Protein Tyrosine Phosphatase 1B Expression Research Articles

Pachymic acid exerts antitumor activities by modulating the Wnt/β-catenin signaling pathway via targeting PTP1B

Objective: To determine the inhibitory effects of pachymic acid on lung adenocarcinoma (LUAD) cells and elucidate its underlying mechanism. Methods: CCK-8, wound healing, Transwell, Western blot, tube formation, and immunofluorescence assays were carried out to measure the effects of various concentrations of pachymic acid on LUAD cell proliferation, metastasis, angiogenesis as well as autophagy. Subsequently, molecular docking technology was used to detect the potential targeted binding association between pachymic acid and protein tyrosine phosphatase 1B (PTP1B). Moreover, PTP1B was overexpressed in A549 cells to detect the specific mechanisms of pachymic acid. Results: Pachymic acid suppressed LUAD cell viability, metastasis as well as angiogenesis while inducing cell autophagy. It also targeted PTP1B and lowered PTP1B expression. However, PTP1B overexpression reversed the effects of pachymic acid on metastasis, angiogenesis, and autophagy as well as the expression of Wnt3a and β-catenin in LUAD cells. Conclusions: Pachymic acid inhibits metastasis and angiogenesis, and promotes autophagy in LUAD cells by modulating the Wnt/β-catenin signaling pathway via targeting PTP1B.

The impact of vitamin D on type 2 diabetes management: boosting PTP1B gene expression and physical activity benefits in rats

BackgroundThe protein tyrosine phosphatase 1B (PTP1B) plays a crucial role in the development of insulin resistance. Aerobic training (AT) and vitamin D (Vit D) supplementation have been shown to individually improve glucose tolerance and diabetes-related factors. However, the impact of their combined effect on PTP1B gene expression and serum irisin in the visceral adipose tissue remains unknown. This study aims to investigate whether 8 weeks of combined AT with Vit D supplementation can improve the expression of PTP1B in adipose tissue and serum irisin in obese rats with type 2 diabetes (T2D).MethodsFifty male Wistar rats were divided into two groups: diabetic (n = 40) and non-diabetic (ND; n = 10). The diabetic rats were further divided into four groups: aerobic training with vitamin D supplementation (D + AT + Vit D; n = 10), aerobic training only (D + AT; n = 10), vitamin D supplementation only (D + Vit D; n = 10), and control (D + C; n = 10). The D + Vit D and D + AT + Vit D groups received 5000 IU of vitamin D via injection once a week, while the D + AT and D + C groups received sesame oil. Diabetes was induced in all groups except the nondiabetic group by intraperitoneal (IP) injection of streptozotocin. At the end of the intervention, blood and adipose tissue samples were collected, and RNA was extracted from adipose tissue for real-time PCR analysis of PPTP1B gene expression.ResultsThere was an increase in serum Vit D and irisin levels and a decrease in HOMA-IR and PTP1B gene expression in the diabetic rat model treated with D + AT and injected with 50,000 IU/kg/week of Vit D. Comparatively, when treated with D + AT + Vit D, the downregulation of PTP1B was significantly higher (p = 0.049; p = 0.004), and there was a significant increase in irisin (p = 0.010; p = 0.001).ConclusionThe present study shows that the combined AT and Vit D supplementation positively impacts the expression of PTP1B in adipose tissue and serum irisin in rats with T2D. These findings suggest that combining AT with Vit D supplementation can provide a new and effective strategy to improve glucose tolerance and diabetes-related factors in individuals with T2D by regulating the expression of PTP1B in adipose tissue and promoting the synthesis of beneficial irisin protein.

