Recent Developments in the Role of Protein Tyrosine Phosphatase 1B (PTP1B) as a Regulator of Immune Cell Signalling in Health and Disease.

Protein tyrosine phosphatase 1B (PTP1B) is a non-receptor tyrosine phosphatase best known for its role in regulating insulin and leptin signalling. Recently, knowledge on the role of PTP1B as a major regulator of multiple signalling pathways involved in cell growth, proliferation, viability and metabolism has expanded, and PTP1B is recognised as a therapeutic target in several human disorders, including diabetes, obesity, cardiovascular diseases and hematopoietic malignancies. The function of PTP1B in the immune system was largely overlooked until it was discovered that PTP1B negatively regulates the Janus kinase-a signal transducer and activator of the transcription (JAK/STAT) signalling pathway, which plays a significant role in modulating immune responses. PTP1B is now known to determine the magnitude of many signalling pathways that drive immune cell activation and function. As such, PTP1B inhibitors are being developed and tested in the context of inflammation and autoimmune diseases. Here, we provide an up-to-date summary of the molecular role of PTP1B in regulating immune cell function and how targeting its expression and/or activity has the potential to change the outcomes of immune-mediated and inflammatory disorders.

New natural protein tyrosine phosphatase 1B inhibitors from Gynostemma pentaphyllum.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease mainly caused by insulin resistance, which can lead to a series of complications such as cardiovascular disease, retinopathy, and its typical clinical symptom is hyperglycaemia. Glucosidase inhibitors, including Acarbose, Miglitol, are commonly used in the clinical treatment of hypoglycaemia. In addition, Protein tyrosine phosphatase 1B (PTP1B) is also an important promising target for the treatment of T2DM. Gynostemma pentaphyllum is a well-known oriental traditional medicinal herbal plant, and has many beneficial effects on glucose and lipid metabolism. In the present study, three new and nine known dammarane triterpenoids isolated from G. pentaphyllum, and their structures were elucidated by spectroscopic methods including HR-ESI-MS,1H and 13C NMR and X-ray crystallography. All these compounds were evaluated for inhibitory activity against α-glucosidase, α-amylase and PTP1B. The results suggested that compounds 7∼10 were potential antidiabetic agents with significantly inhibition activity against PTP1B in a dose-dependent manner.

Real-time monitoring of dephosphorylation process of phosphopeptide and rapid assay of PTP1B activity based on a 100 MHz QCM biosensing platform.

The misregulation of protein phosphatases is a key factor in the development of many human diseases, notably cancers. Here, based on a 100 MHz quartz crystal microbalance (QCM) biosensing platform, the dephosphorylation process of phosphopeptide (P-peptide) caused by protein tyrosine phosphatase 1B (PTP1B) was monitored in real time for the first time and PTP1B activity was assayed rapidly and sensitively. The QCM chip, coated with a gold (Au) film, was used to immobilized thiol-labeled single-stranded 5'-phosphate-DNAs (P-DNA) through Au-S bond. The P-peptide, specific to PTP1B, was then connected to the P-DNA via chelation between Zr4+ and phosphate groups. When PTP1B was injected into the QCM flow cell where the P-peptide/Zr4+/MCH/P-DNA/Au chip was placed, the P-peptide was dephosphorylated and released from the Au chip surface, resulting in an increase in the frequency of the QCM Au chip. This allowed the real-time monitoring of the P-peptide dephosphorylation process and sensitive detection of PTP1B activity within 6 min with a linear detection range of 0.01-100 pM and a detection limit of 0.008 pM. In addition, the maximum inhibitory ratios of inhibitors were evaluated using this proposed 100 MHz QCM biosensor. The developed 100 MHz QCM biosensing platform shows immense potential for early diagnosis of diseases related to protein phosphatases and the development of drugs targeting protein phosphatases.

In silico Analysis of Selected Four-Leaf Water Clover (Marsilea species) Constituents as Human Acetyl Cholinesterase (hAchE), Carbonic Anhydrase II (hCA-II), and Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitory Agents.

