PTPN11 Research Articles

Analogues of Dihydroflavonol and Flavone as Protein Tyrosine Phosphatase 1B Inhibitors from the Leaves of Artocarpus elasticus.

Protein tyrosine phosphatase 1B (PTP1B) is one of the target enzymes whose disruption leads to obesity and diabetes. A series of PTP1B inhibitors were isolated from the leaves of Artocarpus elasticus, used in traditional medicines for diabetes. The isolated inhibitors (1-13), including two new compounds (1 and 2), consisted of dihydroflavonols and flavones. The structural requirements for the PTP1B inhibitory mode and potency were revealed in both skeletons. The two highest PTP1B inhibitory properties were dihydroflavonol 1 and flavone 6 analogs with IC50 values of 0.17 and 0.79 μM, respectively. The stereochemistry also affected inhibitory potencies: trans isomer 1 (IC50= 0.17 μM) vs cis isomer 2 (IC50= 2.24 μM). Surprisingly, the dihydroflavonol and flavone glycosides (11 and 13) displayed potent inhibition with IC50s of 2.39 and 0.22 μM, respectively. Furthermore, competitive inhibitor 1 was applied to time-dependence experiments as a simple slow-binding inhibitor with parameters of Kiapp = 0.064103 μM, k3 = 0.2262 μM-1 min-1, and k4 = 0.0145 min-1. The binding affinities by using the fluorescence quenching experiment were highly correlated with inhibitory potencies: 1 (IC50= 0.17 μM, KSV = 0.4375 × 105 L·mol-1) vs 3 (IC50= 17.79 μM, KSV = 0.0006 × 105 L·mol-1). The specific binding interactions were estimated at active and allosteric sites according to the inhibitory mode by molecular docking.

Pyrazole Scaffold: Potential PTP1B Inhibitors for Diabetes Treatment.

The overexpression of the Protein Tyrosine Phosphatase 1B (PTP1B), a key role in the development of insulin resistance, diabetes (T2DM) and obesity, seems to have a substantial impact as a negative regulator of the insulin and leptin signaling pathways. Therefore, inhibiting PTP1B is a prospective therapeutic approach for the treatment of diabetes and obesity. However, the pyrazole scaffold is expected to be of significant pharmaceutical interest due to its broad spectrum of pharmacological actions. This study aims to focus on the significance of pyrazole scaffold in medicinal chemistry, the impact of PTP1B in diabetes and the therapeutic approach of pyrazole scaffold to treat T2DM. A comprehensive analysis of the published literature in several pharmaceutical and medical databases, such as the Web of Science (WoS), PubMed, ResearchGate, ScienceDirect etc., were indeed successfully completed and classified accordingly. Results: As reviewed, the various derivatives of the pyrazole scaffold exhibited prominent PTP1B inhibitory activity. The result showed that derivatives of oxadiazole and dibenzyl amine, chloro substituents, 1, 3-diaryl pyrazole derivatives with rhodanine-3-alkanoic acid groups, naphthalene and also 1, 3, 5-triazine-1H-pyrazole-triazolothiadiazole derivatives, octyl and tetradecyl derivative, indole- and N-phenylpyrazole-glycyrrhetinic acid derivatives with trifluoromethyl group, 2,3-pyrazole ring-substituted-4,4-dimethyl lithocholic acid derivatives with 4- fluoro phenyl substituted and additional benzene ring in the pyrazole scaffold significantly inhibits PTP1B. In silico study observed that pyrazole scaffold interacted with amino acid residues like TYR46, ASP48, PHE182, TYR46, ALA217 and ILE219. Diabetes is a metabolic disorder that elevates the risk of mortality and severe complications. PTP1B is a crucial component in the management of diabetes and obesity. As a result, PTP1B is a promising therapeutic target for the treatment of T2DM and obesity in humans. We concluded that the pyrazole scaffold has prominent inhibitory potential against PTP1B.