Anti-diabetic effect of anthocyanin cyanidin-3-O-glucoside: data from insulin resistant hepatocyte and diabetic mouse

BackgroundAnthocyanins are a group of natural products widely found in plants. They have been found to alleviate the disorders of glucose metabolism in type 2 diabetes mellitus (T2DM), while the underlying mechanisms remain unclear.MethodsHepG2 and L02 cells were incubated with 0.2 mM PA and 30 mM glucose for 24 h to induce IR, and cells treated with 5 mM glucose were used as the control. C57BL/6 J male mice and db/db male mice were fed with a chow diet and gavaged with pure water or cyanidin-3-O-glucoside (C3G) solution (150 mg/kg/day) for 6 weeks.ResultsIn this study, the anthocyanin C3G, extracted from red bayberry, was found to alleviate disorders of glucose metabolism, which resulted in increased insulin sensitivity in hepatocytes, and achieved by enhancing the glucose consumption as well as glycogen synthesis in insulin resistance (IR) hepatpcytes. Subsequently, the expression of key proteins involved in IR was detected by western blotting analysis. Protein tyrosine phosphatase-1B (PTP1B), a negative regulator of insulin signaling, could reduce cellular sensitivity to insulin by inhibiting the phosphorylation of insulin receptor substrate-2 (IRS-2). Results of this study showed that C3G inhibited the increase in PTP1B after high glucose and palmitic acid treatment. And this inhibition was accompanied by increased phosphorylation of IRS proteins. Furthermore, the effect of C3G on improving IR in vivo was validated by using a diabetic db/db mouse model.ConclusionThese findings demonstrated that C3G could alleviate IR in vitro and in vivo to increase insulin sensitivity, which may offer a new insight for regulating glucose metabolism during T2DM by using the natural dietary bioactive components.C3G promotes the phosphorylation of IRS-2 proteins by suppressing the expression of PTP1B, and then enhances the sensitivity of hepatocyte to insulin.

Differences in the expression of the phosphatase PTP-1B in patients with localized prostate cancer with and without adverse pathological features.

Patients with adverse pathological features (APF) at radical prostatectomy (RP) for prostate cancer (PC) are candidates for adjuvant treatment. Clinicians lack reliable markers to predict these APF preoperatively. Protein tyrosine phosphatase 1B (PTP-1B) is involved in migration and invasion of PC, and its expression could predict presence of APF. Our aim was to compare PTP-1B expression in patients with and without APF, and to explore PTP-1B expression as an independent prognostic factor. Tissue microarrays (TMAs) were constructed using RP archival specimens for immunohistochemical staining of PTP-1B; expression was reported with a standardized score (0-9). We compared median PTP-1B score between cases with and without APF. We constructed two logistic regression models, one to identify the independence of PTP-1B score from biologically associated variables (metformin use and type 2 diabetes mellitus [T2DM]) and the second to seek independence of known risk factors (Gleason score and prostate specific antigen [PSA]). A total of 73 specimens were suitable for TMA construction. Forty-four (60%) patients had APF. The median PTP-1B score was higher in those with APF: 8 (5-9) vs 5 (3-8) (p=0.026). In the logistic regression model including T2DM and metformin use, the PTP-1B score maintained statistical significance (OR 1.21, 95% CI 1.01-1.45, p=0.037). In the model including PSA and Gleason score; the PTP-1B score showed no independence (OR 1.68, 95% CI 0.97-1.41, p=0.11). The area under the curve to predict APF for the PTP-1B score was 0.65 (95% CI 0.52-0.78, p=0.03), for PSA+Gleason 0.71 (95% CI 0.59-0.82, p=0.03), and for PSA+Gleason+PTP-1B score 0.73 (95% CI 0.61-0.84, p=0.001). Patients with APF after RP have a higher expression of PTP-1B than those without APF, even after adjusting for T2DM and metformin exposure. PTP-1B has a good accuracy for predicting APF but does not add to known prognostic factors.

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

PurposeMyocardial 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. MethodsThe 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. ResultsLPS 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. ConclusionATX inhibited LPS-induced mitochondrial apoptosis of H9C2 cells by PTP1B/JNK pathway and PTP1B was the target of ATX.

