Current molecular pharmacology最新文献

Background: Over the last several decades, the AcrAB and OqxAB efflux pumps have been found to cause multidrug resistance (MDR) in various bacteria, most notably Klebsiella pneumoniae. Antibiotic resistance surges with increased expression of the acrAB and oqxAB efflux pumps.

Methods: In accordance with CLSI guidelines, a disk diffusion test was carried out using 50 K. pneumoniae isolates obtained from various clinical samples. CT was computed in treated samples and compared to a susceptible ciprofloxacin strain (A111). The final finding is presented as the fold change in the target gene's expression in treated samples relative to a control sample (A111), normalized to a reference gene. As ΔΔCT = 0 and 2 to the power of 0 = 1, relative gene expression for reference samples is often set to 1 Results: The highest rates of resistance were recognized with cefotaxime (100%), cefuroxime (100%), cefepime (100%), levofloxacin (98%), trimethoprimsulfamethoxazole (80%), and gentamicin (72%), whereas imipenem (34%) had the lowest rates. Overexpression of acrA and acrB, oqxA and oqxB, regulators marA, soxS, and rarA were greater in ciprofloxacin-resistant isolates compared to the reference strain (strain A111). There was also a moderate connection between ciprofloxacin MIC and acrAB gene expression and a moderate connection between ciprofloxacin MIC and oqxAB gene expression.

Conclusion: This work provides a deeper knowledge of the role of efflux pump genes, particularly acrAB and oqxAB, as well as transcriptional regulators marA, soxS, and rarA, in bacterial resistance to ciprofloxacin.

Tumor necrosis factor-alpha (TNFα) is a pleiotropic pro-inflammatory cytokine of the TNF superfamily. It regulates key cellular processes such as death, and proliferation besides its well-known role in immune response through activation of various intracellular signaling pathways (such as MAPK, Akt, NF-κB, etc.) via complex formation by ligand-activated TNFα receptors. TNFα tightly regulates the activity of key signaling proteins via their phosphorylation and/or ubiquitination which culminate in specific cellular responses. Deregulated TNFα signaling is implicated in inflammatory diseases, neurological disorders, and cancer. TNFα has been shown to exert opposite effects on cancer cells since it activates prosurvival as well as anti-survival pathways depending on various contexts such as cell type, concentration, cell density, etc. A detailed understanding of TNFα signaling phenomena is crucial for understanding its pleiotropic role in malignancies and its potential as a drug target or an anticancer therapeutic. This review enlightens complex cellular signaling pathways activated by TNFα and further discusses its role in various cancers.

Background: The mammalian role of the rapamycin (mTOR) pathway is the practical nutrient-sensitive regulation of animal growth and plays a central role in physiology, metabolism, and common diseases. The mTOR is activated in response to nutrients, growth factors, and cellular energy. The mTOR pathway activates in various cellular processes and human cancer diseases. Dysfunction of mTOR signal transduction is associated with metabolic disorders, cancer for instance.

Objective: In recent years, significant achievements envisaged in developing targeted drugs for cancer. The global impact of cancer continues to grow. However, the focus of disease-modifying therapies remains elusive. The mTOR is a significant target in cancer to be considered for mTOR inhibitors, even though the costs are high. Despite many mTOR inhibitors, potent, selective inhibitors for mTOR are still limited. Therefore, in this review, the mTOR structure and protein-ligand interactions of utmost importance to provide the basis for molecular modelling and structure-based drug design are discussed.

Conclusion: This review introduces the mTOR, its crystal structure, and the latest research on mTOR.Besides, the role of mTOR in cancer, its function, and its regulation are reviewed. In addition, the mechanistic role of mTOR signalling networks in cancer and interaction with drugs that inhibit the development of mTOR and crystal structures of mTOR and its complexes are explored. Finally, the current status and prospects of mTOR-targeted therapy are addressed.

Background: Ischemia/reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) that induces inflammation and oxidative stress. The main goal of the current study was to assess the impact of fingolimod on kidney IRI in rats.

Methods: For this purpose, 18 male Wistar rats (220-250g) were divided into three groups including (i) Sham, (ii) I/R, and (iii) fingolimod+I/R. The last group was pretreated with a single dose of fingolimod (1mg/kg) (intraperitoneal injection) before induction of the I/R injury. Kidney function, oxidative stress marker (malondialdehyde), and antioxidant markers (catalase, superoxide dismutase, glutathione, glutathione peroxidase, and total antioxidant capacity) were determined in the kidney tissue of the rats. Moreover, kidney samples were taken for histological analysis.

Results: Fingolimod pre-treatment could significantly improve the glutathione peroxidase (p<0.01) and glutathione (p<0.001) activities along with the total antioxidant capacity levels (p<0.001) when compared to the I/R group. Moreover, significant recovery of kidney function and histology was seen in the fingolimod+ I/R group compared to the I/R group (p<0.01).

