Current Molecular Pharmacology - Volume 17, Issue 1, 2024

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.