A comprehensive review of anti-diabetic activity of vanadium-based complexes via PTP-1B inhibition mechanism

Inorganic salts of the vanadium have been found to mimic insulin in treating diabetic mellitus. In comparison to inorganic vanadium salts, complexes of vanadium with appropriate organic ligands can improve tissue absorption, efficacy, and reduce toxicity of the metal. An organic vanadyl derivative [bis(ethylmaltolato)oxovanadium(IV)] has been reported as a potential diabetes medication and is currently undergoing phase II clinical trials. The mechanism suggests that vanadium complexes inhibit the enzyme protein tyrosine phosphatase-1B(PTP-1B). Pharmacological, Biochemical and genetic evidences strongly suggest that inhibiting the PTP-1B enzyme could treat both diabetes and obesity, making PTP-1B an interesting target for drug development. Studies have also showed that the over expression of PTP-1B is involved in diabetic and obese patients and its inhibition may be an effective strategy in their treatment. Despite the fact that many natural PTP-1B inhibitors demonstrated promising clinical potential, there is no clinically used PTP-1B inhibitor, most likely due to low activity or a lack of selectivity. Search for more potent and selective PTP-1B inhibitors is still going on. As a result, inhibiting protein tyrosine 1B could be a new therapeutic option for patients at risk of type II diabetes mellitus and obesity. Many vanadium compounds are available as of now, as experimental probes for examining the mechanism of altered insulin action. However more studies are needed to establish its clinical use. Hence it has been proposed to prepare and characterize novel vanadium metal complexes with different coordination environments around vanadyl ion and check their anti diabetes activity.

Assessment of antidiabetic activity of three Phenylspirodrimanes from fungus Stachybotrys chartarum MUT 3308 by ADME, QSAR, molecular docking and molecular dynamics simulation studies against protein tyrosine phosphatase 1B (PTP1B)

Phenylspirodrimanes (PSD) are the sesquiterpene quinone type meroterpenoids found in nature. PSDs are found to exhibit inhibitory activity against immunocomplex diseases, and tyrosine kinase receptors. Three of the different PSDs C1, C2, and C3 that have been reported to be isolated from the sponge-associated fungus Stachybotrys chartarum MUT 3308 are selected for studying their possible inhibitory effect against type 2 diabetes mellitus. Mechanistically, blocking protein tyrosine phosphatase 1B (PTP1B) helps to reduce the insulin resistance induction caused by the high expression of PTP1B. The QSAR, ADME, toxicity (T) study was carried out to predict the pharmacokinetic properties and the biological activities of the PSDs. PASS prediction web tool was used to find and select the target proteins 1NNY, and 2HNP. According to the molecular docking simulations, C1 and C2 showed better binding affinity of −8.5 kcal/mol, and −8.1 kcal/mol respectively against 1NNY compared to the control ligand. RMSD, RMSF, Rg, and SASA analysis revealed that both C1, and C2 showed better stability, minor conformational changes, and minor fluctuation upon binding to PTP1B. Protein contact analysis was carried out to validate the residues that are in contact with the ligands according to molecular docking studies. Overall, C1, and C2 could be proposed as novel natural hits to be developed and small modifications of these PSDs could result in inducing the binding affinity significantly, although experimental validation is required for further evaluation of the work. Communicated by Ramaswamy H. Sarma

PTP1B knockdown alleviates BMSCs senescence via activating AMPK-mediated mitophagy and promotes osteogenesis in senile osteoporosis

The senescence of bone marrow mesenchymal stem cells (BMSCs) is the basis of senile osteoporosis (SOP). Targeting BMSCs senescence is of paramount importance for developing anti-osteoporotic strategy. In this study, we found that protein tyrosine phosphatase 1B (PTP1B), an enzyme responsible for tyrosine dephosphorylation, was significantly upregulated in BMSCs and femurs with advancing chronological age. Therefore, the potential role of PTP1B in BMSCs senescence and senile osteoporosis was studied. Firstly, significantly upregulated PTP1B expression along with impaired osteogenic differentiation capacity was observed in D-galactose (D-gal)-induced BMSCs and naturally-aged BMSCs. Furthermore, PTP1B silencing could effectively alleviate senescence, improve mitochondrial dysfunction, and restore osteogenic differentiation in aged BMSCs, which was attributable to enhanced mitophagy mediated by PKM2/AMPK pathway. In addition, hydroxychloroquine (HCQ), an autophagy inhibitor, significantly reversed the protective effects from PTP1B knockdown. In SOP animal model, transplantation of LVsh-PTP1B-transfected D-gal-induced BMSCs harvested double protective effects, including increased bone formation and reduced osteoclastogenesis. Similarly, HCQ treatment remarkably suppressed osteogenesis of LVsh-PTP1B-transfected D-gal-induced BMSCs in vivo. Taken together, our data demonstrated that PTP1B silencing protects against BMSCs senescence and mitigates SOP via activating AMPK-mediated mitophagy. Targeting PTP1B may represent a promising interventional strategy to attenuate SOP.

