Current Molecular Pharmacology - Current Issue

Esophageal carcinoma (ESCA) is a common malignancy characterized by high morbidity and mortality. Our work managed to dissect the modulatory mechanism of E2F1/miR-29c-3p/COL11A1 in the malignant progression and sensitivity of ESCA cells to sorafenib.

Via bioinformatics approaches, we identified the target miRNA. Subsequently, CCK-8, cell cycle analysis, and flow cytometry were used to check the biological influences of miR-29c-3p on ESCA cells. TransmiR, mirDIP, miRPathDB, and miRDB databases were used as tools for the prediction of upstream transcription factors and downstream genes of miR-29c-3p. The targeting relationship of genes was detected via RNA immunoprecipitation and chromatin immunoprecipitation, which was further validated by dual-luciferase assay. Finally, in vitro experiments revealed the way E2F1/miR-29c-3p/COL11A1 affected sorafenib’s sensitivity, and in vivo experiments were used to verify the way E2F1 and sorafenib impacted ESCA tumor growth.

miR-29c-3p, downregulated in ESCA, could suppress ESCA cell viability, arrest the cell cycle in the G0/G1 phase, and impel apoptosis. E2F1 was found to be upregulated in ESCA and it could abate the transcriptional activity of miR-29c-3p. COL11A1 was found to be a downstream target of miR-29c-3p to enhance cell viability, induce cell cycle arrest in S phase, and constrain apoptosis. Cellular and animal experiments together demonstrated that E2F1 abated the sorafenib’s sensitivity of ESCA cells via miR-29c-3p/COL11A1.

E2F1 affected the viability, cell cycle, and apoptosis of ESCA cells by modulating miR-29c-3p/COL11A1, and it attenuated the sensitivity of ESCA cells to sorafenib, shedding new light on the treatment of ESCA.

The first clinically evaluated CBP/β-catenin antagonist, PRI-724, displayed an excellent safety profile administered intravenously via continuous infusion. Eisai recently disclosed a third-generation, orally available, reportedly CBP/β-catenin antagonist, E7386. However, several structural features and the reported cytotoxicity of E7386 were unexpected for a specific CBP/β-catenin antagonist. Therefore, we undertook a comparison of E7386 versus the highly specific bona fide CBP/β-catenin antagonists, ICG-001 and C82, the active agents derived from the prodrug PRI-724.

CBP/β-catenin antagonists rebalance the equilibrium between CBP/β-catenin and p300/β-catenin dependent transcription and may be able to treat or prevent many diseases of aging via maintenance of somatic stem cell pool and regulating mitochondrial function and metabolism involved in differentiation and immune cell function. The safety, efficacy, and therapeutic potential of the specific CBP/β-catenin antagonists, ICG-001, and the second-generation compound, C82, the active agent derived from the pro-drug PRI-724, have been studied extensively in a variety of preclinical disease models and in the clinic for oncology and hepatic fibrosis. However, the lack of oral bioavailability has hampered the further development of PRI-724. Thus, Eisai recently proposed a third-generation, orally available, reportedly CBP/β-catenin antagonist E7386. Here, we have performed a comparative analysis of E7386 with the highly specific bona fide CBP/β-catenin antagonists, ICG-001 and C82.

We utilized a series of previously validated biochemical and transcriptional assays to investigate the selective targeting of the CBP/β-catenin interaction in conjunction with global transcriptional profiling to compare the three small molecules, ICG-001, C82, and E7386.

Our data cast significant doubt that the mechanism of action of E7386 is via specific CBP/β-catenin antagonism.

It can thus be concluded that E7386 is not a specific CBP/β-catenin antagonist.

Circular RNAs (circRNAs) have a vital role in the occurrence of numerous cancers. However, its function and pattern of expression in cervical cancer (CC) remain unclear. This research aims to investigate the hsa_circ_000002’s regulatory mechanism in CC.

Hsa_circ_0000021, miR-3940-3p, and KPNA2 expression levels were estimated through qRT-PCR. Nuclear/cytoplasmic separation was conducted to find the subcellular location of hsa_circ_0000021. Western blot was done to estimate the levels of KPNA2 protein. CCK-8, BrdU, wound healing, transwell, and tumor xenograft assays were performed to study how hsa_circ_0000021/miR-3940-3P/KPNA2 function affect CC. Hsa_circ_0000021’s targeting relationships with miR-3940-3p and KPNA2 were ascertained through RIP and luciferase experiments.

Hsa_circ_0000021 and KPNA2 were overexpressed and inversely associated with the levels of miR-3940-3p in CC. Knocking down either hsa_circ_0000021 or KPNA2 repressed the growth of CC tumors as well as the proliferation, invasion, and migration of CC cells. Silencing miR-3940-3p promoted the malignant proliferation of CC cells. Regarding its mechanism, hsa_circ_0000021 affected the malignant CC cell proliferation via the sponging of miR-3940-3p, which targeted KPNA2.

