Decoding selectivity: computational insights into AKR1B1 and AKR1B10 inhibition.

Understanding selectivity mechanisms of inhibitors towards highly homologous proteins is of paramount importance in the design of selective candidates. Human aldo-keto reductases (AKRs) pertain to a superfamily of monomeric oxidoreductases, which serve as NADPH-dependent cytosolic enzymes to catalyze the reduction of carbonyl groups to primary and secondary alcohols using electrons from NADPH. Among AKRs, AKR1B1 is emerging as a promising target for cancer treatment and diabetes, despite its high structural similarity with AKR1B10, which leads to severe adverse events. Therefore, it is crucial to understand the selectivity mechanisms of AKR1B1 and AKR1B10 to discover safe anticancer candidates with optimal therapeutic efficacy. In this study, multiple computational strategies, including sequence alignment, structural comparison, Protein Contacts Atlas analysis, molecular docking, molecular dynamics simulation, MM-GBSA calculation, alanine scanning mutagenesis and pharmacophore modeling analysis were employed to comprehensively understand the selectivity mechanisms of AKR1B1/10 inhibition based on selective inhibitor lidorestat and HAHE. This study would provide substantial evidence in the design of potent and highly selective AKR1B1/10 inhibitors in future.

Literature analysis of cutaneous adverse reactions induced by tislelizumab.

OBJECTIVE: Tislelizumab may induce immune-related adverse events, especially adverse skin events. Early detection and timely intervention of cutaneous adverse events are crucial to improve patients' quality of life and reduce the disruption of therapeutic regimens. This study aimed to determine the clinical characteristics of cutaneous adverse reactions to tislelizumab and offer a reference for its rational clinical use. METHODS: Case reports of cutaneous adverse reactions induced by tislelizumab were collected from the relevant databases (up to 31 March 2023). Patient age, sex, primary disease, medication use, occurrence of adverse skin conditions, treatment, and outcomes were recorded and descriptively analysed. RESULTS: A total of 13 patients were enrolled, including six males and seven females, aged 55-79 years, with a median age of 75 years and a mean age of 70.92 ± 8.84 years. The original disease was lung carcinoma in none patients, cervical carcinoma in two, and urothelial carcinoma and squamous cell carcinoma in one each. The time from the initiation of medication use to the occurrence of cutaneous adverse reactions ranged from 7 to 177 days. Among the 13 patients, 10 showed improvement after drug withdrawal or symptomatic treatment. Two patients died (one died of disease progression and multiorgan failure, one died of acute coronary syndrome), and one patient's adverse skin reactions persisted without treatment. CONCLUSIONS: Tislelizumab-related cutaneous adverse reactions mostly occur after several days to months of treatment. In clinical practice, evaluation and monitoring should be strengthened. More attention should be paid to erythema and rashes, which may be signs of serious adverse skin reactions. Early detection and intervention can ensure the safe use of drugs and provide greater clinical benefits to patients.

Efficacy and safety of Aprepitant-containing triple therapy for the prevention and treatment of chemotherapy-induced nausea and vomiting: A meta-analysis.

BACKGROUND: Most cancer patients suffer from the pain of chemotherapy-induced nausea and vomiting (CINV). This meta-analysis was performed to evaluate the efficacy and safety of a regimen consisting of aprepitant, dexamethasone, and 5-HT3 receptor antagonists in the prevention and treatment of CINV. METHODS: A systematic literature search was conducted across multiple databases, including PubMed, EMbase, Cochrane Library, MEDLINE, CENTRAL, HEED, CNKI, Wanfang, and VIP, to identify randomized controlled trials (RCTs) investigating the use of triple therapy (aprepitant, 5-HT3 receptor antagonist, and dexamethasone) to prevent and treat CINV. Meta-analysis was performed using RevMan 5.4 and Stata17 software, employing either a fixed-effect or random-effect model based on statistical heterogeneity. RESULTS: A meta-analysis of 23 randomized controlled trials (RCTs) involving 7956 patients was conducted. Efficacy: Results showed significantly improved complete responses (CRs) for CINV in the test group versus the control group in the overall, acute, and delayed phases. Furthermore, in the test group, substantial alleviation of nausea symptoms was observed in the delayed and overall phases but not in the acute phase. Safety: There was no statistically significant difference in the incidence of febrile neutropenia, diarrhea, anorexia, and headache between the 2 groups. The incidence of fatigue and hiccups in the test group was higher than that in the control group; however, the incidence of constipation was significantly lower. CONCLUSIONS: Aprepitant-containing triple therapy is highly effective in the prevention and treatment of CINV, with reliable medication safety.

Palbociclib induces cell senescence and apoptosis of gastric cancer cells by inhibiting the Notch pathway.

Palbociclib (PD0332991), a selective cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has been reported to exert anticancer activity in some cancers, including gastric cancer (GC). However, the role of palbociclib in GC remains largely unknown. The present study aimed to investigate the effects of palbociclib on the progression of GC and the potential mechanisms underlying its effects. The colony formation, proliferation, senescence, as well as apoptosis and cell cycle progression of AGS and HGC-27 cells following treatment with palbociclib were analyzed using colony formation assays, MTT assays, senescence-associated ß-galactosidase (SA-ß-gal) staining and flow cytometry, respectively. The protein expression levels of Bax, Caspase-3, Bcl-2, p16, p21, p53, Notch1, Notch2 and hairy and enhancer of split 1 (Hes1) were measured in AGS and HGC-27 cells using western blotting. Moreover, the mRNA expression levels of Notch1, Notch2 and Hes1 in AGS and HGC-27 cells were determined by reverse transcription-quantitative PCR. In the present study, palbociclib significantly inhibited cell proliferation and induced cell senescence, cell cycle arrest and apoptosis in both cell lines in a dose-dependent manner. Additionally, palbociclib significantly increased the expression levels of Bax, Caspase-3, p16, p21 and p53, whilst decreasing the expression of Bcl-2, Notch1, Notch2 and Hes1 in AGS and HGC-27 cells. Furthermore, the Notch pathway activator Jagged-1/FC reversed the effects of palbociclib on cell proliferation, apoptosis, senescence and cell cycle progression. These findings demonstrated that palbociclib could inhibit proliferation and induce senescence, cell cycle arrest and apoptosis in GC cells by inhibiting the Notch pathway.