RESUMEN

BACKGROUND: There is a high diversity of beta-lactamases in gram negative pathogens, making them difficult to treat. In the presence of OXA-1 and ampC, PTZ is no longer clinically relevant when treating Enterobacterales expressing ESBLs. Further, MBL infections are often treated with the combination of ceftazidime/avibactam with aztreonam. . It has recently been reported that NDM-expressing E. coli isolates co-harboring PBP3 insert develops resistance to this triple combination. METHODS: A pentaplex PCR is developed and validated to simultaneously detect blaCTX-M, blaOXA-1, blaCMY, blaNDM, and the PBP3 insert in whole genome sequenced E. coli and K. pneumoniae isolates. In addition, the isolates chosen for pentaplex PCR evaluation were tested for their minimum inhibitory concentrations (MICs) against piperacillin/tazobactam, cefoperazone/sulbactam (C/S), ertapenem, imipenem, meropenem, ceftazidime/avibactam, aztreonam/avibactam, cefepime/taniborbactam, and cefiderocol. RESULTS: The developed pentaplex PCR showed 100 % reproducibility with the antimicrobial resistance profile generated from whole genome sequenced data. PTZ and C/S are not effective against ESBL and/or OXA-1 expressing E. coli and K. pneumoniae isolates and do not offer any activity against CMY co-producers. Further, the combined effect of CMY, NDM and PBP3 inserts impacts aztreonam/avibactam activity and reduces the susceptibility to 40 % in E. coli isolates. While, aztreonam/avibactam showed potent activity against NDM-expressing K. pneumoniae isolates. Importantly, cefepime/taniborbactam and cefiderocol showed limited activity against NDM-expressing E. coli and K. pneumoniae isolates. CONCLUSION: The pentaplex PCR was effective in detecting four beta-lactamases (blaCTX-M, blaOXA-1, blaCMY, blaNDM) as well as PBP3 inserts. It is expected that using pentaplex PCR as a diagnostic test for resistance detection in clinical practice will improve patient outcomes by providing prompt and targeted treatment.

RESUMEN

Diabetes is a prevalent metabolic disorder associated with various complications. Inhibition of α-glucosidase and α-amylase enzymes is an effective strategy for managing non-insulin-dependent diabetes mellitus. This study aimed to investigate the antioxidant and antidiabetic potential of Ormocarpum cochinchinense leaf through in vitro and in silico approaches. The methanol extract exhibited the highest phenolic and flavonoid content over solvent extracts aqueous, acetone, hexane, and chloroform, the same has been correlating with strong antioxidant activity. Furthermore, the methanol extract demonstrated significant inhibitory effects on α-amylase and α-glucosidase enzymes, indicating its potential as an antidiabetic agent. Molecular docking analysis identified compounds, including myo-inositol, with favorable binding energies comparable to the standard drug metformin. The selected compounds displayed strong binding affinity towards α-amylase and α-glucosidase enzymes. Structural dynamics analysis revealed that myo-inositol formed a more stable complex with the enzymes. These findings suggest that O. cochinchinense leaf possesses antioxidant and antidiabetic properties, making it a potential source for developing therapeutic agents.

Asunto(s)

Antioxidantes , Hipoglucemiantes , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Antioxidantes/farmacología , Antioxidantes/química , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/química , alfa-Glucosidasas/metabolismo , Metanol , Simulación del Acoplamiento Molecular , Extractos Vegetales/química , alfa-Amilasas/metabolismo , Hojas de la Planta/metabolismo , Inositol/farmacología

RESUMEN

Protracted use of paracetamol at therapeutic/toxic doses readily induces major organ toxicity and poor clinical efficacy. Caesalpinia bonducella seeds possess a diverse range of biological and therapeutic activities. Thus, our study aimed to scrutinize the toxic effects of paracetamol and the potential renal and intestinal protective effects of Caesalpinia bonducella seed extract (CBSE). To Wistar rats, CBSE was administered for 8 days (300 mg/kg, p.o.) with or without paracetamol (2000 mg/kg, p.o.) on the 8th day. Pertinent toxicity assessments in the kidney and intestine were analyzed at the end of the study. The CBASE's phytochemical components were examined using gas chromatography-mass spectrometry (GC-MS). After the study period, study findings evidenced that paracetamol intoxication induced elevation of renal enzyme indicators, oxidative damage, imbalance with the pro/anti-inflammatory production and pro/anti-apoptotic mediators, and tissue injury; all repercussions were alleviated by pre-treatment with CBASE. CBASE considerably reduced (P < 0.05) paracetamol-induced kidney and intestine injury by limiting caspase-8/3 signaling and amplification of inflammation in renal and intestinal tissue by significantly reducing pro-inflammatory cytokine production. As per the GC-MS report, three main bioactive components-Piperine, Isocaryophyllene, and Tetradec-13-en-11-yn-1-ol were predominant and have protective activities. Our study ascertains that CBSE pre-treatment exerts potent renal and intestine protection against paracetamol intoxication. Thus, CBSE could be a prospective therapeutic candidate for protecting the kidney and intestine from the severity of paracetamol intoxication.