The Missing Piece of the Puzzle: Unveiling the Role of PTPN11 Gene in Multiple Osteochondromas in a Large Cohort Study

This study is aimed at investigating the clinical and genetic characteristics of 244 unrelated probands diagnosed with multiple osteochondromas (MO). The diagnosis of MO typically involves identifying multiple benign bone tumors known as osteochondromas (OCs) through imaging studies and physical examinations. However, cases with both OCs and enchondromas (ECs) may indicate the more rare condition metachondromatosis (MC), which is assumed to be distinct disease. Previous cohort studies of MO found heterozygous loss-of-function (LoF) variants only in the EXT1 or EXT2 genes, with DNA diagnostic yield ranging from 78 to 95%. The PTPN11 gene, which is causative for MC, was not previously investigated as a gene candidate for MO. In this study, we detected a total of 177 unique single nucleotide and copy number variants in three genes across 220 probands, consisting of 80 previously reported and 97 novel variants. Specifically, we identified five cases with OCs and no ECs as well as four cases with MC carrying LoF variants in the PTPN11 gene and two additional cases with ECs harboring variants in the EXT1/2 genes. These findings suggest a potential overlap between the MO and MC both phenotypically and genetically. These findings highlight the importance of expanding genetic testing beyond the EXT1 and EXT2 genes in MO cases, as other genes such as PTPN11 may also be causative. This can improve the accuracy of diagnosis and treatment for individuals with MO and MC. It is essential to determine whether MO and MC represent distinct diseases or if they encompass a broader clinical spectrum.

Computer-Aided Strategy on 5-(Substituted benzylidene) Thiazolidine-2,4-Diones to Develop New and Potent PTP1B Inhibitors: QSAR Modeling, Molecular Docking, Molecular Dynamics, PASS Predictions, and DFT Investigations.

A set of 5-(substituted benzylidene) thiazolidine-2,4-dione derivatives was explored to study the main structural requirement for the design of protein tyrosine phosphatase 1B (PTP1B) inhibitors. Utilizing multiple linear regression (MLR) analysis, we constructed a robust quantitative structure-activity relationship (QSAR) model to predict inhibitory activity, resulting in a noteworthy correlation coefficient (R2) of 0.942. Rigorous cross-validation using the leave-one-out (LOO) technique and statistical parameter calculations affirmed the model's reliability, with the QSAR analysis revealing 10 distinct structural patterns influencing PTP1B inhibitory activity. Compound 7e(ref) emerged as the optimal scaffold for drug design. Seven new PTP1B inhibitors were designed based on the QSAR model, followed by molecular docking studies to predict interactions and identify structural features. Pharmacokinetics properties were assessed through drug-likeness and ADMET studies. After that density functional theory (DFT) was conducted to assess the stability and reactivity of potential diabetes mellitus drug candidates. The subsequent dynamic simulation phase provided additional insights into stability and interactions dynamics of the top-ranked compound 11c. This comprehensive approach enhances our understanding of potential drug candidates for treating diabetes mellitus.

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.

Protein tyrosine phosphatase 1B contributes to neuropathic pain by aggravating NF-κB and glial cells activation-mediated neuroinflammation via promoting endoplasmic reticulum stress.