A four-leaf water clover (Marsilea species) has been reported to exhibit various biological activities. In the present study, we aimed to evaluate 23 selected constituents of a four-leaf water clover (Marsilea species) as potent inhibitory agents of human acetyl cholinesterase (hAchE), carbonic anhydrase II (hCA-II), and protein tyrosine phosphatase 1B (hPTP-1B) using an in silico method. The 23 selected constituents of the four-leaf water clover (Marsilea species) were studied on the docking behavior of hAchE, hCA-II, and hPTP-1B by using the Webina docking method. In addition to docking, toxicity analysis was also performed using the pkCSM web server. Toxicity analysis has shown that 10 ligands (44%) of the four-leaf water clover (Marsilea species) were predicted to have hERG II (human ether-a-go-go-related gene) inhibition activity. The docking analysis showed that marsilin has exhibited the maximum binding energy (-11.3 kcal/mol) with the hAchE, whereas it fails to dock with both the target enzymes (hCA-II and hPTP-1B). Thus, the present find provides a new understanding about the 23 selected ligands of the four-leaf water clover (Marsilea species) as potent inhibitory agents of human acetyl cholinesterase (hAchE), carbonic anhydrase II (hCA-II), and protein tyrosine phosphatase 1B (hPTP-1B).

A fast and efficient method for screening and evaluation of hypoglycemic ingredients of Traditional Chinese Medicine acting on PTP1B by capillary electrophoresis.

As a pivotal enzyme that regulates dephosphorylation in cell activities and participates in the insulin signaling pathway, protein tyrosine phosphatase 1B (PTP1B) is considered to be an important target for the therapy of diabetes. In this work, a rapid and efficient inhibitor screening method of PTP1B was established based on capillary electrophoresis (CE), and used for screening and evaluating the inhibition effect of Traditional Chinese Medicine on PTP1B. Response Surface Methodology was used for optimizing the conditions of analysis. After method validation, the enzyme kinetic study and inhibition test were performed. As a result, the IC50 of PTP1B inhibitors Ⅳ and ⅩⅧ were consistent with reported values measured by a conventional method. It was found that the extracts of Astragalus membranaceus (Fisch) Bunge and Morus alba L. showed prominent inhibition on the activity of PTP1B, which were stronger than the positive controls. Meanwhile, on top of the excellent advantages of CE, the whole analysis time is less than 2 min. Thus, the results demonstrated that a fast and efficient screening method was successfully developed. This method could be a powerful tool for screening inhibitors from complex systems. It can also provide an effective basis for lead compound development in drug discovery.

Melanoxetin: A Hydroxylated Flavonoid Attenuates Oxidative Stress and Modulates Insulin Resistance and Glycation Pathways in an Animal Model of Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (DM) continues to escalate, necessitating innovative therapeutic approaches that target distinct pathways and address DM complications. Flavonoids have been shown to possess several pharmacological activities that are important for DM. This study aimed to evaluate the in vivo effects of the flavonoid melanoxetin using Goto-Kakizaki rats. Over a period of 14 days, melanoxetin was administered subcutaneously to investigate its antioxidant, anti-inflammatory, and antidiabetic properties. The results show that melanoxetin reduced insulin resistance in adipose tissue by targeting protein tyrosine phosphatase 1B. Additionally, melanoxetin counteracted oxidative stress by reducing nitrotyrosine levels and modulating superoxide dismutase 1 and hemeoxygenase in adipose tissue and decreasing methylglyoxal-derived hydroimidazolone (MG-H1), a key advanced glycation end product (AGE) implicated in DM-related complications. Moreover, the glyoxalase 1 expression decreased in both the liver and the heart, correlating with reduced AGE levels, particularly MG-H1 in the heart. Melanoxetin also demonstrated anti-inflammatory effects by reducing serum prostaglandin E2 levels, and increasing the antioxidant status of the aorta wall through enhanced acetylcholine-dependent relaxation in the presence of ascorbic acid. These findings provide valuable insights into melanoxetin's therapeutic potential in targeting multiple pathways involved in type 2 DM, particularly in mitigating oxidative stress and glycation.

Eremane, viscidane and isozizaene diterpenoids from the leaves of Eremophila rigida and their absolute configurations.