RESUMEN

Paracetamol is the most predominantly used antipyretic and analgesic drug. As paracetamol is metabolised mostly in the liver, both deliberate and unintentional overdoses of paracetamol are reported to provoke severe hepatotoxicity, including liver failure. Caesalpinia bonducella seed is well known for its medicinal and therapeutic properties. However, there is no report on its potential protective effects against paracetamol-instigated hepatotoxicity. Therefore, we studied the protective effects of aqueous seed extract of Caesalpinia bonducella (ASECB) on paracetamol-instigated hepatotoxicity in rats. Thirty female albino rats were divided into five groups: control, paracetamol-intoxicated, ASECB + paracetamol, silymarin + paracetamol, and ASECB alone. The rats were assessed for liver enzyme markers (alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase), antioxidant activity (superoxide dismutase, catalase, reduced glutathione, glutathione peroxidase), lipid peroxidation (malondialdehyde), histopathological, cytokine levels (pro-inflammatory cytokines TNF-α and IL-6, and anti-inflammatory cytokine IL-10), and protein expression (pro-apoptotic markers caspase 3 and caspase 8 and anti-apoptotic marker Bcl-2) after the 8-day study period. Repercussions of paracetamol intoxication induced upregulation of liver enzyme markers, antioxidant depletion, malondialdehyde production, decreased expression of Bcl-2 and IL-10, and overexpression of apoptotic and pro-inflammatory mediators, which were attenuated by pre-treatment with ASECB. ASECB markedly mitigated paracetamol-instigated liver injury by suppressing caspase-8/3 signalling and inflammatory infiltration in liver tissue by significantly reducing TNF-α and IL-6. In conclusion, ASECB pre-treatment exerts potent liver protection against paracetamol-instigated hepatotoxicity evidenced by mitigation of oxidative stress, lipid peroxidation, inflammation, and apoptosis.

Asunto(s)

Caesalpinia , Enfermedad Hepática Inducida por Sustancias y Drogas , Ratas , Femenino , Animales , Acetaminofén/toxicidad , Acetaminofén/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Caspasa 8/metabolismo , Caspasa 8/farmacología , Caesalpinia/metabolismo , Interleucina-6/metabolismo , Interleucina-10/metabolismo , Caspasa 3/metabolismo , Antioxidantes/farmacología , Estrés Oxidativo , Hígado/metabolismo , Citocinas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Malondialdehído/metabolismo

RESUMEN

Cancer, which killed ten million people in 2020, is expected to become the world's leading health problem and financial burden. Despite the development of effective therapeutic approaches, cancer-related deaths have increased by 25.4% in the last ten years. Current therapies promote apoptosis and oxidative stress DNA damage and inhibit inflammatory mediators and angiogenesis from providing temporary relief. Thioredoxin-binding protein (TXNIP) causes oxidative stress by inhibiting the function of the thioredoxin system. It is an important regulator of many redox-related signal transduction pathways in cells. In cancer cells, it functions as a tumor suppressor protein that inhibits cell proliferation. In addition, TXNIP levels in hemocytes increased after immune stimulation, suggesting that TXNIP plays an important role in immunity. Several studies have provided experimental evidence for the immune modulatory role of TXNIP in cancer impediments. TXNIP also has the potential to act against immune cells in cancer by mediating the JAK-STAT, MAPK, and PI3K/Akt pathways. To date, therapies targeting TXNIP in cancer are still under investigation. This review highlights the role of TXNIP in preventing cancer, as well as recent reports describing its functions in various immune cells, signaling pathways, and promoting action against cancer.