Design, Synthesis, and In Vivo Evaluation of Isosteviol Derivatives as New SIRT3 Activators with Highly Potent Cardioprotective Effects.

Cardiovascular diseases (CVDs) persist as the predominant cause of mortality, urging the exploration of innovative pharmaceuticals. Mitochondrial dysfunction stands as a pivotal contributor to CVDs development. Sirtuin 3 (SIRT3), a prominent mitochondrial deacetylase known for its crucial role in protecting mitochondria against damage and dysfunction, has emerged as a promising therapeutic target for CVDs treatment. Utilizing isosteviol, a natural ent-beyerene diterpenoid, 24 derivatives were synthesized and evaluated in vivo using a zebrafish model, establishing a deduced structure-activity relationship. Among these, derivative 5v exhibited significant efficacy in doxorubicin-induced cardiomyopathy in zebrafish and murine models. Subsequent investigations revealed that 5v selectively elevated SIRT3 expression, leading to the upregulation of SOD2 and OPA1 expression, effectively preventing mitochondrial dysfunction, mitigating oxidative stress, and preserving cardiomyocyte viability. As a novel structural class of SIRT3 activators with robust therapeutic effects, 5v emerges as a promising candidate for further drug development.

IL-1α facilitates GSH synthesis to counteract oxidative stress in oral squamous cell carcinoma under glucose-deprivation.

Understanding the intrinsic mechanisms underpinning cancer metabolism and therapeutic resistance is of central importance for effective nutrition-starvation therapies. Here, we report that Interleukin 1A (IL1A) mRNA and IL-1α protein facilitate glutathione (GSH) synthesis to counteract oxidative stress and resistance against nutrition-starvation therapy in oral squamous cell carcinoma (OSCC). The expression of IL1A mRNA was elevated in the case of OSCC associated with unfavorable clinical outcomes. Both IL1A mRNA and IL-1α protein expression were increased under glucose-deprivation in vitro and in vivo. The transcription of IL1A mRNA was regulated in an NRF2-dependent manner in OSCC cell lines under glucose-deprivation. Moreover, the IL-1α conferred resistance to oxidative stress via GSH synthesis in OSCC cell lines. The intratumoral administration of siRNAs against IL1A mRNA markedly reversed GSH production and sensitized OSCC cells to Anlotinib in HN6 xenograft models. Overall, the current study demonstrates novel evidence that the autocrine IL-1α favors endogenous anti-oxidative process and confers therapeutic resistance to nutrition-starvation in OSCCs.

Sexual and Reproductive Health Outcomes Among Adolescent Females During the COVID-19 Pandemic.

BACKGROUND AND OBJECTIVES: Coronavirus disease 2019 (COVID-19) posed a significant threat to adolescents' sexual and reproductive health. In this study, we examined population-level pregnancy and sexual health-related care utilization among adolescent females in Ontario, Canada during the pandemic and evaluated relationships between these outcomes and key sociodemographic characteristics. METHODS: This was a population-based, repeated cross-sectional study of >630 000 female adolescents (12-19 years) during the prepandemic (January 1, 2018-February 29, 2020) and COVID-19 pandemic (March 1, 2020-December 31, 2022) periods. Primary outcome was pregnancy; secondary outcomes were contraceptive management visits, contraception prescription uptake, and sexually transmitted infection (STI) management visits. Poisson models with generalized estimating equations for clustered count data were used to model pre-COVID-19 trends and forecast expected rates during the COVID-19 period. Absolute rate differences between observed and expected outcome rates for each pandemic month were calculated overall and by urbanicity, neighborhood income, immigration status, and region. RESULTS: During the pandemic, lower-than-expected population-level rates of adolescent pregnancy (rate ratio 0.87; 95% confidence interval [CI]:0.85-0.88), and encounters for contraceptive (rate ratio 0.82; 95% CI:0.77-0.88) and STI management (rate ratio 0.52; 95% CI:0.51-0.53) were observed. Encounter rates did not return to pre-pandemic rates by study period end, despite health system reopening. Pregnancy rates among adolescent subpopulations with the highest pre-pandemic pregnancy rates changed least during the pandemic. CONCLUSIONS: Population-level rates of adolescent pregnancy and sexual health-related care utilization were lower than expected during the COVID-19 pandemic, and below-expected care utilization rates persist. Pregnancy rates among more structurally vulnerable adolescents demonstrated less decline, suggesting exacerbation of preexisting inequities.

Identifying Patterns of Primary Care Antibiotic Prescribing for a Spinal Cord Injury (SCI) Cohort Using an Electronic Medical Records (EMR) Database.

Background: Individuals with a spinal cord injury (SCI) are considered higher users of antibiotics. However, to date there have been no detailed studies investigating outpatient antibiotic use in this population. Objectives: (1) To describe primary care antibiotic prescribing patterns in adults with SCI rostered to a primary care physician (PCP), and (2) to identify patient or PCP factors associated with number of antibiotics prescribed and antibiotic prescription duration. Methods: A retrospective cohort study using linked health administrative and electronic medical records (EMR) databases from January 1, 2013 to December 31, 2015 among 432 adults with SCI in Ontario, Canada. Negative binomial regression analyses were conducted to identify patient or physician factors associated with number of antibiotics prescribed and prescription duration. Results: During the study period, 61.1% of the SCI cohort received an antibiotic prescription from their PCP. There were 59.8% of prescriptions for urinary tract infections (UTI) and 24.6% of prescriptions for fluoroquinolones. Regression analysis found catheter use was associated with increased number of antibiotics prescribed (relative risk [RR] = 3.1; 95% CI, 2.3-4.1; p < .001) and late career PCPs, compared to early-career PCPs, prescribed a significantly longer duration (RR = 1.8; 95% CI, 1.1-3.1; p = .02). Conclusion: UTIs were the number one prescription indication, and fluoroquinolones were the most prescribed antibiotic. Catheter use was associated with number of antibiotics, and PCP's years of practice was associated with duration. The study provided important information about primary care antibiotic prescribing in the SCI population and found that not all individuals received frequent antibiotics prescriptions.