Previously undescribed eremane, viscidane, and isozizaene diterpenoids, eremorigidanes A-F, along with six known O-methylated flavonoids and three known triterpenoids were isolated and identified from the leaves of Eremophila rigida Chinnock by combined use of high-resolution PTP1B inhibition profiling, semipreparative- and analytical-scale HPLC separations, HPLC-PDA-HRMS analysis, and NMR spectroscopy. The absolute configuration of the unreported diterpenoids were determined by comparison of their experimental and calculated ECD spectra as well as by biosynthetic arguments. All isolates were evaluated for their PTP1B inhibitory activities, which revealed the flavonoid penduletin (3) to show inhibition with an IC50 value of 18.3 µM, and the triterpenoids 3,4-seco-olean-12-ene-3,28-dioic acid (15), oleanolic acid (16), and 3-oxo-oleanolic acid (17) to show inhibition with IC50 values of 55.7, 9.9, and 6.3 µM, respectively. The preliminary structure-activity relationship (SAR) of isolated flavonoids and triterpenoids is discussed. Plausible biosynthetic steps involved in eremane and isozizaene metabolism are presented and discussed.

New chromone derivatives bearing thiazolidine-2,4-dione moiety as potent PTP1B inhibitors: Synthesis and biological activity evaluation.

A series of chromone derivatives bearing thiazolidine-2,4-dione moiety (5 âˆ¼ 37) were synthesized and evaluated for their PTP1B inhibitory activity, interaction analysis and effects on insulin pathway in palmitic acid (PA)-induced HepG2 cells. The results showed that all derivatives presented potential PTP1B inhibitory activity with IC50 values of 1.40 ± 0.04 âˆ¼ 16.83 ± 0.54 µM comparing to that of positive control lithocholic acid (IC50: 9.62 ± 0.14 µM). Among them, compound 9 had the strongest PTP1B inhibitory activity with the IC50 value of 1.40 ± 0.04 µM. Inhibition kinetic study revealed that compound 9 was a reversible mixed-type inhibitor against PTP1B. CD spectra results confirmed that compound 9 changed the secondary structure of PTP1B by their interaction. Molecular docking explained the detailed binding between compound 9 and PTP1B. Compound 9 also showed 19-fold of selectivity for PTP1B over TCPTP. Moreover compound 9 could recovery PA-induced insulin resistance by increasing the phosphorylation of IRSI and AKT. CETSA results showed that compound 9 significantly increased the thermal stability of PTP1B.

Astaxanthin suppresses LPS-induced myocardial apoptosis by regulating PTP1B/JNK pathway in vitro.

PURPOSE: Myocardial injury induced by sepsis can increase the patient's mortality, which is an important complication of sepsis. Myocardial apoptosis plays a key role in septic myocardial injury. Here we explored the potential mechanism of astaxanthin (ATX) inhibiting myocardial apoptosis induced by lipopolysaccharide (LPS) in vitro. METHODS: The H9C2 cell experiment was conducted in three parts. In the first part, we set up three groups: control group, LPS group (10 µg/ml), a model of septic myocardial injury, and LPS + ATX (5, 10, 30 µM); In the second part, we set up four groups: control group, LPS group, LPS + PTP1B-IN-1, a protein tyrosine phosphatase 1B (PTP1B) inhibitor, and LPS + PTP1B-IN-1 + ATX; In the third part, we set up four groups: control group, LPS group, LPS + Anisomycin, a c-Jun N-terminal kinase (JNK) activator, and LPS + Anisomycin + ATX. We assessed H9C2 cell viability using the Cell Counting Kit-8 (CCK-8) assay. We observed cell apoptosis using flow cytometry analysis. We tested the mitochondrial membrane potential (ΔΨm) using JC-1 staining. To identify the molecular targets of ATX, Astaxanthin targets were predicted through the SwissTargetPrediction database. We verified the binding affinity of ATX and its targets using microscale thermophoresis (MST). We investigated the p-JNK expression using immunofluorescence staining. Finally, Western blot was used to evaluate PTP1B, JNK, p-JNK and the mitochondrial apoptosis-associated protein expression. RESULTS: LPS inhibited H9C2 cell viability in a time-dependent manner and ATX treatment enhances H9C2 cell viability in a concentration dependent manner after LPS administration. ATX inhibited the LPS-induced apoptosis and loss of mitochondrial membrane potential in H9C2 cells. As predicted by the SwissTargetPrediction database, PTP1B was a potential target of ATX, and the interaction between ATX and PTP1B was further verified by MST. ATX attenuated the LPS-induced protein expression of PTP1B and p-JNK, regardless of PTP1B inhibition. Both immunofluorescence staining and Western blotting showed that ATX suppressed the LPS-induced p-JNK expression in H9C2 cells, regardless of Anisomycin administration. In addition, by adding Anisomycin to overexpress JNK, ATX inhibited the LPS-induced apoptosis, loss of mitochondrial membrane potential and upregulation of mitochondrial apoptosis-associated proteins in H9C2 cells via JNK signaling. CONCLUSION: ATX inhibited LPS-induced mitochondrial apoptosis of H9C2 cells by PTP1B/JNK pathway and PTP1B was the target of ATX.