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

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. Three extracts of Solidago virgaurea were prepared, and their antidiabetic potentials were evaluated by various cell-free, cell-based, and in vivo studies. 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. Our findings suggested that the Solidago virgaurea extract might have great potential in the prevention and treatment of diabetes.

HM-chromanone from Portulaca oleracea L. inhibits protein tyrosine phosphatase 1B and mitigates glucose production in insulin-resistant HepG2 cells

This study aimed to identify the effect of (E)-5-hydroxy-7-methoxy-3-(2′-hydroxybenzyl)-4-chromanone (HM-chromanone), isolated from Portulaca oleracea L., on tyrosine phosphatase 1B (PTP1B) and glucose production in insulin-resistant HepG2 cells. The results revealed that HM-chromanone significantly decreases PTP1B expression and glucose production in insulin-resistant HepG2 cells. Furthermore, a molecular docking stimulation showed HM-chromanone inhibits PTP1B by binding to its active site. Additionally, HM-chromanone was found to significantly modulate insulin receptor substrate-1 (IRS1) by decreasing phosphorylated serine 307 and increasing phosphorylated tyrosine 612 and activating phosphatidylinositol 3-kinase (PI3K) in insulin-resistant HepG2 cells. Furthermore, HM-chromanone augmented the phosphorylation of Akt and forkhead box protein O1 in insulin-resistant HepG2 cells in a dose-dependent manner at the concentrations of 15–60 μM. Additionally, it significantly reduced the expression of glucose 6-phosphatase and phosphoenolpyruvate carboxykinase, which are main enzymes included in hepatic gluconeogenesis. Consequently, HM-chromanone was confirmed to significantly decrease glucose production and increase glucose uptake in insulin-resistant HepG2 cells.

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.

Ursonic acid from Artemisia montana exerts anti-diabetic effects through anti-glycating properties, and by inhibiting PTP1B and activating the PI3K/Akt signaling pathway in insulin-resistant C2C12 cells

Artemisia is one of the largest genera in the plant family Asteraceae and has long been used in traditional medicine for its antitussive, analgesic, antihypertensive, antitoxic, antiviral, antimalarial, and anti-inflammatory properties. However, the anti-diabetic activity of Artemisia montana has not been broadly studied. The goal of this study was to determine whether extracts of the aerial parts of A. montana and its main constituents inhibit protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase activities. We isolated nine compounds from A. montana including ursonic acid (UNA) and ursolic acid (ULA), which significantly inhibited PTP1B with IC50 values of 11.68 and 8.73 μM, respectively. In addition, UNA showed potent inhibitory activity against α-glucosidase (IC50 = 61.85 μM). Kinetic analysis of PTP1B and α-glucosidase inhibition revealed that UNA was a non-competitive inhibitor of both enzymes. Docking simulations of UNA demonstrated negative binding energies and close proximity to residues in the binding pockets of PTP1B and α-glucosidase. Molecular docking simulations between UNA and human serum albumin (HSA) revealed that UNA binds tightly to all three domains of HSA. Furthermore, UNA significantly inhibited fluorescent AGE formation (IC50 = 4.16 μM) in a glucose-fructose-induced HSA glycation model over the course of four weeks. Additionally, we investigated the molecular mechanisms underlying the anti-diabetic effects of UNA in insulin-resistant C2C12 skeletal muscle cells and discovered that UNA significantly increased glucose uptake and decreased PTP1B expression. Further, UNA increased GLUT-4 expression level by activating the IRS-1/PI3K/Akt/GSK-3 signaling pathway. These findings clearly demonstrate that UNA from A. montana shows great potential for treatment of diabetes and its complications.

