Losmapimod ameliorates doxorubicin-induced cardiotoxicity through attenuating senescence and inflammatory pathways.

Irreversible cardiotoxicity limits the clinical application of doxorubicin (DOX). DOX-induced cardiotoxicity has been associated with induction of senescence and activation of the p38 MAPK pathway. Losmapimod (LOSM), an orally active p38 MAPK inhibitor, is an anti-inflammatory agent with cardioprotective effects. Nevertheless, the effect of LOSM against DOX-induced cardiotoxicity has not been reported. In this study, we determined the effects of LOSM on DOX-induced chronic cardiotoxicity in C57BL/6 N mice. Five-week-old C57BL/6 N mice were fed diet containing LOSM (estimated daily intake 12 mg/kg/day) or a control diet for four days. Thereafter, mice were randomized to receive six weekly intraperitoneal injections of either DOX (4 mg/kg) or saline. Three days after the last injection, cardiac function was assessed by trans-thoracic echocardiography. Activation of p38, JNK, and ERK1/2 MAPKs were assessed by immunoblotting in the heart and liver. Gene expressions of senescence, inflammatory, oxidative stress, and mitochondrial function markers were quantified using real-time PCR and serum inflammatory markers were assessed by Luminex. Our results demonstrated that LOSM attenuated p38 MAPK activation, ameliorated DOX-induced cardiac dysfunction, and abrogated DOX-induced expression of the senescence marker p21Cip1. Additionally, LOSM demonstrated anti-inflammatory effects, with reduced cardiac Il-1α and Il-6 gene expression in DOX-treated mice. Systemic inflammation, assessed by serum cytokine levels, showed decreased IL-6 and CXCL1 in both DOX-treated mice and mice on LOSM diet. LOSM significantly increased mitofusin2 gene expression, which may enhance mitochondrial fusion. These findings underscore the potential therapeutic efficacy of p38 MAPK inhibition, exemplified by LOSM, in ameliorating DOX-induced cardiotoxicity, senescence, and inflammation.

Hysteropathological Correlation in Abnormal Uterine Bleeding in a Tertiary Care Hospital in South India.

Background: Abnormal uterine bleeding is a common problem mainly encountered in reproductive age group and post-menopausal women. Hysteroscopy is a safe, simple, well tolerated and reliable procedure for the diagnosis of AUB across all age groups. The aim of the study is to determine the association of hysteroscopy and histopathologic examination (HPE) findings in abnormal uterine bleeding. The secondary objective of the study are to enumerate the hysteroscopy findings in patients with AUB and to evaluate the pattern of AUB. Materials and Methods: Observational cross-sectional study among 60 women in reproductive and post-menopausal age group presenting with features/symptoms suggestive of abnormal uterine bleeding were studied. All patients reporting in the outpatient department (OPD) and who are eligible to participate were included in the study, after obtaining written informed consent. Detailed history, Clinical examination, Ultrasound pelvis and endometrial thickness assessment is done. Hysteroscopic findings were compared against histopathological findings. Results: The various patterns of bleeding documented in our study population were menorrhagia, metrorrhagia, menometrorrhagia, polymenorrhea, and post-menopausal bleeding. Out of these patterns, the commonest was menorrhagia at 50.0% and post-menopausal bleeding at 26.67%. In our study population, the various hysteroscopy findings were strawberry, tongue-shaped projections, pebble stones, polypoidal patterns, and cerebroid patterns. Out of these, the most common was a polypoidal pattern, strawberry pattern, and tongue-shaped projections with 45%, 31.67%, and 26.7%, respectively. The most common histopathology finding was secretory and proliferative constituting 35% and 26.67%, respectively. Carcinoma endometrium constitutes about 6.67% of the study population. The sensitivity, specificity, PPV, and NPV of strawberry appearance in hysteroscopy in comparison with secretory changes in histopathology were 52.38%, 79.49%, 57.89%, and 75.61%, respectively. The sensitivity, specificity, PPV, and NPV of tongue-shaped projections appearance in hysteroscopy in comparison with HPE findings was 60%, 76.36%, 18.75%, and 95.45%, respectively. The sensitivity, specificity, PPV, and NPV of polypoidal pattern in hysteroscopy in comparison with Endometrial hyperplasia in histopathology was 66.67%, 56.14%, 7.41%, and 96.97%, respectively. The sensitivity, specificity, PPV, and NPV of cerebroid appearance in hysteroscopy in comparison with carcinoma endometrium in histopathology were 75.0%, 100%, 100%, and 98.25%, respectively. This correlation of cerebroid pattern with carcinoma endometrium was highly significant. Among all correlations, the highly reliable was in Carcinoma endometrium followed by endometrial polyps. Conclusion: Hysteroscopy has high sensitivity and specificity in diagnosing intrauterine pathology especially endometrial cancer followed by endometrial polyps. Among the various patterns of abnormal uterine bleeding, menorrhagia was the most common. A combination of hysteroscopy and endometrial sampling was found to increase diagnostic accuracy in patients with abnormal uterine bleeding and will effectively guide us in planning the appropriate management for these patients.

The Cardioprotective and Anticancer Effects of SGLT2 Inhibitors: JACC: CardioOncology State-of-the-Art Review.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally approved for type 2 diabetes mellitus, have demonstrated efficacy in reducing cardiovascular events, particularly heart failure, in patients with and without diabetes. An intriguing research area involves exploring the potential application of SGLT2 inhibitors in cardio-oncology, aiming to mitigate the cardiovascular adverse events associated with anticancer treatments. These inhibitors present a unique dual nature, offering both cardioprotective effects and anticancer properties, conferring a double benefit for cardio-oncology patients. In this review, the authors first examine the established cardioprotective effects of SGLT2 inhibitors in heart failure and subsequently explore the existing body of evidence, including both preclinical and clinical studies, that supports the use of SGLT2 inhibitors in the context of cardio-oncology. The authors further discuss the mechanisms through which SGLT2 inhibitors protect against cardiovascular toxicity secondary to cancer treatment. Finally, they explore the potential anticancer effects of SGLT2 inhibitors along with their proposed mechanisms.