Neuropathic pain is a prevalent and highly debilitating condition that impacts millions of individuals globally. Neuroinflammation is considered a key factor in the development of neuropathic pain. Accumulating evidence suggests that protein tyrosine phosphatase 1B (PTP1B) plays a crucial role in regulating neuroinflammation. Nevertheless, the specific involvement of PTP1B in neuropathic pain remains largely unknown. This study aims to examine the impact of PTP1B on neuropathic pain and unravel the underlying molecular mechanisms implicated. In the current study, we evaluated the paw withdrawal threshold (PWT) of male rats following spared nerve injury (SNI) to assess the presence of neuropathic pain. To elucidate the underlying mechanisms, western blotting, immunofluorescence, and electron microscopy techniques were employed. Our results showed that SNI significantly elevated PTP1B levels, which was accompanied by an increase in the expression of endoplasmic reticulum (ER) stress markers (BIP, p-PERK, p-IRE1α, and ATF6) and phosphorylated NF-κB in the spinal dorsal horn. SNI-induced mechanical allodynia was impaired by the treatment of intrathecal injection of PTP1B siRNA or PTP1B-IN-1, a specific inhibitor of PTP1B. Moreover, the intrathecal administration of PTP1B-IN-1 effectively suppressed the expression of ER stress markers (BIP, p-PERK/p-eIF2α, p-IRE1α, and ATF6), leading to the inhibition of NF-κB, microglia, and astrocytes activation, as well as a decrease in pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β. However, these effects were reversed by intrathecal administration of tunicamycin (Tm, an inducer of ER stress). Additionally, intrathecal administration of Tm in healthy rats resulted in the development of mechanical allodynia and the activation of NF-κB-mediated neuroinflammatory signaling. The upregulation of PTP1B induced by SNI facilitates the activation of NF-κB and glial cells via ER stress in the spinal dorsal horn. This, in turn, leads to an increase in the production of pro-inflammatory cytokines, thereby contributing to the development and maintenance of neuropathic pain. Therefore, targeting PTP1B could be a promising therapeutic strategy for the treatment of neuropathic pain.

Interactions between TNFAIP3, PTPN22, and TRAF1-C5 gene polymorphisms in patients with primary Sjögren's syndrome.

The aim of our study was to investigate whether TNFAIP3, PTPN22, and TRAF1-5 single nucleotide polymorphisms (SNPs) are associated with susceptibility, severity, or serological markers in primary Sjögren's syndrome (pSS). The cases and controls study was conducted between December 2021 and June 2022. TNFAIP3 rs10499194C/T, rs6920220G/A, and rs2230926T/G, PTPN22 rs2476601C/T and rs33996649G/A, and TRAF1-C5 rs10818488G/A polymorphisms were genotyped in 154 female pSS patients (mean age: 45.2±6.8 years) and 313 female control subjects (mean age: 50.3±7.5 years) using the TaqMan® SNP genotyping assay. An association analysis between TNFAIP3, PTPN22, and TRAF1-C5 SNPs and susceptibility, clinical characteristics, and serological markers of pSS was performed. Interactions between TNFAIP3, PTPN22, and TRAF1-C5 SNPs were also evaluated in patients and controls. The genotype and allele frequencies showed no association with susceptibility, severity, or serological markers of pSS. Nevertheless, several interactions between TNFAIP3 and TRAF1-C5 or TNFAIP3, PTPN22, and TRAF1-C5 genotypes were associated with susceptibility to pSS (p<0.01). Individual TNFAIP3, PTPN22, and TRAF1-C5 SNPs are not associated with susceptibility, severity, or serological markers of pSS. However, genetic interactions between TRAF1-C5 and TNFAIP3 or TNFAIP3, PTPN22, and TRAF1-C5 SNPs are risk factors for pSS.

An in silico analysis of the interaction of marine sponge-derived bioactive compounds with type 2 diabetes mellitus targets DPP-4 and PTP1B

