Search Results (247)

We explore the structural and electronic properties of representative insulin-mimetic oxovanadium and zinc complexes as computed in vacuum, in water clusters and upon binding to PTEN and PTP1B phosphatases. Albeit diverse, the enzymes’ active sites represent evolutionary variant choices of the same type of biochemistry. Though different in respect to covalency and the orbital nature of bonding, theory predicts comparable ionic radii, bond lengths and square pyramidal coordination for the considered vanadyl and zinc systems when in an aqueous environment. Employing docking, DFT and quantum mechanics/molecular mechanics methods, we address possible polar interactions in the protein environments and compute infrared/Raman modes and optical electronic properties, which may be suitable for the structural analysis of the specific chemical moieties in binding studies. Accounting for how protein embedding may alter the electronic states of metal centres, we discuss artificial intelligence-assisted protein field engineering to assist biomedical and quantum information applications. Full article

Diabetes mellitus has emerged as a global public health crisis, with Type 2 diabetes (T2D) constituting over 90% of cases. Current treatments are palliative, primarily focusing on blood glucose modulation. This review systematically evaluates 181 bioactive compounds isolated from 66 marine fungal strains for their inhibitory activities against key diabetes-related enzymes, including α-glucosidase, protein tyrosine phosphatase 1B (PTP1B), dipeptidyl peptidase-4 (DPP-4), glycogen synthase kinase-3β (GSK-3β), and fatty acid-binding protein 4 (FABP4). These compounds, categorized into polyketides, alkaloids, terpenoids, and lignans, exhibit multitarget engagement and nanomolar-to-micromolar potency. The review highlights the potential of marine fungal metabolites as novel antidiabetic agents, emphasizing their structural novelty and diverse mechanisms of action. Future research should focus on overcoming challenges related to yield and extraction, leveraging advanced technologies such as genetic engineering and synthetic biology to enhance drug development. Full article

The golden pompano ranks at the top of production in current China’s marine fish aquaculture; however, there has been long-standing controversy regarding its valid scientific name. Multiple latin names were used simultaneously to refer to golden pompano, such as Trachinotus ovatus, T. blochii, T. mookalee and T. anak. Moreover, two distinct morphological species are regarded as deserving the scientific name T. ovatus. In this study, we employed DNA barcoding to determine which particular species the “golden pompano” represents and to explore the potential synonyms and cryptic species within T. ovatus and its closely related species. We analyzed the DNA barcodes of golden pompano samples from various aquaculture farms in China’s main production regions, as well as most species within the genus Trachinotus. The phylogenetic analyses revealed that all T. ovatus sequences clustered into two divergent clades with a large genetic distance, and the two clades were geographically separated, being from the Indo-west Pacific and the East Atlantic regions, respectively. Based on the type locality information and historical distribution records, we support the validity of the naming of Trachinotus ovatus from the Indo-west Pacific, and the so-called Trachinotus ovatus from the East Atlantic may represent a cryptic species. All the golden pompano samples were clustered into the Indo-west Pacific T. ovatus clade, with a considerably small intragroup genetic distance, which suggests that the golden pompano in China should be identified as the species Trachinotus ovatus. The golden pompano, T. blochii and T. mookalee were completely separated into distinct monophyletic clades in the phylogenetic trees, which indicated that they are different species. The T. anak clustered with the monophyletic clade of Indo-west Pacific T. ovatus and the genetic distance between them was at the intraspecific difference level. This implied that the T. anak might be the junior synonym of T. ovatus. The species delimitations based on the ABGD and bPTP methods are in agreement with the findings from phylogenetic analyses. The above results help to form a consistent viewpoint regarding the naming of the golden pompano and provide new understandings for the taxonomy of the genus Trachinotus. Full article