High-resolution double vision of the allosteric phosphatase PTP1B.

Protein tyrosine phosphatase 1B (PTP1B) plays important roles in cellular homeostasis and is a highly validated therapeutic target for multiple human ailments, including diabetes, obesity and breast cancer. However, much remains to be learned about how conformational changes may convey information through the structure of PTP1B to enable allosteric regulation by ligands or functional responses to mutations. High-resolution X-ray crystallography can offer unique windows into protein conformational ensembles, but comparison of even high-resolution structures is often complicated by differences between data sets, including non-isomorphism. Here, the highest resolution crystal structure of apo wild-type (WT) PTP1B to date is presented out of a total of ∼350 PTP1B structures in the PDB. This structure is in a crystal form that is rare for PTP1B, with two unique copies of the protein that exhibit distinct patterns of conformational heterogeneity, allowing a controlled comparison of local disorder across the two chains within the same asymmetric unit. The conformational differences between these chains are interrogated in the apo structure and between several recently reported high-resolution ligand-bound structures. Electron-density maps in a high-resolution structure of a recently reported activating double mutant are also examined, and unmodeled alternate conformations in the mutant structure are discovered that coincide with regions of enhanced conformational heterogeneity in the new WT structure. These results validate the notion that these mutations operate by enhancing local dynamics, and suggest a latent susceptibility to such changes in the WT enzyme. Together, these new data and analysis provide a detailed view of the conformational ensemble of PTP1B and highlight the utility of high-resolution crystallography for elucidating conformational heterogeneity with potential relevance for function.

Protein tyrosine phosphatase 1B is a regulator of alpha-actinin4 in the glomerular podocyte.

Glomerular podocytes are instrumental for the barrier function of the kidney, and podocyte injury contributes to proteinuria and the deterioration of renal function. Protein tyrosine phosphatase 1B (PTP1B) is an established metabolic regulator, and the inactivation of this phosphatase mitigates podocyte injury. However, there is a paucity of data regarding the substrates that mediate PTP1B actions in podocytes. This study aims to uncover novel substrates of PTP1B in podocytes and validate a leading candidate. To this end, using substrate-trapping and mass spectroscopy, we identified putative substrates of this phosphatase and investigated the actin cross-linking cytoskeletal protein alpha-actinin4. PTP1B and alpha-actinin4 co-localized in murine and human glomeruli and transiently transfected E11 podocyte cells. Additionally, podocyte PTP1B deficiency in vivo and culture was associated with elevated tyrosine phosphorylation of alpha-actinin4. Conversely, reconstitution of the knockdown cells with PTP1B attenuated alpha-actinin4 tyrosine phosphorylation. We demonstrated co-association between alpha-actinin4 and the PTP1B substrate-trapping mutant, which was enhanced upon insulin stimulation and disrupted by vanadate, consistent with an enzyme-substrate interaction. Moreover, we identified alpha-actinin4 tandem tyrosine residues 486/487 as mediators of its interaction with PTP1B. Furthermore, knockdown studies in E11 cells suggest that PTP1B and alpha-actinin4 are modulators of podocyte motility. These observations indicate that PTP1B and alpha-actinin4 are likely interacting partners in a signaling node that modulates podocyte function. Targeting PTP1B and plausibly this one of its substrates may represent a new therapeutic approach for podocyte injury that warrants additional investigation.