Type 2 diabetes is a medical condition involving elevated blood glucose levels resulting from impaired or improper insulin utilization. As the number of type 2 diabetes cases increases each year, there is an urgent need to develop novel drugs having new targets and/or complementing existing therapeutic protocols. In this regard, marine sponge-derived compounds hold great potential due to their potent biological activity and structural diversity. In this study, a small library of 50 marine sponge-derived compounds were examined for their activity towards type 2 diabetes targets, namely dipeptidyl peptidase-4 (DPP-4) and protein tyrosine phosphatase 1B (PTP1B). The compounds were first subjected to molecular docking on protein models based on their respective co-crystal structures to assess binding free energies (BFE) and conformations. Clustering analysis yielded BFE that ranged from 24.54 kcal/mol to −9.97 kcal/mol for DPP-4, and from −4.98 kcal/mol to −8.67 kcal/mol for PTP1B. Interaction analysis on the top ten compounds with the most negative BFE towards each protein target showed similar intermolecular interactions and key interacting residues as in the previously solved co-crystal structure. These compounds were subjected to absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling to characterize drug-likeness and combining the results from these analyses, (S)-6’-debromohamacanthin B was identified as a potential multi-target inhibitor of DPP-4 and PTP1B, having favorable protein interaction, no Lipinski violations, good gastrointestinal (GI) tract absorption, blood-brain barrier (BBB) penetration, and no predicted toxicity. Finally, the interaction of (S)-6’-debromohamacanthin B with the two proteins was validated using molecular dynamics simulations over 100 ns through RMSD, radius of gyration, PCA, and molecular mechanics Poisson-Boltzmann surface area (MMPBSA) confirming favorable interactions with the respective proteins. Communicated by Ramaswamy H. Sarma

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.

Development, biological evaluation, and molecular modelling of some benzene-sulfonamide derivatives as protein tyrosine phosphatase-1B inhibitors for managing diabetes mellitus and associated metabolic disorders.

Exploring new inhibitors with good bioavailability and high selectivity for managing type 2 diabetes mellitus (T2DM) and its associated complications is a major challenge for research, academia, and the pharmaceutical industry. Protein tyrosine phosphatase-1B (PTP1B) arose as an important negative regulator in insulin signaling pathways associated with metabolic disorders, including T2DM and obesity. Novel neutral compounds with a benzene-sulfonamide scaffold were designed and synthesized based on structural- and ligand-based drug design strategies for fragment growth. Promising hits against PTP1B were identified through in vitro enzymology inhibition assay. Mechanistic aspects of the compound's different inhibition activities were rigorously investigated through molecular docking coupled with explicit dynamics simulations. Four identified hits, 3c, 8, 10a, and 11, with sub-micromolar PTP-1B IC50 and significant predicted pharmacokinetic and pharmacodynamic parameters, were further biologically evaluated for their anti-diabetic, anti-obesity, anti-inflammatory, and anti-oxidant effects in a high-fat diet (HFD) + streptozotocin (STZ)-induced T2DM rat model. All these hit compounds exhibited a significant anti-diabetic and anti-obesity effect and a significant efficacy in reducing oxidative stress and increasing anti-oxidant enzymes while reducing inflammatory markers. Improving compound potency was further highlighted by improving the pharmacokinetic profile of the most active compound, 10a, through nano formulation. Compound 10a nano formulation showed the most promising anti-diabetic and anti-obesity effects and a remarkable histopathological improvement in all organs studied.

Unveiling the potential of marine-derived diterpenes from the order Alcyonacea as promising anti-obesity agents

Metabolic syndrome (MS) represents a global health challenge characterized by various metabolic disorders, including HOMA-IR (insulin resistance), obesity, dyslipidemia, and hypertension. In our pursuit of identifying natural alternatives for the development of effective and safe anti-obesity medications, we examined the potential of the methanolic extract of the Red Sea derived soft coral Sarcophyton glaucum, where serum levels of glucose, insulin, HOMA-IR, lipid profile, fetuin A and B, PTP1Β (Protein tyrosine phosphatase 1B), adropin and omentin were determined. Furthermore, the expression of the UCP1 (Uncoupling protein 1) and PPARGC1A (Peroxisome proliferator–activated receptor-g coactivator-1a) genes have been assessed, to evaluate the anti-obesity potential of S. glaucum organic extract. Our findings demonstrated a significant decrease in glucose, HOMA-IR, cholesterol, triglyceride, LDL-C, fetuin A and B, and PTP1Β levels, accompanied by a significant increase in insulin, HDL-C, adropin, omentin, UCP1, and PPARGC1A expression after treatment with the soft coral extract. These promising outcomes can be attributed to the remarkable ingredients present in the extract, which were further supported by histopathological findings. In addition, a virtual screening protocol including molecular docking (MDock) and Structure-Activity Relationships (SARs) of 27 marine diterpenes was also explored to identify potential PTP1Β inhibitors targeting simultaneously the catalytic site and allosteric site, as well as fetuin A modulators. Moreover, the six most promising predicted marine diterpenes (4, 8, 9, 10, 13 and 14) were investigated for their pharmacokinetic properties, druglike nature and medicinal chemistry friendliness using the SwissADME platform. Of these, four marine diterpenes (4, 8, 9, and 10) were predicted to exhibit the appropriate drug-like properties.