Conclusion: Fingolimod pretreatment could improve renal function, antioxidant capacity, and histological alterations after I/R injury. Hence, it might protect the kidney against IRI-related kidney damage including AKI and transplantation.

The Brazilian biodiversity may bring new perspectives to the therapy of Inflammatory Bowel Diseases (IBD) and intestinal cancer. The effect of Brazilian Green Propolis in reducing ulcerative colitis in mice has already been described, as well as high amounts of the prenylated compound Artepellin C (ARC). The search for new pharmacological targets for IBD is also advancing. Among possibilities is the p21-activated kinase (PAK1), overexpressed and activated in the intestinal mucosa during IBD and colitis-associated colorectal cancer (CAC). PAK 1 contributes to tissue inflammation by reducing the expression of peroxisome proliferator-activated receptor type γ (PPAR47) and increasing activation of nuclear factor (NF)-κB. At least in vitro, inhibition of PAK1 has been reported to mitigate NF-κB-mediated inflammation in intestinal cells and ARC inhibits PAK1 activation. Given this pharmacological potential of ARC and the role of PAK1 in IBD and CAC, this perspective collected information that encourages future research to test the hypothesis that ARC can maintain intestinal integrity under the inflammatory and neoplastic stimulus and that inhibition of PAK1/NF-κB signaling and favoring PPAR-γ activity is pivotal in this action. Therefore, future studies employing in vitro and in vivo steps, using murine and human enterocytes and rodents submitted to ulcerative colitis and CAC models are incentivized by the data gathered here, favor retirar essas palavras: mostly in vitro studies, before clinical trials. Therefore, the perspective presented here points to an interesting path in the search for a drug useful in inflammatory and neoplastic intestinal diseases, which may have ARC as a prototype, acting on a target not yet explored clinically.

Cancer is one of the most deadly diseases involving dysregulated cell proliferation. Chemotherapeutic drugs have serious drawbacks of nonspecific toxicity and drug resistance. Tyrosine kinases are a significant class of enzymes of protein kinases. The four members of the trans-membrane family of tyrosine kinase receptors known as the human epidermal growth factor receptors (EGFR), ErbB1/HER1, ErbB2/HER2/neu, ErbB3/HER3, and ErbB4/HER4, are overexpressed in many forms of cancer. These receptors are crucial for cell division, invasion, metastasis, angiogenesis, and uncontrolled activation of cancer cells. In this context, an attractive combination of anticancer drug targets is ErbB1 and ErbB2. Numerous cancer types exhibit overexpression of ErbB1 and ErbB2, which is linked to poor prognosis and causes resistance to ErbB1-targeted therapy. Further, it has been reported in recent years that the use of peptides as anticancer agents have the potential to circumvent the drawbacks of the currently used chemotherapeutic drugs. Among them, short peptides have several advantages when compared to small molecules. The present report reviews the importance of tyrosine kinases as targets for cancer, the role of peptides as therapeutic agents, and the investigations that have been carried out by earlier workers for targeting both ErbB1 and ErbB2 using therapeutic peptides.

Background: Diabetic mellitus is responsible for triggering many conditions, such as neuropathy, nephropathy, and retinopathy. Hyperglycemia leads to the development of oxidative stress conditions, activation of pathways, and generation of metabolites, leading to complications like neuropathy and nephropathy.

Objective: This paper aims to discuss the mechanism of actions, pathways, and metabolites triggered due to the development of neuropathy and nephropathy post-long-haul diabetes in patients. The therapeutic targets are also highlighted, proving to be a potential cure for such conditions.

Methods: Research works were searched from international and national databases with keywords like "diabetes," "diabetic nephropathy," "NADPH," "oxidative stress," "PKC," "Molecular mechanisms," " cellular mechanisms," "complications of diabetes," and "factors." The databases searched were PubMed, Scopus, Directory of open access journals, Semantic Scholar, Core, Europe PMC, EMBASE, Nutrition, FSTA- Food Science and Technology, Merck Index, Google Scholar, PubMed, Science Open, MedlinePlus, Indian citation index, World Wide Science, and Shodhganga.

Results: Pathways causing protein kinase C (PKC) activation, free radical injury, oxidative stress, and aggravating the conditions of neuropathy and nephropathy were discussed. In diabetic neuropathy and nephropathy, neurons and nephrons are affected to the extent that their normal physiology is disturbed, thus leading to further complications and conditions of loss of nerve sensation in diabetic neuropathy and kidney failure in diabetic nephropathy. Current treatment options available for the management of diabetic neuropathy are anticonvulsants, antidepressants, and topical medications, including capsaicin. According to AAN guidelines, pregabalin is recommended as the first line of therapy, whereas other drugs currently used for treatment are gabapentin, venlafaxine, opioids, amitriptyline, and valproate. Drug targets for treating diabetic neuropathy must suppress the activated polyol pathways, kinase C, hexosamine, and other pathways, which amplify neuroinflammation. Targeted therapy must focus on the reduction of oxidative stress and proinflammatory cytokines and suppression of neuroinflammation, NF-κB, AP-1, etc. Conclusion: Potential drug targets must be considered for new research on the treatment of neuropathy and nephropathy conditions.