Background: The phylogenetic resolution within the Gloydius halys-intermedius Complex remains debatable due to the following reasons: loci selection in previous studies varied between authors; limited dataset (1−5 mitochondrial or nuclear gene fragments); lack of sampling density; and nodal supports at specific nodes remain weak, specifically within Gloydius cognatus, G. halys, and G. stejnegeri. Objectives: To revise the taxonomic and phylogenetic relationships within the G. halys-intermedius Complex, we reconstructed the molecular phylogeny and performed species delimitation based on the complete mitochondrial genomes. Methods: In this study, twelve nomenclatural groups of Gloydius species were involved in the computation of Bayesian phylogenomic inference, five of the twelve nomenclature groups were newly sequenced, while the rest were acquired from the National Center for Biotechnology Information (NCBI). The Bayesian phylogenomic inference was constructed based on 13 mitochondrial protein-coding genes. Species delimitation was performed by two distance-based methods (ABGD and ASAP) and two tree-based methods (GMYC and bPTP). Results: This research resolved the systematic relationship within the G. intermedius Complex with the support of mitogenome-based phylogenomics, while indicating cryptic diversity within the Gloydius halys-intermedius Complex: G. intermedius samples from South Korea show as paraphyletic to the cluster of the samples from northeastern China. Species delimitation results based on four models resemble each other, supporting Gloydius caucasicus, G. cognatus, G. halys, and G. stejnegeri, each representing full species. The species delimitation results of this research also resemble the nomenclatural species based on previous morphometrical results. This research indicates that species delimitation efforts based on the phylogenomic approach would likely resolve complex evolutionary relationships. Full article

Triple-negative breast cancer (TNBC) is a type of breast cancer characterized by high molecular heterogeneity. Owing to the lack of effective therapeutic strategies, patients with TNBC have a poor prognosis. Prunella vulgaris L. has the effects of reducing swelling, dissolving knots and treating breast carbuncles and mammary rocks. Modern pharmacological studies have reported that it can effectively inhibit the growth of breast cancer. The main active antitumor components of Prunella vulgaris are triterpenoids (PVT); however, the role and potential mechanism of PVT in TNBC remain unexplored. Our study aimed to further explore the inhibitory effects of PVT on TNBC and the associated mechanism. The results showed that 19 compounds associated with PVT were identified, 9 of which were triterpenoids. The percentages of ursolic acid and oleanolic acid in PVT were 34.51% and 11.32%, respectively. Triterpenes of Prunella vulgaris significantly inhibited the proliferation, migration and invasion of MDA-MB-231 cells and promoted their apoptosis in a concentration-dependent manner. PVT could also effectively downregulate the mRNA and protein expression levels of Ptp1b, Pi3k, Akt and mtor and upregulate the mRNA and protein expression levels of Il-24 in MDA-MB-231 cells. In mice with tumors of TNBC, PVT significantly reduced tumor growth and the expression levels of PTP1B, CXCL12, CXCR4, PI3K, AKT, mTOR and other proteins in TNBC tumor tissue and upregulated the expression of IL-24. This study showed that PVT played an anti-TNBC role by regulating the PTP1B/PI3K/AKT/mTOR signaling pathway and the IL-24/CXCL12/CXCR4 signaling axis. Full article

The diversity of non-biting midges (Chironomidae, Diptera) remains an unresolved topic, with estimates of species numbers ranging from 6000 to 15,000 according to various authors. To assess Chironomidae diversity in Lithuania, we evaluate the effectiveness of COI gene-based species delimitation methods for providing rapid diversity estimates. Nevertheless, differences between tree-based and distance-based approaches can result in varying group classifications, which may cause species numbers to be overestimated or underestimated. For our study, we analyzed a dataset of 109 specimens sampled from six Lithuanian streams. By applying multiple methods, such as Assemble Species by Automatic Partitioning (ASAP), Automatic Barcode Gap Discovery (ABGD), the generalized mixed Yule-coalescent (GMYC) model, and the Bayesian implementation of the Poisson Tree Processes (bPTP) model, we found that species estimates ranged from 28 to 58. Among these methods, ASAP proved to be the most effective for our dataset, identifying 58 putative species. These results reinforce our assumption that the current understanding of Chironomidae species diversity is incomplete. Full article

As a part of our ongoing search for bioactive constituents of Artemisia capillaris, we isolated 4-O-caffeoyl-2-C-methyl-d-threonic acid (PPT-14). This is a rare caffeic acid ester derivative that is reported here for the first time in the Artemisia species, which is the third occurrence in any plant species worldwide. In this study, we evaluated the anti-diabetic potential of PPT-14 using in vitro and in silico approaches. PPT-14 demonstrated significant inhibitory activity against two crucial enzymes linked to diabetes progression and complications: protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR). These had IC₅₀ values of 64.92 and 19.50 µM, respectively. Additionally, PPT-14 exhibited free radical scavenging activity with 2,2-diphenyl-2-picrylhydrazyl (IC₅₀ 14.46 µM). Molecular docking and 200 ns molecular dynamics simulations confirmed that there were stable binding interactions with the key residues of PTP1B and AR, highlighting strong affinity and dynamic stability. Pharmacokinetic analyses revealed favorable water solubility, adherence to Lipinski’s Rule of Five, and minimal interactions with cytochrome P450 enzymes, indicating the drug-like potential of PPT-14. Toxicity studies confirmed its safety profile, showing no genotoxicity, hepatotoxicity, or significant toxicity risks, with an acceptable oral LD₅₀ value of 2.984 mol/kg. These findings suggest that PPT-14 could be a promising multitarget lead compound for ameliorating diabetes and its associated complications. Full article