Potential protein tyrosine phosphatase 1B and α-glucosidase inhibitory flavonoids from Erythrina variegata: Experimental and computational results

Erythrina variegata L., a member of the Fabaceae family, is a valuable medicinal plant with a rich history of traditional medicinal uses. However, its potential as an antidiabetic agent has remained largely unexplored. In this study, three isoflavonoid compounds, namely eryvarin M (1), eryvarin H (2), and neobavaisoflavone (3), were isolated from E. variegata. These compounds displayed significant inhibitory effects on both protein tyrosine phosphatase 1B and α-glucosidase enzymes. The specific attachment position of the prenyl group to the isoflavonoid skeleton plays a pivotal role in determining the variation in their activity. Moreover, the results obtained from docking simulations corroborate the experimental findings, confirming the robust binding affinities of these metabolites toward the target proteins. The docking analysis further highlights that these compounds exhibit highly negative values of binding-free energies against proteins, indicative of their favorable binding affinities. In addition, the formation of hydrogen bonds in the binding region contributes to their binding interactions. These findings significantly enhance our understanding of the therapeutic potential of both E. variegata and its isoflavonoids as potential inhibitors for diabetes and related metabolic disorders, shedding light on their promising role in the field of diabetes research.

Leopard syndrome without lentigenes: A rare presentation and literature review

Abstract: Leopard syndrome (LS) has presentations of lentigines, conduction abnormalities in the heart, hypertelorism of the eyes, stenosis of the pulmonary artery, cryptorchidism, mental retardation, and sensorineural deafness. Another condition known as Noonan syndrome (NS) has many overlapping symptoms. LS is due to germ-line mutations in the PTPN11 gene. The same genetic mutation also leads to NS. Here, we described a 10-year-old male child presented with failure to thrive, decreased appetite, large atrial septal defect, and developmental delay and later on diagnosed with LS by whole-genome sequencing. In this case, characteristic lentigines are absent, which puts the pediatrician in a dilemma. However, by using the diagnostic criteria set by Voron since 1976, we are able to reach a clinical diagnosis of LS.

Site Identification by Ligand Competitive Saturation (SILCS) Based Design and Synthesis of Novel Allosteric Inhibitors of Protein Tyrosine Phosphatase 1B (PTP 1B)

Site Identification by Ligand Competitive Saturation (SILCS) Based Design and Synthesis of Novel Allosteric Inhibitors of Protein Tyrosine Phosphatase 1B (PTP 1B)

Role of apigenin in targeting metabolic syndrome: A systematic review.