Cinnamaldehyde supplementation acts as an insulin mimetic compound improving glucose metabolism during adolescence, but not during adulthood, in healthy male rats.

Adolescence is a critical period of increased vulnerability to nutritional modifications, and adolescents may respond differently from adults to dietary intake and nutraceuticals. Cinnamaldehyde, a major bioactive compound of cinnamon, improves energy metabolism, as has been shown in studies conducted primarily in adult animals. We hypothesized that cinnamaldehyde treatment may have a higher impact on the glycemic homeostasis of healthy adolescent rats than on healthy adult rats. Male adolescent (30 days) or adult (90 days) Wistar rats received cinnamaldehyde (40 mg/kg) for 28 days by gavage. The oral glucose tolerance test (OGTT), liver glycogen content, serum insulin concentration, serum lipid profile, and hepatic insulin signaling marker expression were evaluated. Cinnamaldehyde-treated adolescent rats showed less weight gain (P = 0.041), improved OGTT (P = 0.004), increased expression of phosphorylated IRS-1 (P = 0.015), and a trend to increase phosphorylated IRS-1 (P = 0.063) in the liver of adolescent rats in the basal state. None of these parameters was modified after treatment with cinnamaldehyde in the adult group. Cumulative food intake, visceral adiposity, liver weight, serum insulin, serum lipid profile, hepatic glycogen content, and liver protein expression of IRβ, phosphorylated IRβ, AKT, phosphorylated AKT, and PTP-1B in the basal state were similar between both age groups. In a healthy metabolic condition, cinnamaldehyde supplementation affects glycemic metabolism in adolescent rats while promoting no changes in adult rats.

Efficacy of Young Cinnamomum zeylanicum Blume Bark on Hyperglycemia and PTPase Activity in Type 2 Diabetes.

Diabetes is a major public health concern and natural easy-going remedies are being searched. Since Cinnamomum zeylanicum Blume has a low coumarin concentration and possibleinsulin-enhancing properties, it is preferred over all other cinnamon species. Although similar research has been done on humans, there have been very few studies on this particular species, and none among South Asians. Moreover, no human trial that properly described their intervening agent (C. zeylanicum) and checked its efficacy at the molecular level along with clinical variables was conducted. Therefore, the current research aimed to explore the effects of C. zeylanicum on the glycemic index, lipid profile, and expression of the protein tyrosine phosphatase 1 B (PTP1B) enzyme in the peripheral blood mononuclear cells (PBMC) in type 2 diabetes. We examined the presence of bioactive compounds in young C. zeylanicum bark (Alba grade) from native Sri Lanka using gas chromatography-mass spectrometry, high-performance thin-layer chromatography, and thin-layer chromatography before introducing it in the clinical study where trans-Cinnamaldehyde was found to be a major chemical constituent (>60%). Then, from January 2020 to March 2022, a randomized double-blinded placebo-controlled trial was carried out in the Diabetic Clinic at AIIMS Rishikesh. A total of 154 diabetic patients were enrolled and were taken either cinnamon or placebo capsules (1.5 g/day) for 120 days on an empty stomach with warm water along with their conventional treatment. Reduction in fasting blood glucose levels in the cinnamon group was found -35.50% (95% CI, -173 to 58.4), whereas in the placebo group change was 5.00% (95% CI, -165 to 224). For glycosylated hemoglobin, it differed -0.85% (95% CI, -8.2 to 1.6) in the cinnamon group compared to the placebo where it was found 0.15% (95% CI, -6.1 to 5.5).PTP1B expression in PBMC was determined from pre- and post-trial blood samples using the Western Blot, and significant inhibition was also observed (p=0.039).The study result depicts, C. zeylanicum is emerging as a beneficial plant for type 2 diabetes in Northern India and could be used as an adjunctive treatment rather than as a standalone managerial remedy.