Red blood cells (RBCs) are the main cells of the blood, perform numerous functions within the body and are in continuous contact with endogenous and exogenous molecules. In this context, the study aims to investigate the effect of epicatechin (EC) (flavan-3-ols) on the erythrocytes, analyzing the protective effect of the molecule and the action exerted on metabolism and RBC membrane. The effect of EC on RBC viability has been evaluated through the change in hemolysis and methemoglobin, assessing caspase 3 activity and performing a cytofluorometric analysis. Next, the impact of the molecule on RBC metabolism was assessed by measuring anion flux kinetics, ATP production, and phosphatase activity. Finally, an evaluation of the potential protection against different stressors was performed. Our results show no detrimental effects of EC on RBCs (no change in hemolysis or methemoglobin and no caspase 3 activation recorded); rather, a protective effect was recorded given the reduction in hemolysis induced by hydrogen peroxide treatment and temperature increase. The increase in anion exchange and intracellular ATP values, with the inhibition of phosphatase PTP1B activity, highlights several biochemical alterations induced by EC. The present results contribute to clarifying the influence of EC on RBCs, confirming the beneficial effects of catechins. Full article

Background/Objectives: Tuberculosis (TB) is one of the leading infectious causes of death worldwide, highlighting the importance of identifying new anti-TB agents. In previous research, our team identified antimycobacterial activity in Kielmeyera membranacea leaf extract; therefore, this study aims to conduct further exploration of its potential. Methods: Classical chromatography was applied for fractionation and spectrometric techniques were utilized for chemical characterization. For in vitro tests, samples were assessed against Mycobacterium tuberculosis and Mycobacterium marinum. The toxicity and efficacy of active samples were evaluated in vivo using different zebrafish models. Chemogenomics studies were applied to predict the isolated active compound’s potential mode of action. Results: We performed fractionation of K. membranacea ethanolic extract (EE) and then its dichloromethane fraction (DCM), and the biflavonoid podocarpusflavone A (PCFA) was isolated and identified as a promising active compound. The EE and PCFA were found to be non-toxic to zebrafish larvae and were able to inhibit M. tuberculosis growth extracellularly. Additionally, PCFA demonstrated antimycobacterial activity within infected macrophages, especially when combined with isoniazid. In addition, the EE, DCM, and PCFA have shown the ability to inhibit M. marinum’s growth during in vivo zebrafish larvae yolk infection. Notably, PCFA also effectively countered systemic infection established through the caudal vein, showing a similar inhibitory activity profile to rifampicin, both at 32 µM. A reduction in the transcriptional levels of pro-inflammatory cytokines confirmed the infection resolution. The protein tyrosine phosphatase B (PtpB) of M. tuberculosis, which inhibits the macrophage immune response, was predicted as a theoretical target of PCFA. This finding is in agreement with the higher activity observed for PCFA intracellularly and in vivo on zebrafish, compared with the direct action in M. tuberculosis. Conclusions: Here, we describe the discovery of PCFA as an intracellular inhibitor of M. tuberculosis and provide evidence of its in vivo efficacy and safety, encouraging its further development as a combination drug in novel therapeutic regimens for TB. Full article

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

Fucosylated chondroitin sulfate (FCS) was prepared from Bohadschia ocellata using protease hydrolysis. The structural characteristics of FCS were confirmed through chemical composition analysis using FTIR spectroscopy, ¹H NMR, and ¹³C NMR. FCS from B. ocellata (FCS-Bo) exhibited an average molecular weight of approximately 122 kDa. The biological activities of FCS-Bo, including anticoagulant, anti-cancer, and Protein Tyrosine Phosphatase 1B (PTP1B) inhibition, were evaluated. FCS-Bo displayed potent anticoagulant properties, markedly extending activated partial thromboplastin time, prothrombin time, and thrombin time when compared to the heparin control. In anti-cancer bioactivity research, FCS-Bo efficiently inhibited colony formation in the colon cancer cell lines HCT-116, HT-29, and DLD-1, achieving inhibition rates of up to 65%. Additionally, FCS-Bo exhibited significant inhibition of PTP1B, with an IC₅₀ as low as 0.0326 µg/mL, suggesting its potential for improving insulin sensitivity and managing conditions such as type 2 diabetes and obesity. Full article