Aim: In the present study, we aimed to investigate the effects of Fenbufen treatment on the SAP model induced by caerulein and lipopolysaccharide.

Background: Severe acute pancreatitis (SAP) is an extremely dangerous disease with high mortality, which is associated with inflammatory response and acinar cell death. The caspase family plays an important role in cell death, such as caspase-1 and caspase-11 in pyroptosis. In recent years, caspases have been shown to be a novel pharmacological target of Fenbufen.

Objective: Effects of Fenbufen on pancreatic tissue damage and serum levels of lipase and amylase in SAP in mice; Effect of Fenbufen on caspase-1 pathway in SAP in mice; Effect of Fenbufen on caspase-1/caspase-11-mediated pyroptosis of PACs in SAP in mice; Effect of Fenbufen on isolated PACs and caspase-1/caspase-11-mediated pyroptosis in vitro.

Methods: In vivo, eighteen female C57BL/6 mice were randomly divided into 3 groups: the NC group, the SAP group, and the Fenbufen +SAP group with 6 mice in each group. The SAP model was induced by intraperitoneal injection of caerulein and lipopolysaccharide. The pathological changes in pancreatic and the serum levels of lipase and amylase and the relative gene and protein expressions in each group were compared. In vitro, pancreatic acinar cells were assigned to 5 groups: medium group, SAP group, Fenbufen 100μM group, Fenbufen 200μM group, and Fenbufen 400μM group. The cell damage and the relative gene and protein expressions in each group were evaluated.

Results: Our results showed that Fenbufen ameliorated the severity of SAP and decreased the serum levels of lipase and amylase. Meanwhile, the in vivo and in vitro data demonstrated that Fenbufen inhibited the activation of caspase-1 and caspase-11, decreasing the levels of IL-1β, IL-18, and GSDMD. In in vitro experiments, we found that by inhibiting the activation of caspase-1 and caspase-11, Fenbufen significantly reduced lactate dehydrogenase (LDH) excretion by acinar cells.

Conclusion: In general, our data showed that Fenbufen could protect the pancreatic acinar cell from injury by inhibiting pyroptosis.

Although Amyloid beta plaque and neurofibrillary tangles are considered the two main hallmarks of Alzheimer's disease (AD), the mechanism by which they contribute is not clearly understood. Cellular senescence (CS) has been demonstrated to be a key characteristic of AD. Recent research suggests that persistent buildup of senescent cells over time results in protracted activation of inflammatory stress as an organism ages because of the accumulation of irreversible DNA damage and oxidative stress as well as the deterioration of immune system function. Studies on both humans and animals have shown evidence that CS is a crucial factor in AD. The brains of AD patients have been found to have senescent glial cells and neurons, and removal of these senescent cells results in a decrease in Amyloid beta plaque and Neurofibrillary tangles, along with improved cognitive functions. This review summarises recent results and the mechanism by which CS contributes to the development of AD, and how the elimination of senescent cells may be a therapeutic target in the management of AD.

Background: Fangchinoline (Fan) is extracted from traditional Chinese medicine (called Fangji), or the root of Stephania tetrandra Moore. Fangji is well-known in Chinese medical literature for treating rheumatic diseases. Sjogren's syndrome (SS) is a rheumatic disease whose progression can be mediated via CD4+ T cell infiltration.

Objective: This study identifies the potential role of Fan in inducing apoptosis in Jurkat T cells.

Methods: First, we explored the biological process (BP) associated with SS development by performing a gene ontology analysis of SS salivary gland-related mRNA microarray data. The effect of Fan on Jurkat cells was investigated by analyzing the viability, proliferation, apoptosis, reactive oxygen species (ROS) production, and DNA damage.

Results: Biological process analysis showed that T cells played a role in salivary gland lesions in patients with SS, indicating the significance of T cell inhibition in SS treatment. Viability assays revealed that the half-maximal inhibitory concentration of Fan was 2.49 μM in Jurkat T cells, while the proliferation assay revealed that Fan had an inhibitory effect on the proliferation of Jurkat T cells. The results of the apoptotic, ROS, agarose gel electrophoresis, and immunofluorescence assays showed that Fan induced oxidative stress-induced apoptosis and DNA damage in a dosedependent manner.

Conclusion: These results indicate that Fan could significantly induce oxidative stress-induced apoptosis and DNA damage and inhibit the proliferation of Jurkat T cells. Moreover, Fan further enhanced the inhibitory effect on DNA damage and apoptosis by inhibiting the pro-survival Akt signal.