Comprehensive Bioinformatics Analysis Reveals PTPN1 (PTP1B) Is a Promising Immunotherapy Target Associated with T Cell Function for Liver Cancer.

Recently, PTP1B was identified as a novel immune checkpoint whose removal can unleash T cell responses. However, research on the influence of PTP1B as an immune regulator on liver cancer is limited. This study aimed to investigate the immunological correlation and function of PTP1B in liver cancer. The expression profiles and corresponding clinical information of liver cancer patients were obtained from the TCGA and ICGC databases. GSE146115 and GSE98638 retrieved from the GEO database were used for the single-cell RNA-seq analysis. The mRNA expression of PTP1B (PTPN1) was increased in patients with most malignancies (all p < 0.05), including liver cancer (p < 0.001). Furthermore, up-regulated PTPN1 was connected to advanced tumor stage (p < 0.05) and worse prognosis (p < 0.01) in liver cancer. Through Cox regression analysis, PTPN1 was considered as an independent prognosis factor of overall survival (p < 0.05) and acted as a high-risk factor (hazard ratio > 1). Gene function and pathway analysis suggested PTPN1 was involved in T cell-related immune responses. Moreover, a close relationship was also found between PTPN1 expression and immune checkpoints as well as immune cells, especially with T cell-related checkpoints (all p < 0.001) and T cells (all p < 0.001). Single-cell RNA-seq analysis further illustrated that the enrichment of PTPN1 in the T cell population may be linked to its exhaustion in the liver cancer microenvironment. Overall, PTPN1 (PTP1B) closely related to T cell may function as an immunotherapy target for liver cancer.

Thiourea derivatives inhibit key diabetes-associated enzymes and advanced glycation end-product formation as a treatment for diabetes mellitus.

This study was designed to screen novel thiourea derivatives against different enzymes, such as α-amylase, α-glucosidase, protein tyrosine phosphatase 1 B, and advanced glycated end product (AGEs). A cytotoxicity analysis was performed using rat L6 myotubes and molecular docking analysis was performed to map the binding interactions between the active compounds and α-amylase and α-glucosidase. The data revealed the potency of five compounds, including E (1-(2,4-difluorophenyl)-3-(3,4-dimethyl phenyl) thiourea), AG (1-(2-methoxy-5-(trifluoromethyl) phenyl)-3-(3-methoxy phenyl) thiourea), AF (1-(2,4-dichlorophenyl)-3-(4-ethylphenyl) thiourea), AD (1-(2,4-dichlorophenyl)-3-(4-ethylphenyl) thiourea), and AH (1-(2,4-difluorophenyl)-3-(2-iodophenyl) thiourea), showed activity against α-amylase. The corresponding percentage inhibitions were found to be 85 ± 1.9, 82 ± 0.7, 75 ± 1.2, 72 ± 0.4, and 65 ± 1.1%, respectively. These compounds were then screened using in vitro assays. Among them, AH showed the highest activity against α-glucosidase, AGEs, and PTP1B, with percentage inhibitions of 86 ± 0.4% (IC50 =47.9μM), 85 ± 0.7% (IC50 =49.51 μM), and 85 ± 0.5% (IC50 =79.74 μM), respectively. Compound AH showed an increased glucose uptake at a concentration of 100 μM. Finally, an in vivo study was conducted using a streptozotocin-induced diabetic mouse model and PTP1B expression was assessed using real-time PCR. Additionally, we examined the hypoglycemic effect of compound AH in diabetic rats compared to the standard drug glibenclamide.

Multi-omics analyses of tumor-associated immune-infiltrating cells with the novel immune checkpoint protein tyrosine phosphatase 1B (PTP1B) in extracellular matrix of brain-lower-grade-glioma (LGG) and uveal-melanoma (UVM).