A focussed library of pyridyl and 2-hydroxyphenyl chalcones were synthesized and tested for growth inhibitory activity against Mycobacterium tuberculosis H37Rv, and normal and cancer breast cell lines. Pyridyl chalcones bearing lipophilic A-ring, e.g., dichloro-phenyl-(14), pyrene-1-yl (20)- and biphenyl-4-yl (21) moieties were found to be the most potent of the series inhibiting the growth of M. tuberculosis H37Rv with IC₉₀ values ranging from 8.9–28 µM. Aryl chalcones containing a 3-methoxyphenyl A-ring and either p-Br-phenyl (25) or p-Cl-phenyl (26) B-rings showed an IC₉₀ value of 28 µM. Aryl-chalcones were generally less toxic to HepG2 cells compared to pyridyl-chalcones. Dose-dependent antiproliferative activity against MDA468 cells was observed for trimethoxy-phenyl (16) and anthracene-9-yl (19) pyridyl-chalcones with IC₅₀ values of 0.7 and 0.3 µM, respectively. Docking studies revealed that chalone 20 was predicted to bind to the M. tuberculosis protein tyrosine phosphatases B (PtpB) with higher affinity compared to a previously reported PtpB inhibitor. Full article

During the present study, DNA sequence and morphological data were used to delineate species boundaries in the velvet worm, Peripatopsis sedgwicki species complex. The combined mitochondrial cytochrome c oxidase subunit one (COI) and the nuclear 18S rRNA loci were phylogenetically analyzed using Bayesian inference and maximum likelihood platforms that both demonstrated the presence of four, statistically well-supported clades (A–D). In addition, five species delimitation methods (ASAP, bPTP, bGMYC, STACEY and iBPP) were used on the combined DNA sequence data to identify possible novel lineages. All five species delimitation methods supported the distinction of the Fort Fordyce Nature Reserve specimens in the Eastern Cape province, however, in the main P. sedgwicki s.l. species complex, the species delimitation methods revealed a variable number of novel operational taxonomic units. Gross morphological characters were of limited utility, with only the leg pair number in the Fort Fordyce Nature Reserve specimens and the white head-collar of the Van Stadens Wildflower Nature Reserve specimens being diagnostic. The RADseq results from the earlier study of P. sedgwicki s.l. provided highly congruent results with the four clades observed in the present study. The distribution of P. sedgwicki s.s. (clade B) is restricted to the western portions of its distribution in the Afrotemperate forested regions of the Western Cape Province, South Africa. Three novel species, P. collarium sp. nov., (clade C) P. margaritarius sp. nov., (clade A) and P. orientalis sp. nov., (clade D) are described, of which the first two species are narrow range endemics. The present study, along with several recent systematic studies of velvet worms affirms the importance of fine-scale sampling to detect and document the alpha taxonomic diversity of Onychophora. Full article

As part of our ongoing research on new anti-diabetic compounds from ethnopharmacologically consumed plants, two previously undescribed lupane-type triterpenoids (1 and 2) with dicarboxylic groups, an undescribed nor-taraxastane-type triterpenoid (3), and 14 known compounds (4–17) were isolated from the leaves of Cleistocalyx operculatus. Extensive spectroscopic analysis (IR, HRESIMS, 1D, and 2D NMR) was used for structure elucidation, while the known compounds were compared to reference data reported in the scientific literature. All the isolates (1–17) were evaluated for their inhibitory effects on the protein tyrosine phosphatase 1B (PTP1B) enzyme. Compounds 6, 9, and 17 showed strong PTP1B inhibitory activities. The mechanism of PTP1B inhibition was studied through enzyme kinetic experiments. A non-competitive mechanism of inhibition was determined using Lineweaver–Burk plots for compounds 6, 9, and 17. Additionally, Dixon plots were employed to determine the inhibition constant. Further insights were gained through a structure–activity relationship study and molecular docking analysis of isolated compounds with the PTP1B crystal structure. Moreover, all isolates (1–17) were tested for their stimulatory effects on the uptake of 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl) amino]-D-glucose (2-NBDG) in differentiated 3T3-L1 adipocyte cells. Compounds 6, 13, and 17 exhibited strong glucose absorption stimulation activity in a dose-dependent manner. Full article

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. Full article