Metabolic syndrome (MetS) is a cluster of metabolic abnormalities that has a high prevalence worldwide. Apigenin is a flavonoid present in several vegetables and fruits and has anti-inflammatory, anti-oxidant, and anti-MetS properties. This study aims to systematically review the effects of apigenin against MetS and the relevant molecular and cellular mechanisms of action, pharmacokinetics features, and potential structure-activity relationship. Electronic databases including Scopus, PubMed, Science Direct and Cochrane Library were searched for in vivo, and in vitro, and human studies with the following keywords: "apigenin" and "metabolic syndrome or insulin resistance syndrome", "fatty liver", "hypertension or blood pressure", "diabetes or blood glucose", "dyslipidemia", "heart or cardiovascular " and "obesity" in title/abstract. Data were collected from 2000 until 2021 (up to April). Only papers published in the English language were included. Forty-six full-text articles out of 1016 retrieved papers were reviewed and underwent quality assessment by investigators. Anti-obesity activity of apigenin is mainly through attenuating adipocyte differentiation by suppressing the mitotic clonal expansion and the adipogenesis-related factors. Its anti-diabetic effects can be exerted through inhibition of protein tyrosine phosphatase1B expression, maintaining the activity of anti-oxidant enzymes, reducing intracellular ROS production, cellular DNA damage, protein carbonylation, and attenuating β-cell apoptosis. Moreover, apigenin could attenuate dyslipidemia and subsequent atherosclerotic conditions through down-regulating sterol regulatory element-binding proteins (SREBP)-1c, SREBP-2, stearyl-CoA desaturase-1, and 3-hydroxy-3-methyl-glutaryl-CoA reductase. Apigenin as a dietary bioactive compound would be a promising candidate for improving MetS and its components.

Detection of pathogenic variants related to severe dominant monogenic diseases by non-invasive prenatal testing (NIPT-SGD)

Non-invasive prenatal testing (NIPT) as a screening method for common chromosomal abnormalities such as trisomy 21, 18, and 13 has been widely adopted. In the last five years, the possibility of NIPT to detect common single-gene disorders (SGD) due to de novo mutations or paternal inherited had been reported worldwide. Our report describes the first cases in Vietnam that identified pathogenic/likely pathogenic variants by NIPT-SGD in fetuses. These findings were compared with the diagnostic testing (whole exome sequencing/WES) on amniotic fluid/placenta tissue/umbilical cord blood samples. Single-gene NIPT detected pathogenic variants in the fetuses on TSC2, FGFR3, FGFR2 (two cases), and PTPN11 genes. All results coincided with the subsequent diagnosis. Preliminary research showed the potential of cell-free fetal DNA analysis for prenatal screening of dominant single-gene mutations.

In silico extension on the antidiabetic potential of Euonymus laxiflorus natural compounds onto the inhibitability against protein tyrosine phosphatase 1B

Euonymus laxiflorus bioactive compounds 1-β-D-glucopyranosyloxy-3,5-dimethoxy-4-hydroxybenzene (1), Walterolactone A/B β-D-pyranoglucoside (2), Gallocatechin (3), Leonuriside A (4), Methyl galloate (5), and Catechin (6) were experimentally evidenced for their multi-inhibition against α-glucosidase and α-amylase. In this work, they were subjected to a combination of computational platforms on tyrosine phosphatase 1B (UniProtKB-PTP1B). As the results, the overall potentiality for bio-inhibitory applications is primarily evaluated by the order: 1 (DSaverage -12.2 kcal.mol-1; polarisability 45.5 Å; no toxicity; ground-state energy -1222.73 a.u.; dipole moment 0.989 Debye) &gt; 2 (DSaverage -9.7 kcal.mol-1; polarisability 39.4 Å; no toxicity; ground-state energy -1070.08 a.u.; dipole moment 6.726 Debye) &gt; 4 (DSaverage -9.1 kcal.mol-1; polarisability 45.1 Å; no toxicity; ground-state energy -1222.73 a.u.; dipole moment 4.895 Debye). Altogether, the retrievals encourage further attempts to test the inhibitory effects of 2 against tyrosine phosphatase 1B and improve the dipole moment of 1 to enhance its biological applicability.

Coriaceumins A-D, the First Nitrogen-Containing Crenulide Diterpenoids from the Brown Alga Dictyota coriacea Collected in the East China Sea.