Immune checkpoint inhibitors represented by PD-1 have greatly changed the way cancer is treated. In addition to PD-1, new immune checkpoints are constantly excavated to better treat cancer. Recently, protein tyrosine phosphatase 1B (PTP1B) was identified as a new immune checkpoint and played a critical role in the treatment of tumors by inhibiting the proliferation and cytotoxicity of T cells induced by tumor antigen. To explore the targeting role of PTP1B in precision tumor therapy, we deeply analyzed the expression and prognosis of PTP1B in all tumors. Survival analysis results indicated that PTP1B was highly expressed in most tumor tissues and indicated poor prognosis in acute-myeloid-leukemia (LAML), brain-lower-grade-glioma (LGG), kidney-renal clear-cell-carcinoma (KIRC) and uveal-melanoma (UVM). The methylation status of PTP1B in these four tumors exhibited hypomethylation and mutation landscape showed that PTP1B had its specific characteristics in genomic instability and heterogeneity. The homologous recombination deficiency (HRD) and loss of heterozygosity (LOH) were positive related to PTP1B expression in liver-hepatocellular-carcinoma (LIHC) and kidney-chromophobe (KICH), while the immunescore and immune infiltration displayed a significant positive correlation with PTP1B expression in LGG and UVM. Drug sensitivity tests showed that the PTP1B inhibitor MSI-1436 had a sensitivity effect suppressing tumor cell viability and suggested it enhanced the efficacy of PD-1 inhibitors in cancers.

The role of PTP1B (PTPN1) in the prognosis of solid tumors: A meta-analysis.

Background:Protein tyrosine phosphatase 1B (PTP1B) played different role in different solid tumors, and was associated with the prognosis of solid tumors. However, the roles existed controversy. This meta-analysis was performed to determine whether PTP1B was relevant to the prognosis of solid tumors.Materials and methods:A literature search in Web of Science, Embase and PubMed databases were performed up to November 1, 2021. A meta-analysis dealed with PTP1B assessment in solid tumors, providing clinical stages and survival comparisons according to the PTP1B status.Results:High PTP1B expression was significantly associated with later clinical stage of solid tumors (Odds ratio [OR] 2.25, 95% confidence interval [CI]: 1.71–2.98, P < .001). For solid tumors, the hazard ratio (HR) for disease free survival (DFS) detrimental with high PTP1B expression compared with low PTP1B expression was 1.07 (95%CI: 0.67–1.73, P = .77) with the obvious heterogeneity (P = .03, I2 = 66%). The HR of overall survival (OS) for solid tumors with high PTP1B expression versus low PTP1B expression was 1.26 (95%CI: 1.03–1.55, P = .03) with significant publication bias (t = 3.28, P = .005). Subgroup analysis indicated that the high expression of PTP1B was remarkably correlated with poor OS in colorectal carcinoma, only (HR = 1.43; 95%CI: 1.18–1.74; P = .003).Conclusions:High PTP1B expression is significantly associated with later clinical stage of solid tumors. The high expression of PTP1B is remarkably correlated with poor OS in colorectal carcinoma, only. There is no definite conclusion that PTP1B was, or not associated with DFS and OS of solid tumors because of heterogeneity and publication bias. Whether PTP1B can be used as a biomarker for predicting the prognosis of solid tumors needs further study.

Overexpression of miR-210 ameliorates endothelial dysfunction in type 2 diabetic mice

