The objective is to provide valuable insights into the application of different pharmaceuticals in the field of diabetes mellitus treatment. Also, the therapeutic approach for diabetic patients infected with COVID-19 will be highlighted. Recent clinical and experimental studies evidence the Egyptian experience. Finally, as per the knowledge of the state of the art, our conclusion and future perspective will be declared.

Association of polymorphism of NLRP3, ICAM-1, PTPN22, INS genes in childhood onset type 1 diabetes in a Pakistani population.

Type 1 diabetes (T1D) is an organ-specific autoimmune disorder characterized by the destruction of pancreatic β cells, leading to absolute insulin deficiency. The genes NLRP3, ICAM-1, PTPN22, and INS are reportedly associated with T1D in other populations. However, the genetic pattern of T1D in the Pakistani population is not clear. This study aimed to find the association of polymorphisms in the PTPN22, INS, NLRP3, and ICAM-1 genes with T1D susceptibility in the Pakistani population. This case-control study includes 100 T1D patients (3-14 years), recruited randomly from the pediatric endocrinology department of Fatima Memorial Hospital, Lahore, Pakistan and 100 age-matched healthy controls were selected from different localities of the same population. The polymorphisms in PTPN22 (rs601, rs33996649, rs2488457), INS (rs80356664), NLRP3 (rs10754558, rs35829419), and ICAM-1 (rs1799969, rs5498) genes were genotyped by Sanger sequencing. The genotypic and allelic frequencies, haplotypes, and linkage disequilibrium were computed using the genetic toolset PLINK to investigate their relationship to T1D. The results indicate that the occurrence of the GT genotype of the rs33996649 variant is significantly higher in children with T1D compared to a control group of healthy individuals (P = 0.001, OR: 2.0, 95% CI = 0.15-0.45). Furthermore, the CT genotype of rs2488457 was notably associated with T1D patients (P = 0.007, OR: 2.8, 95% CI = 0.56-0.67). The CG genotype of rs80356664 showed a slight association with T1D (P = 0.03, OR: 1.9, 95% CI = 0.35-0.59). The prevalence of the AT genotype of rs10754558 showed a strong association with T1D (P = 0.005, OR: 3.4, 95% CI = 0.45-0.69). The TG genotype of rs5498 was also strongly associated with T1D (P = 0.009, OR: 2.8, 95% CI = 0.75-0.89). The present study provides evidence that SNPs in the PTPN22, INS, NLRP3, and ICAM-1 genes are associated with the development of T1D. Further research is needed to explore their potential use in genetic screening and personalized medication.

Proposed mechanisms of action participating in the hypoglycemic effect of the traditionally used Croton guatemalensis Lotsy and junceic acid, its main compound.

Croton guatemalensis Lotsy (Euphorbiaceae) is an important traditional medicine that is used by the Cakchiquels of Guatemala to control hyperglycemia in patients with type 2 diabetes. Previous studies have shown that administration of this plant induces an acute hypoglycemic effect during fasting and that the main compound is junceic acid, a diterpenoid with a clerodane skeleton; however, junceic acid has not been reported to have hypoglycemic activity in the literature. As the mechanisms involved in the hypoglycemic effect of C. guatemalensis remain unknown, the objective of the present investigation was to elucidate the hypoglycemic mechanisms of this species, as well as its major compound, junceic acid. The results indicated that, similar to complete extract, junceic acid exhibited a hypoglycemic effect in hyperglycemic rats. Both C. guatemalensis extract and junceic acid inhibited the activity of two rate-limiting enzymes involved in hepatic glucose production; however, compared with chlorogenic acid, junceic acid had a more potent effect on glucose-6-phosphatase levels than chlorogenic acid, which was used as a positive control. Furthermore, both fasting and postprandial insulin levels decreased in healthy and hyperglycemic rats despite reduced blood glucose levels in both metabolic states, suggesting a potential insulin-sensitizing effect. However, neither of these compounds potentiated the effect of insulin in insulin tolerance tests nor inhibited the enzyme activity of protein tyrosine phosphatase 1B, a negative regulator of the insulin pathway. Therefore, the insulin-sensitizing effect is thought to be independent of insulin and mediated by potential activation of the AMP-activated protein kinase pathway. The specific activation of this master regulator in β-cells results in the inhibition of insulin secretion in a healthy state and the restoration of the insulin response under conditions of glucotoxicity; these effects were observed after the administration of the extract and junceic acid in healthy and hyperglycemic rats. Overall, the main findings of this study establish a basis of the mechanisms of action of C. guatemalensis and its main compound, junceic acid, in terms of their hypoglycemic effect.

Discovery of Novel PTP1B Inhibitors by High-throughput Virtual Screening.

To Discover novel PTP1B inhibitors by high-throughput virtual screening Background: Type 2 Diabetes is a significant global health concern. According to projections, the estimated number of individuals affected by the condition will reach 578 million by the year 2030 and is expected to further increase to 700 million deaths by 2045. Protein Tyrosine Phosphatase 1B is an enzymatic protein that has a negative regulatory effect on the pathways involved in insulin signaling. This regulatory action ultimately results in the development of insulin resistance and the subsequent elevation of glucose levels in the bloodstream. The proper functioning of insulin signaling is essential for maintaining glucose homeostasis, whereas the disruption of insulin signaling can result in the development of type 2 diabetes. Consequently, we sought to utilize PTP1B as a drug target in this investigation. The purpose of our study was to identify novel PTP1B inhibitors as a potential treatment for managing type 2 diabetes. To discover potent PTP1B inhibitors, we have screened the Maybridge HitDiscover database by SBVS. Top hits have been passed based on various drug-likeness rules, toxicity predictions, ADME assessment, Consensus Molecular docking, DFT, and 300 ns MD Simulations. Two compounds have been identified with strong binding affinity at the active site of PTP1B along with drug-like properties, efficient ADME, low toxicity, and high stability. The identified molecules could potentially manage T2DM effectively by inhibiting PTP1B, providing a promising avenue for therapeutic strategies.