New dammarane-type triterpenoids from hydrolyzate of total Gynostemma pentaphyllum saponins with protein tyrosine phosphatase 1B inhibitory activity.

Protein tyrosine phosphatase 1B (PTP1B) is a key factor and regulator of glucose, lipid metabolism throughout the body, and a promising target for treatment of type 2 diabetes mellitus (T2DM). Gynostemma pentaphyllum is a famous oriental traditional medicinal herbal plant and functional food, which has shown many beneficial effects on glucose and lipid metabolism. The aim of the present study is to assess the inhibitory activity of five new and four known dammarane triterpenoids isolated from the hydrolysate product of total G. pentaphyllum saponins. The bioassay data showed that all the compounds exhibited significant inhibitory activity against PTP1B. The structure-activity relationship showed that the strength of PTP1B inhibitory activity was mainly related to the electron-donating group on its side chain. Molecular docking analysis suggested that its mechanism may be due to the formation of competitive hydrogen bonding between the electron-donating moiety and the Asp48 amino acid residues on the PTP1B protein.

A PTP1B-Cdk3 Signaling Axis Promotes Cell Cycle Progression of Human Glioblastoma Cells through an Rb-E2F Dependent Pathway.

PTP1B plays a key role in developing different types of cancer. However, the molecular mechanism underlying this effect is unclear. To identify molecular targets of PTP1B that mediate its role in tumorigenesis, we undertook a SILAC-based phosphoproteomic approach, which allowed us to identify Cdk3 as a novel PTP1B substrate. Substrate trapping experiments and docking studies revealed stable interactions between the PTP1B catalytic domain and Cdk3. In addition, we observed that PTP1B dephosphorylates Cdk3 at tyrosine residue 15 in vitro and interacts with it in human glioblastoma cells. Next, we found that pharmacological inhibition of PTP1B or its depletion with siRNA leads to cell cycle arrest with diminished activity of Cdk3, hypophosphorylation of Rb, and the downregulation of E2F target genes Cdk1, Cyclin A, and Cyclin E1. Finally, we observed that the expression of a constitutively active Cdk3 mutant bypasses the requirement of PTP1B for cell cycle progression and expression of E2F target genes. These data delineate a novel signaling pathway from PTP1B to Cdk3 required for efficient cell cycle progression in an Rb-E2F dependent manner in human GB cells.

In Vitro and In Vivo Evaluation of the Antidiabetic Activity of Solidago virgaurea Extracts.

Background: Solidago virgaurea (Asteraceae) has been used for more than 700 years for treating cystitis, chronic nephritis, urolithiasis, rheumatism, and inflammatory diseases. However, the antidiabetic activity of Solidago virgaurea has been rarely studied. Methods: Three extracts of Solidago virgaurea were prepared, and their antidiabetic potentials were evaluated by various cell-free, cell-based, and in vivo studies. Results: We found that the Solidago virgaurea contained multiple bioactive phytochemicals based on the GC-MS analysis. The Solidago virgaurea extracts effectively inhibited the functions of the carbohydrate digestive enzyme (α-glucosidase) and protein tyrosine phosphatase 1B (PTP1B), as well as decreased the amount of advanced glycation end products (AGEs). In the L6 myotubes, the Solidago virgaurea methanolic extract remarkably enhanced the glucose uptake via the upregulation of glucose transporter type 4 (GLUT4). The extract also significantly downregulated the expression of PTP1B. In the streptozotocin-nicotinamide induced diabetic mice, the daily intraperitoneal injection of 100 mg/kg Solidago virgaurea methanolic extract for 24 days, substantially lowered the postprandial blood glucose level with no obvious toxicity. The extract's anti-hyperglycemic effect was comparable to that of the glibenclamide treatment. Conclusion: Our findings suggested that the Solidago virgaurea extract might have great potential in the prevention and treatment of diabetes.

Medicinal Aspects of PTP 1B Inhibitors as Anti-Breast Cancer Agents: An Overview.