Hsa_circ_0000021 regulates the miR-3940-3p/KPNA2 axis to promote CC occurrence. This potentially is a novel target for CC treatment.

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.

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 ∆∆CT = 0 and 2 to the power of 0 = 1, relative gene expression for reference samples is often set to 1

The highest rates of resistance were recognized with cefotaxime (100%), cefuroxime (100%), cefepime (100%), levofloxacin (98%), trimethoprim-sulfamethoxazole (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.

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.

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.

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.

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.

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.

Potential drug targets must be considered for new research on the treatment of neuropathy and nephropathy conditions.

This study was performed to evaluate the protective effects of chrysin (CH) on metabolic impairment and pancreatic injury caused by sub-chronic chlorpyrifos (CPF) intoxication in male rats.

Forty male Wistar rats were randomly allocated into five groups (n=8). Intraperitoneal injections of chrysin (12.5, 25 and 50 mg/kg for 45 days) and CPF (10 mg/kg for 45 days) gavage were performed. Present findings indicated that the serum levels of glucose, total cholesterol, and low-density lipoprotein-cholesterol, as well as body weight, were increased in the CPF-exposed group.

It was also found that CPF decreased superoxide dismutase activity as well as increased malondialdehyde and nitric oxide levels in the pancreatic tissue of exposed animals. Histopathological examination also confirmed the toxic effects of CPF on pancreatic tissue as mostly evidenced by infiltration of inflammatory cells and necrosis. CH (50 mg/kg) decreased blood glucose concentration (p < 0.05), TG (p < 0.05), and LDL-C in CPF-exposed animals. CH decreased the pancreas levels of MDA in all treated CPF-exposed groups versus the non-treated CPF-exposed group (p < 0.05, p < 0.001, p < 0.001, respectively). A significant difference was not seen in the NO and MDA levels and SOD activity between CH-treated (50 mg/kg) animals exposed to CPF and controls. A significant difference was not seen in the NO and MDA levels and SOD activity between CH-treated (50 mg/kg) animals exposed to CPF and controls.

A significant difference was not seen in the NO and MDA levels and SOD activity between CH-treated (50 mg/kg) animals exposed to CPF and controls. In conclusion, CH could prevent initiate and progress of CPF-induced metabolic impairment by modulating oxidative stress in pancreatic tissue as a target organ of organophosphorus pesticides.

As people age, physical impairments may have a deleterious role on skeletal muscles. Sarcopenia Clinical Practice Guidelines 2017 and the European Working Group on Sarcopenia in older people are two organizations that have published essential guidelines on the definition of “Sarcopenia”. Sarcopenia is a geriatric syndrome, characterized by skeletal muscle mass degeneration brought on by ageing, which lowers muscular function and quality. Moreover, Sarcopenia can be classified as primary or age-associated Sarcopenia and secondary Sarcopenia. Also, secondary Sarcopenia occurs when other diseases such as diabetes, obesity, cancer, cirrhosis, myocardial failure, chronic obstructive pulmonary disease, and inflammatory bowel disease also contribute to muscle loss. Furthermore, Sarcopenia is linked with a high risk of negative outcomes, considering a gradual reduction in physical mobility, poor balance, and increased fracture risks which ultimately leads to poor quality of life.

In this comprehensive review, we have elaborated on the pathophysiology, and various signaling pathways linked with Sarcopenia. Also, discussed the preclinical models and current interventional therapeutics to treat muscle wasting in older patients.

In a nutshell, a comprehensive description of the pathophysiology, mechanisms, animal models, and interventions of Sarcopenia. We also shed light on pharmacotherapeutics present in clinical trials which are being developed as potential therapeutic options for wasting diseases. Thus, this review could fill in the knowledge gaps regarding Sarcopenia-related muscle loss and muscle quality for both researchers and clinicians.

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

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.

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.

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.

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.

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

Clinically, abdominal aortic aneurysms (AAA) can be treated with surgical intervention, but there is currently no effective drug for the disease.

This study analyzed the biomedical data of single-cell RNA sequencing (scRNA-seq), RNA-seq and the network medical data of drug-target interaction as well as protein-protein interaction to identify key targets and potential drug compounds of AAA.

Firstly, we identified 10 types of cells from AAA and nonaneurysmal control samples and screened monocyte, mast cell, smooth muscle cell and 327 genes showing significant differences between non-dilated PVATs and dilated PVATs. To further explore the association of three types of cells in AAA, we screened the common DEGs associated with the three types of cells and then identified 10 potential therapeutic targets for AAA. SLC2A3 and IER3 were the key targets that were the most closely related to immune score and significantly related to inflammatory pathways. We then designed a network-based proximity measure to identify potential drugs targeting SLC2A3. Finally, with computer simulation, we found that the compound with the highest affinity to SLC2A3 protein was DB08213, which was embedded into the SLC2A3 protein cavity and formed close contact with various amino acid residues, and was stable during the 100-ns MD simulation.

This study provided a computational framework for drug design and development. It revealed key targets and potential therapeutic drug compounds for AAA, which might contribute to the drug development for AAA.