A phytochemical investigation of an East China Sea collection of the brown alga Dictyota coriacea has led to the isolation of four novel nitrogen-containing crenulide diterpenoids, named coriaceumins A-D (1-4), two rare nitrogenous xenicane diterpenoids, dictyolactams C (5) and D (6), and one known crenulide diterpenoid, hydroxycrenulide (7). The structures of the new compounds were elucidated by detailed spectroscopic data analyses, including HRESIMS and 1D/2D NMR. The absolute configurations were determined by a comparison of the experimental ECD spectra with the spectra computed by DFT-based quantum chemical calculations. Coriaceumins A-D (1-4) represent the first examples of nitrogen-containing crenulide diterpenoids. In a bioassay, compounds 2, 3, 5, and 7 were found to exhibit different levels of inhibitory effects against protein tyrosine phosphatase 1B (PTP1B) with IC50 values ranging from 7.3 to 19 μM. In addition, the primary structure-activity relationships of all the isolates were summarized.

Neosophoflavonoids A–C, A class of highly oxidized hybrid flavonoids from Sophora flavescens with antidiabetic effects

Three highly oxidized hybrid flavonoids neosophoflavonoids A–C (1, 2a, and 2b) were isolated from the roots of Sophora flavescens. Neosophoflavonoid A possesses a unique highly oxidized heptacyclic 6/6/6/6/6/6/5 system. Neosophoflavonoids B and C are isomers and share the same highly oxidized hexacyclic 6/6/6/6/6/6 systems. Their planar structures were elucidated from 1D/2D nuclear magnetic resonance (NMR), ultraviolet spectroscopy (UV), infrared spectroscopy (IR), and high resolution electrospray ionization mass spectroscopy (HRESIMS) data. Their absolute configurations were determined by thorough GIAO 13C NMR (DP4+) calculation protocol and electronic circular dichroism (ECD) calculation method. The plausible biosynthetic routes for the compounds were also proposed. All compounds exhibited significant protein tyrosine phosphatase-1B (PTP1B) inhibitory activity with half maximal inhibitory concentration (IC50) values 3.94 ± 0.01, 0.38 ± 0.13, and 0.70 ± 0.01 µmol/L, respectively. In addition, compared to a positive control fenofibrate (Feno) at 20 µmol/L, compounds 2a and 2b exhibited stronger inhibitory effects on lipid accumulation in the oleic acid (OA)-induced cell model at 5 and 10 µmol/L.

The synergistic regulatory effect of PTP1B and PTK inhibitors on the development of Oedaleus decorus asiaticus Bei-Bienko

Tyrosine phosphorylation is crucial for controlling normal cell growth, survival, intercellular communication, gene transcription, immune responses, and other processes. protein tyrosine phosphatase (PTP) and protein tyrosine kinases (PTK) can achieve this goal by regulating multiple signaling pathways. Oedaleus decorus asiaticus is an important pest that infests the Mongolian Plateau grassland. We aimed to evaluate the survival rate, growth rate, overall performance, and ovarian developmental morphology of the 4th instar nymphs of O. decorus asiaticus while inhibiting the activity of protein tyrosine phosphatase-1B (PTP1B) and PTK. In addition, the expression and protein phosphorylation levels of key genes in the MAPK signaling pathway and antioxidant enzyme activity were assessed. The results showed no significant differences in survival rate, growth rate, or overall performance between PTP1B inhibitor treatment and control. However, after PTK inhibitor treatment, these indexes were significantly lower than those in the control. The ovarian size of female larvae after 15 days of treatment with PTK inhibitors showed significantly slower development, while female larvae treated with PTP1B exhibited faster ovarian growth than the control group. In comparison to controls and nymphs treated with PTK inhibitors, the expression and phosphorylation levels of key genes in the MAPK signaling pathway under PTP1B inhibitor treatments were significantly higher in 4th instar nymphs. However, reactiveoxygen (ROS) species levels and the activities of NADPH oxidase and other antioxidant enzymes were considerably reduced, although they were significantly greater in the PTK inhibitor treatment. The results suggest that PTP1B and PTK feedback inhibition in the mitogen-activated-protein kinases (MAPK) signal transfer can regulate the physiological metabolism of the insect as well as its developmental rate. These findings can facilitate future uses of PTP1B and PTK inhibitors in controlling insect development to help control pest populations.