MiR-210 as a therapeutic target in diabetes-associated endothelial dysfunction.

MicroRNA (miR)-210 function in endothelial cells and its role in diabetes-associated endothelial dysfunction are not fully understood. We aimed to characterize the miR-210 function in endothelial cells and study its therapeutic potential in diabetes. Two different diabetic mouse models (db/db and Western diet-induced), miR-210 knockout and transgenic mice, isolated vessels and human endothelial cells were used. miR-210 levels were lower in aortas isolated from db/db than in control mice. Endothelium-dependent relaxation (EDR) was impaired in aortas from miR-210 knockout mice, and this was restored by inhibiting miR-210 downstream protein tyrosine phosphatase 1B (PTP1B), mitochondrial glycerol-3-phosphate dehydrogenase 2 (GPD2), and mitochondrial oxidative stress. Inhibition of these pathways also improved EDR in both diabetic mouse models. High glucose reduced miR-210 levels in endothelial cells and impaired EDR in mouse aortas, effects that were reversed by overexpressing miR-210. However, plasma miR-210 levels were not affected in individuals with type 2 diabetes (T2D) following improved glycaemic status. Of note, genetic overexpression using miR-210 transgenic mice and pharmacological overexpression using miR-210 mimic in vivo ameliorated endothelial dysfunction in both diabetic mouse models by decreasing PTP1B, GPD2 and oxidative stress. Genetic overexpression of miR-210 altered the aortic transcriptome, decreasing genes in pathways involved in oxidative stress. miR-210 mimic restored decreased nitric oxide production by high glucose in endothelial cells. This study unravels the mechanisms by which down-regulated miR-210 by high glucose induces endothelial dysfunction in T2D and demonstrates that miR-210 serves as a novel therapeutic target.

Exploring the active components and potential mechanisms of Rhodiola heterodonta for alleviating T2DM based on network pharmacology

Type 2 diabetes mellitus (T2DM), a metabolic disease that poses a serious threat to human health, is characterized by sustained hyperglycemia due to dysregulated insulin secretion. Rhodiola heterodonta (R. heterodonta) is an edible plant, and its root is a popular herbal tea for lowering blood sugar in Tajikistan's folk remedy. However, R. heterodonta has not received much attention outside of the former Soviet Union. Furthermore, the hypoglycemic components of R. heterodonta and their underlying mechanisms are poorly understood. In this study, we extracted R. heterodonta roots and obtained R. heterodonta root extract (RHRE) through preliminary purification. RHRE significantly inhibited the activities of α-glucosidase (α-GAA) and protein tyrosine phosphatase 1B (PTP1B), thus highlighting its powerful hypoglycemic effect. Twenty-six compounds were identified in RHRE by LC-MS/MS analysis, with flavonoids and phenolic acids existing as the predominant components. Network pharmacology further predicted that the PI3K/AKT pathway is crucial for the anti-T2DM effects of RHRE, and molecular docking suggested the significant binding affinities between the key components of RHRE and PTP1B. Importantly, RHRE exerted its hypoglycemic effect by modulating the PTP1B/PI3K/AKT/GSK3β pathway in insulin-resistance L6 and L02 cells. Additionally, RHRE exhibited antioxidant activity and potent DPPH and ABTS radical scavenging abilities. Ferroptosis, an emerging modality of cell death driven by ROS-induced lipid peroxidation, is considerably linked to the progression of T2DM. RHRE alleviated oxidative stress and inhibited ferroptosis through the activation of the Nrf2/HO-1/SLC7A11/GPX4 axis and the downregulation of ACSL4 expression. In conclusion, our study indicates that RHRE is a potential source of antioxidant and hypoglycemic bioactive compounds and can be used for the development of health products and functional foods for the prevention of T2DM.

Virtual and in Vitro Screening Employing a Repurposing Approach Reveal 13-cis-Retinoic Acid is a PTP1B Inhibitor.

Current treatments for type 2 diabetes (T2D) mainly rely on exercise, dietary control, and anti-diabetic drugs to enhance insulin secretion and improve insulin sensitivity. However, there is a need for more therapeutic options, as approved drugs targeting different pharmacological objectives are still unavailable. One potential target that has attracted attention is the protein tyrosine phosphatase 1B (PTP1B), which negatively regulates the insulin signaling pathway. In this work, a comprehensive computational screening was carried out using cheminformatics and molecular docking on PTP1B, employing a rigorous repurposing approach. The screening involved approved drugs and compounds under research as anti-diabetics that bind to targets such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and α-glucosidase. Several computational hits were then meticulously tested in vitro against PTP1B, with 13-cis-retinoic acid (3a) showing an IC50 of 0.044 mM and competitive inhibition. Molecular dynamics studies further confirmed that 3a can bind to the catalytic binding site of PTP1B. Finally, 3a is the first time it has been reported as an inhibitor of PTP1B, making it a potentially valuable candidate for further studies in D2T treatment.