Protein tyrosine phosphatase 1B (PTP1B) has gained interest as a therapeutic target for type 2 diabetes and obesity. Besides metabolic signalling, PTP1B is a positive regulator of signalling pathways linked to ErbB2-induced breast tumorigenesis. Substantial evidence proves that its overexpression is involved in breast cancer, which suggests that selective PTP1B inhibition might be effective in breast cancer treatment. Therefore, huge research is being carried out on PTP1B inhibitors and their activity against breast cancer development. To date, only two PTP1B inhibitors, viz. ertiprotafib and trodusquemine, have entered clinical trials. The discovery of selective inhibitors of PTP1B could open a new avenue in breast cancer treatment. In this review, we provide an extensive overview on the involvement of PTP1B in breast cancer, its pathophysiology, with special attention on the discovery and development of various natural as well as synthetic PTP1B inhibitors. This study will provide significant information to the researchers developing PTP1B inhibitors for breast cancer treatment.

Anti-Diabetic Activity of Glycyrrhetinic Acid Derivatives FC-114 and FC-122: Scale-Up, In Silico, In Vitro, and In Vivo Studies.

Type 2 diabetes (T2D) is one of the most common diseases and the 8th leading cause of death worldwide. Individuals with T2D are at risk for several health complications that reduce their life expectancy and quality of life. Although several drugs for treating T2D are currently available, many of them have reported side effects ranging from mild to severe. In this work, we present the synthesis in a gram-scale as well as the in silico and in vitro activity of two semisynthetic glycyrrhetinic acid (GA) derivatives (namely FC-114 and FC-122) against Protein Tyrosine Phosphatase 1B (PTP1B) and α-glucosidase enzymes. Furthermore, the in vitro cytotoxicity assay on Human Foreskin fibroblast and the in vivo acute oral toxicity was also conducted. The anti-diabetic activity was determined in streptozotocin-induced diabetic rats after oral administration with FC-114 or FC-122. Results showed that both GA derivatives have potent PTP1B inhibitory activity being FC-122, a dual PTP1B/α-glucosidase inhibitor that could increase insulin sensitivity and reduce intestinal glucose absorption. Molecular docking, molecular dynamics, and enzymatic kinetics studies revealed the inhibition mechanism of FC-122 against α-glucosidase. Both GA derivatives were safe and showed better anti-diabetic activity in vivo than the reference drug acarbose. Moreover, FC-114 improves insulin levels while decreasing LDL and total cholesterol levels without decreasing HDL cholesterol.

Can Allostery Be a Key Strategy for Targeting PTP1B in Drug Discovery? A Lesson from Trodusquemine.

Protein tyrosine phosphatase 1B (PTP1B) is an enzyme crucially implicated in aberrations of various signaling pathways that underlie the development of different human pathologies, such as obesity, diabetes, cancer, and neurodegenerative disorders. Its inhibition can prevent these pathogenetic events, thus providing a useful tool for the discovery of novel therapeutic agents. The search for allosteric PTP1B inhibitors can represent a successful strategy to identify drug-like candidates by offering the opportunity to overcome some issues related to catalytic site-directed inhibitors, which have so far hampered the development of drugs targeting this enzyme. In this context, trodusquemine (MSI-1436), a natural aminosterol that acts as a non-competitive PTP1B inhibitor, appears to be a milestone. Initially discovered as a broad-spectrum antimicrobial agent, trodusquemine exhibited a variety of unexpected properties, ranging from antidiabetic and anti-obesity activities to effects useful to counteract cancer and neurodegeneration, which prompted its evaluation in several preclinical and clinical studies. In this review article, we provide an overview of the main findings regarding the activities and therapeutic potential of trodusquemine and their correlation with PTP1B inhibition. We also included some aminosterol analogues and related structure-activity relationships that could be useful for further studies aimed at the discovery of new allosteric PTP1B inhibitors.

Role of Protein Tyrosine Phosphatase 1B Inhibitor in Early Brain Injury of Subarachnoid Hemorrhage in Mice.

