Latest ArticlesTo explore the effect of crocin on gastric mucosal epithelial cells injury induced by clopidogrel and the molecular mechanism.
The gastric mucosal epithelial cells GES-1 were divided into control group, model group (0.5 mmol ·L-1 clopidogrel), and crocin low, medium, and high concentration (0.1, 1, 10 nmol·L-1) groups, and additionally divided into anti-miR-NC group, miR-877-5p inhibitor group, crocin (10 nmol·L-1) + miR-NC group, crocin (10 nmol·L-1) + miR-877-5p mimic group. MTT and colony formation assays were used to detect cell survival rate and the number of colony formation. Flow cytometry was used to detect cell apoptosis. qRT-PCR was used to detect the expression level of miR-877-5p. Western blot was used to detect the expression of occludin, zonula occluden-1 (ZO-1), and p-P38 protein.
Compared with the control group, the survival rate and the number of cell clone formation in model group were decreased, the apoptosis rate and the expression of miR-877-5p and p-P38 were increased, and the expressions of occludin and ZO-1 were decreased (P<0.05). Compared with the model group, the survival rate and the number of cell clone formation in the crocin medium and high concentration groups were increased, the apoptosis rate and the expression of miR-877-5p and p-P38 were decreased, and the expression of occludin and ZO-1 were increased (P<0.05). Compared with the anti-miR-NC group, the survival rate, the number of cell clone formation, and expression of occludin and ZO-1 were increased in the miR-877-5p inhibitor group, and apoptosis rate and expression of miR-877-5p and p-P38 were decreased (P<0.05).Compared with the crocin+miR-NC group, the survival rate, the number of cell clone formation, and the expression of occludin and ZO-1 were decreased in the crocin+miR-877-5p mimic group, while the apoptosis rate and the expression of miR-877-5p and p-P38 were increased (P<0.05).
Crocin may inhibit clopidogrel-induced apoptosis of gastric epithelial cells and promote cell proliferation by down-regulating miR-877-5p.
To evaluate the effects of glucagon-like peptide-1 receptor agonists (GLP-1RA) on gastrointestinal adverse reactions in patients with type 2 diabetes mellitus (T2DM).
The databases PubMed, Embase, and Cochrane Library were systematic searched for randomized controlled trials of GLP-1RA for the treatment of T2DM from the time of construction until October 1st, 2023, with one GLP-1RA as the drug in the trial arm and placebo or another GLP-1RA as the drug in the control arm. Bayesian network meta-analysis was used to explore the risk of gastrointestinal adverse reactions, such as nausea, vomiting, anorexia, constipation, dyspepsia, and diarrhea.
Forty-five papers were included, involving 27 729 patients. The overall incidence of gastrointestinal adverse reactions caused by GLP-RA was 11.66%. Compared with placebo, tirzepatide caused the highest risk of nausea, diarrhea, dyspepsia, and anorexia, lixisenatide caused the highest risk of vomiting, and semaglutide caused the highest risk of constipation. Compared with placebo, all GLP-1RA except loxenatide significantly increased the risk of vomiting; all GLP-1RA except lixisenatide significantly increased the risk of diarrhea; all GLP-1RA significantly increased the risk of constipation except tirzepatide and lixisenatide; all GLP-1RA significantly decreased appetite and increased the risk of dyspepsia (P<0.05).
GLP-1RA significantly increased the risk of gastrointestinal adverse reactions in T2DM patients, and different drugs have different risks of various symptoms, among which tirzepatide has a higher risk of gastrointestinal symptoms, which deserves clinical attention and vigilance.
To study the mechanism of gigantol inhibiting the proliferation of pancreatic carcinoma (PC) cells by targeting urokinase-type plasminogen activator (PLAU).