Abstract Background MicroRNA (miR)-210 plays a protective role in many cardiometabolic diseases, and its levels are reduced in whole blood, erythrocytes, and plasma in type 2 diabetes mellitus (T2DM). Our recent study demonstrated that miR-210 is downregulated in carotid artery plaques from patients with T2DM compared to non-diabetic patients. However, the functional role of miR-210 in endothelial dysfunction is not fully understood. Purpose This study aimed to investigate the potential therapeutic value of miR-210 overexpression against T2DM-associated endothelial dysfunction. Methods miR-210 transgenic mice (TG) at age of 8 weeks were subjected to Western Diet (WD) for 12 weeks. During the last 10 days of the diet regime, doxycycline or vehicle dissolved in drinking water was given to switch on miR-210 (miR-210/on) expression or keep it off (miR-210/off), respectively. Age-matched wild-type (WT) control mice received normal chow through the same period. Additionally, WT and T2DM db/db mice at age of 15–20 weeks received tail vein injections of miR-210 mimic or miR-210 scramble oligonucleotides. All animals were euthanized at the end of the treatment or 72h after the i.v. injections for determination of endothelial function by acetylcholine-induced endothelium-dependent relaxation (EDR) of isolated aortic segments from all groups of mice using wire myographs. The expression of protein tyrosine phosphatase 1B (PTP1B; a miR-210 target protein) and the levels of 4-hydroxynonenal (4-HNE; an oxidative stress marker) were measured in aortic segments by immunohistochemistry. All animal experiments and procedures were performed according to the guidelines by the U.S National Institutes of Health (NIH publication no 85–23, revised 1996). Results EDR in aortic segments from miR-210/off TG mice fed WD and T2DM db/db mice injected with miR-210 scramble was significantly impaired compared to vessels from WT controls fed with regular chow (Fig. 1A, B). Of note, EDR was markedly improved or even restored in aortae from miR-210/on TG mice treated with WD and T2DM db/db mice injected with miR-210 mimic (Fig. 1A, B). Furthermore, the expression of PTP1B and the levels of 4-HNE, which is formed by lipid peroxidation, were significantly elevated in the aortae from miR-210/off TG mice treated with WD when compared to WT controls (Fig. 2A–D). The expression was attenuated in aortae of miR-210/on TG mice treated with WD compared to miR-210/off TG mice (Fig. 2A–D). There was a significant increase in the expression of PTP1B and a trend to increased 4-HNE levels in aortae of db/db mice injected with miR-210 scramble vs. control mice (Fig. 2E–H). A significant reduction in PTP1B but not 4-HNE was observed in db/db mice injected with miR-210 mimic (Fig. 2E–H). Conclusion Genetic and pharmacological overexpression of miR-210 ameliorates endothelial dysfunction in mice fed with WD and db/db mice. Increasing miR-210 levels may become a potential treatment strategy. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Swedish Heart and Lung Foundation

6-Formyl Umbelliferone, a Furanocoumarin from Angelica decursiva L., Inhibits Key Diabetes-Related Enzymes and Advanced Glycation End-Product Formation.

Over the years, great attention has been paid to coumarin derivatives, a set of versatile molecules that exhibit a wide variety of biological activities and have few toxic side effects. In this study, we investigated the antidiabetic potential of 6-formyl umbelliferone (6-FU), a novel furanocoumarin isolated from Angelica decursiva. Numerous pharmacological activities of 6-FU have been previously reported; however, the mechanism of its antidiabetic activity is unknown. Therefore, we examined the action of 6-FU on a few candidate-signaling molecules that may underlie its antidiabetic activity, including its inhibition of protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, human recombinant aldose reductase (HRAR), and advanced glycation end-product (AGE) formation (IC50 = 1.13 ± 0.12, 58.36 ± 1.02, 5.11 ± 0.21, and 2.15 ± 0.13 μM, respectively). A kinetic study showed that 6-FU exhibited mixed-type inhibition against α-glucosidase and HRAR and competitive inhibition of PTP1B. Docking simulations of 6-FU demonstrated negative binding energies and close proximity to residues in the binding pockets of those enzymes. We also investigated the molecular mechanisms underlying 6-FU’s antidiabetic effects. 6-FU significantly increased glucose uptake and decreased PTP1B expression in insulin-resistant C2C12 skeletal muscle cells. Moreover, 6-FU (0.8–100 μM) remarkably inhibited the formation of fluorescent AGEs in glucose-fructose-induced human serum albumin glycation over the course of 4 weeks. The findings clearly indicate that 6-FU will be useful in the development of multiple target-oriented therapeutic modalities for the treatment of diabetes and diabetes-related complications.