Clinically, early brain injury (EBI), which refers to the acute injuries to the whole brain in the phase of the first 72 h following subarachnoid hemorrhage (SAH), is intensely investigated to improve neurological and psychological function. Additionally, it will be meaningful to explore new therapeutic approaches for EBI treatment to improve the prognosis of patients with SAH. To investigate the underlying neuroprotection mechanism in vitro, the Protein tyrosine phosphatase 1B inhibitor (PTP1B-IN-1) was put in primary neurons induced by OxyHb to observe neuroapoptosis, neuroinflammation, and ER stress. Then, one hundred forty male mice were subjected to Experiment two and Experiment three. The mice in the SAH24h + PTP1B-IN-1 group were given an intraperitoneal injection of 5 mg/kg PTP1B-IN-1 30 min before anesthesia. SAH grade, neurological score, brain water content, Western blot, PCR, and Transmission Electron Microscopy (TEM) were performed to observe the underlying neuroprotection mechanism in vivo. Overall, this study suggests that PTP1B-IN-1 could ameliorate neuroapoptosis, neuroinflammation, and ER stress in vitro and in vivo by regulating the IRS-2/AKT signaling pathway, suggesting that PTP1B-IN-1 may be a candidate drug for the treatment of early brain injury after SAH.

Sitagliptin Mitigates Diabetic Nephropathy in a Rat Model of Streptozotocin-Induced Type 2 Diabetes: Possible Role of PTP1B/JAK-STAT Pathway.

Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus. This study examined the therapeutic effects of sitagliptin, a dipeptidyl peptidase inhibitor, on DN and explored the underlying mechanism. Male Wistar albino rats (n = 12) were intraperitoneally administered a single dose of streptozotocin (30 mg/kg) to induce diabetes. Streptozotocin-treated and untreated rats (n = 12) were further divided into normal control, normal sitagliptin-treated control, diabetic control, and sitagliptin-treated diabetic groups (n = 6 in each). The normal and diabetic control groups received normal saline, whereas the sitagliptin-treated control and diabetic groups received sitagliptin (100 mg/kg, p.o.). We assessed the serum levels of DN and inflammatory biomarkers. Protein tyrosine phosphatase 1 B (PTP1B), phosphorylated Janus kinase 2 (P-JAK2), and phosphorylated signal transducer activator of transcription (P-STAT3) levels in kidney tissues were assessed using Western blotting, and kidney sections were examined histologically. Sitagliptin reduced DN and inflammatory biomarkers and the expression of PTP1B, p-JAK2, and p-STAT3 (p < 0.001) and improved streptozotocin-induced histological changes in the kidney. These results demonstrate that sitagliptin ameliorates inflammation by inhibiting DPP-4 and consequently modulating the PTP1B-related JAK/STAT axis, leading to the alleviation of DN.

An Arylbenzofuran, Stilbene Dimers, and Prenylated Diels-Alder Adducts as Potent Diabetic Inhibitors from Morus bombycis Leaves.

Morus bombycis has a long history of usage as a treatment for metabolic diseases, especially, diabetes mellitus (DM). Thus, we aimed to isolate and evaluate bioactive constituents derived from M. bombycis leaves for the treatment of DM. According to bioassay-guided isolation by column chromatography, eight compounds were obtained from M. bombycis leaves: two phenolic compounds, p-coumaric acid (1) and chlorogenic acid methyl ester (2), one stilbene, oxyresveratrol (3), two stilbene dimers, macrourin B (4) and austrafuran C (6), one 2-arylbenzofuran, moracin M (5), and two Diels-Alder type adducts, mulberrofuran F (7) and chalcomoracin (8). Among the eight isolated compounds, the anti-DM activity of 3-8 (which possess chemotaxonomic significance in Morus species) was evaluated by inhibition of α-glucosidase, protein tyrosine phosphatase 1B (PTP1B), human recombinant aldose reductase (HRAR), and advanced glycation end-product (AGE) formation as well as by scavenging peroxynitrite (ONOO-), which are crucial therapeutic targets of DM and its complications. Compounds 4 and 6-8 significantly inhibited α-glucosidase, PTP1B, and HRAR enzymes with mixed-type and non-competitive-type inhibition modes. Furthermore, the four compounds had low negative binding energies in both enzymes according to molecular docking simulation, and compounds 3-8 exhibited strong antioxidant capacity by inhibiting AGE formation and ONOO- scavenging. Overall results suggested that the most active stilbene-dimer-type compounds (4 and 6) along with Diels-Alder type adducts (7 and 8) could be promising therapeutic and preventive resources against DM and have the potential to be used as antioxidants, anti-diabetic agents, and anti-diabetic complication agents.