PC cells (PANC-1 and SW1990) were treated with different concentrations of gigantol. The cells activity was detected by CCK-8, and half-maximal inhibitory concentration (IC50) was calculated. Cell clone assay was performed to detect the effects of gigantol on cells growth ability. The effects of gigantol on cells growth cycle and apoptosis were detected by flow cytometer. The targets of gigantol were analyzed by bioinformatics, expressions of these targets in PC tissues and their relationship with poor clinical phenotypes were analyzed.PC cells were transfected with PLAU or vector plasmid, and divided into normal group (vector plasmid), gigantol group (45 μmol·L-1 or 50 μmol·L-1) and gigantol + PLAU (PLAU plasmid) group. The effects of gigantol on cells proliferation, clone, cells cycle and apoptosis by targeting PLAU were observed. The expression of PLAU protein in cells was detected by Western blot. The inhibitory effects of gigantol on cells proliferation in vivo were detected by xenograft assay in nude mice.The expression of proliferating cell antigen (Ki67) was detected by immunohistochemistry.
Compared with the normal group, gigantol group showed a significant decrease in cell proliferation and clone number (P<0.05), and an increase in the number of G0/G1-phase cells, a decrease in the number of S-phase cells (P<0.05), and an increase in the number of apoptotic cells (P<0.05). There were no significant difference in the number of G2/M-phase cells between the two groups (P<0.05). Bioinformatics results showed that PLAU was the target of gigantol, which was up-regulated in PC tissues and related to poor clinical phenotypes of PC. Gigantol could inhibit the expression of PLAU protein in PC cells, showing concentration and time dependence (P<0.05). PLAU protein expression, proliferation activity and clone number, and the number of S-phase cells in PC cells were higher in the gigantol +PLAU group than in the gigantol group, while the number of apoptotic cells was less than in the gigantol group (P<0.05). In the nude mice experiments, the volume and weight of transplanted tumors in the gigantol group were significantly lower than those in the normal group (P<0.05), and the relative expression of Ki67 in tumor tissues was lower than that in the normal group (P<0.05).
Gigantol can inhibit the proliferation of PC cells, affect cells cycle and promote apoptosis by targeting the expression of PLAU protein.
To assess the in vitro antibacterial activity of polymyxin B in combination with meropenem, amikacin, and fosfomycin against carbapenem-resistant Enterobacteriaceae (CRE) strains carrying various resistance genes.
A total of 76 CRE strains isolated from the clinical laboratory of our hospital between 2019 and 2021 were collected for identification and confirmation of carbapenemase genotype. The minimum inhibitory concentrations (MIC) of polymyxin B, meropenem, amikacin, and fosfomycin against CRE were determined using the broth microdilution method.The in vitro combined sensitivity tests of polymyxin B with meropenem, amikacin, and fosfomycin were performed using the microdilution checkerboard method to calculate the fractional inhibitory concentration index (FICI) for determining their interactions.
Among the 76 strains of CRE, 24 strains were identified to carry the blaKPC, while 28 strains carried the blaNDM and another 24 strains carried the blaOXA-48-like. The drug-resistance rates of CRE strains to polymyxin B, meropenem, amikacin, and fosfomycin were determined as 3%, 92%, 39%, and 45%, respectively. The highest synergistic + partial synergistic rate was observed in combination of polymyxin B with meropenem (54%), followed by fosfomycin (43%) and amikacin (18%). For CRE carrying blaKPC, blaOXA-48-like, or blaNDM, the synergistic + partial synergistic rates of polymyxin B combined with fosfomycin were 37%, 42%, and 50%, respectively, while combined with meropenem were 75%, 21%, and 64%, respectively, and combined with amikacin were 8%, 25%, and 21%, respectively. No antagonistic effect was observed between polymyxin B and these three antibiotics.
The combination of polymyxin B and meropenem exhibits the best synergistic antibacterial effect against CRE, and the combined effect is related to the drug-resistance genotype of bacteria, so active detection of drug-resistance genes can help to promote the rational use of antibiotics in clinical practice.
There are many factors affecting the prognosis of tumor patients, and the related mechanisms are still unclear, among which anesthetics also have certain influence on the prognosis of tumor patients. Benzodiazepines are widely used in surgical anesthesia for tumor patients due to their sedative properties. Previous studies have found that diazepam and midazolam can inhibit the proliferation of tumor cells and induce apoptosis or necrosis. In addition, midazolam can also stabilize the perioperative state of patients, improve the efficacy of chemotherapy drugs, and thus improve the prognosis of patients. Remimazolam can improve the prognosis of tumor patients by alleviating intraoperative stress and immunosuppression. The direct effect of remimazolam on the prognosis of these tumor patients and the related mechanisms need to be further explored.
Opioid drugs activate G protein and （or） β-arrestin protein signaling pathways by acting on opioid receptors, which can generate analgesia and anesthesia effects, but the accompanying respiratory depression is a serious and common clinical problem. Until now, one of the goals of the basic research and therapeutic application of opioid drugs is to separate the analgesic effect from the respiratory depression side effect, so as to develop new opioid drugs with strong analgesic activity and reduced respiratory depression side effect. At present, peripheral selective opioid agonists, biased opioid agonists, mixed opioid agonists, endogenous opioid peptides and opioid splicing variant agonists have been developed successively, of which the biased opioid agonist oliceridine （TRV130） has been marketed. As the research progresses, more new opioid drugs will be used in clinical treatment to improve drug safety.
Drug-induced cardiotoxicity is one of the important reasons for the failure of drug development, and it is urgent to establish methods to screen the impact of drugs on the heart in the early stage. However, the traditional drug safety evaluation models are unable to meet the requirements of drug development. Therefore, the development of efficient and inexpensive drug safety evaluation and mechanism study models are very important for the development of new drugs and rational clinical application of drugs. In recent years, in addition to traditional animal models, the zebrafish, Drosophila,and Caenorhabditis elegans have been used for drug safety research. Based on transgenic technology, humanized animal models with gene expression profiles and regulation similar to that of humans can be established, and the development and application of such models can be used to solve the problem of species differences in drug research. In addition, non-animal methods such as organ chips, organoids, and network toxicology have also been developed. The novel cardiac safety evaluation models would be helpful for drug cardiotoxicity prevention and treatment, as well as drug development.
In recent years, many new drug treatment targets have been found, which provided the basis for the precise treatment of antipsychotic drugs and promoted the research and development of new antipsychotic drugs. The development of trace amine-associated receptor 1 agonist, glycine transporter-1 inhibitor, peripherally restricted muscarinic receptor antagonist, 5-hydroxytryptamine 2A/2C receptor inverse agonist and other new drugs have provided new possibilities for the treatment of psychotic symptoms and attracted much attention due to their significant efficacy and mild adverse reactions.
Recurrent vulvovaginal candidiasis （RVVC） is one of the common recurrent and refractory diseases that troubles women. Oteseconazole, the first drug for the treatment of RVVC, is an oral azole metallic enzyme inhibitor targeting fungal sterol 14α-demethylase （CYP51） developed by Mycovia Pharmaceuticals, Inc., and was approved for sale in the United States on April 26, 2022. Clinical trials have shown that oteseconazole has a significant therapeutic effect on RVVC with minimal adverse reactions.
The difficulties in diagnosing rare diseases, seeking medical treatment, and low drug accessibility have become a public health governance challenge in China and even globally. The fragmentation of China’s rare disease prevention and protection system is evident, and relevant policies urgently require legal authorization and solidification.Research and development of rare disease drugs lack effective legal and policy incentives. Special legislation is an effective way to solve the dilemma of rare disease prevention and protection. Promoting special legislation for rare diseases in China at present is an inherent requirement for achieving social justice and protecting the right to health of patients. There is a broad social consensus and mature experience outside the region for reference. The functional positioning of special legislation for the prevention and protection of rare diseases should be clarified, a reasonable value orientation for differential treatment should be established, and the construction of special legislation for rare diseases should be promoted through adhering to the idea of central coordination and local pilot parallel promotion.
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