Myocardial SERCA2 protects against cardiac damage and dysfunction caused by inhaled bromine.

Myocardial sarcoendoplasmic reticulum calcium ATPase 2 (SERCA2) activity is critical for heart function. We have demonstrated that inhaled halogen (chlorine or bromine) gases inactivate SERCA2, impair calcium homeostasis, increase proteolysis, and damage the myocardium ultimately leading to cardiac dysfunction. To further elucidate the mechanistic role of SERCA2 in halogen induced myocardial damage we utilized bromine exposed cardiac specific SERCA2 knockout (KO) mice (tamoxifen administered SERCA(flox/flox) Tg(aMHC-MerCreMer) mice) and compared them to the oil administered controls (FF). We performed echocardiography and hemodynamic analysis to investigate cardiac function 24h after bromine (600 ppm, for 30 min) exposure and measured cardiac injury markers in plasma, proteolytic activity in cardiac tissue and performed electron microscopy of the left ventricle (LV). Cardiac specific SERCA2 knockout mice demonstrated enhanced toxicity to bromine. Bromine exposure increased ultrastructural damage, perturbed LV shape geometry, and demonstrated acutely increased phosphorylation of phospholamban in the KO mice. Bromine exposed KO mice revealed significantly enhanced mean arterial pressure (MAP) and sphericity index, decreased LV end diastolic diameter LVEDD and LV end systolic pressure (LVESP), when compared to the bromine exposed control FF mice. Strain analysis showed loss of synchronicity, evidenced by an irregular endocardial shape in systole and irregular vector orientation of contractile motion across different segments of the LV in KO mice, both at baseline and after bromine exposure. These studies underscore the critical role of myocardial SERCA2 in preserving cardiac ultrastructure and function during toxic halogen gas exposures. Significance Statement Due to their increased industrial production and transportation, halogens like chlorine and bromine pose an enhanced risk of exposure to the public. Our studies have demonstrated that inhalation of these halogens leads to the inactivation of cardiopulmonary SERCA2 and results in calcium overload. Using cardiac specific SERCA2 knockout mice these studies further validated the role of SERCA2 in bromine-induced myocardial injury. These studies highlight the increased susceptibility of individuals with pathological loss of cardiac SERCA2 to the effects of bromine.

ZNF397 Deficiency Triggers TET2-driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer.

Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified Zinc Finger Protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a Ten-Eleven Translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that a TET2 inhibitor can eliminate the resistance to AR targeted therapies in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate cancer acquires lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity.

A computed tomography (CT)-based morphometric study of various skull base parameters and their anatomical relationships relevant to endoscopic endonasal skull base surgery.

Background: Endoscopic skull base surgery requires a thorough understanding of skull base anatomy. Orientation to regional anatomy to avoid complications like internal carotid artery injury can be assisted by knowledge of certain bony landmarks. These landmarks are themselves highly variable structures. This study focuses on the radiological morphometric characterization of these landmarks, which can be of great assistance to surgeons for better planning of endoscopic skull base approaches. Methods: Computed tomography scans of patients without skull base pathologies were analyzed retrospectively for the following parameters - Vidian canal (VC) length, VC and foramen rotundum (FR) distance from midline, the angle between the axis of VC and petrous internal carotid artery (pICA) and between VC and palatovaginal canal, the horizontal, vertical and direct distances between VC and FR and the patterns of sphenoid sinus (SS) pneumatization. Results: The VC-pICA angle was more obtuse and VC and FR were placed farther off the midline on the left as compared to the right side. Similarly, the distances between VC and FR were more on the left side. The VC length and distance of VC and FR from the midline were longer in males than in females. The VC-pICA angle was more obtuse in females. The post-sellar variant was the predominant pneumatization pattern seen (57.9%), and the incidence of lateral recess pneumatization was 15%. Conclusion: The results of our study can be utilized for a better understanding of the anatomy of the skull base. In skull base pathologies with distorted anatomical landmarks, a basic understanding of their interrelations can be used to have a better anatomical orientation. All these measures can help in avoiding complications and make extended endoscopic approaches safe.

Exploring the modulatory effects of sotagliflozin on dyslipidemia in mice: The role of glucagon, fibroblast growth factor 21 and glucagon-like peptide 1.

Sotagliflozin is the first dual SGLT1/2 inhibitor antidiabetic drug approved by the US Food and Drug Administration for the management of heart failure. SGLT1/2 inhibition is observed to potentiate the secretion of the incretin hormone, glucagon-like peptide-1 (GLP-1). The current preclinical research sought to investigate the effect of sotagliflozin on the secretion of fat-regulating peptides such as GLP-1, glucagon and fibroblast growth factor 21 (FGF21) and their prospective association with sotagliflozin's potential beneficial effects on dyslipidaemia. During an oral fat tolerance test in mice, sotagliflozin substantially increased GLP-1 and insulin concentrations. Although sotagliflozin alone did not ameliorate postprandial lipemia, its combination with linagliptin (DPP-IV inhibitor) significantly improved lipid tolerance comparable to orlistat (lipase inhibitor). In a triton-induced hypertriglyceridemia model, sotagliflozin, along with other medications (fenofibrate, exenatide and linagliptin) reduced fat excursion; however, co-administration with linagliptin provided no extra advantage. Furthermore, sotagliflozin stimulated glucagon secretion in the alpha TC1.6 cells and healthy mice, which resulted in an increased circulating FGF21 and ß-hydroxybutyrate concentration. Finally, chronic treatment of sotagliflozin in high-fat diet (HFD)-fed obese mice resulted in reduced body weight gain, liver triglyceride, cholesterol, interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α) levels compared with the placebo group. However, the addition of linagliptin did not provide any additional benefit. In conclusion, sotagliflozin was found to have an effect on GLP-1 and also stimulate the release of glucagon and FGF21, which are important for regulating fat metabolism. Therefore, sotagliflozin might represent a potential therapeutic approach for the treatment of diabetic dyslipidemia and steatohepatitis.

Functional and Neuropsychological Outcome After Surgical Treatment of Moyamoya Disease.

BACKGROUND: Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive stenosis of the supraclinoid internal carotid artery. As a result of chronically decreased brain perfusion, eloquent areas of the brain become hypoperfused, leading to cognitive changes in patients. Repeated infarcts and bleeds produce clinically apparent neurologic deficits. OBJECTIVES: 1) To study the functional and neuropsychological outcome in MMD after revascularization surgery. 2) To find postrevascularization correlation between functional and neuropsychological improvement and radiologic improvement. METHODS: A single-center prospective and analytic study was carried out including 21 patients with MMD during the study period from March 2021 to December 2022. Patients were evaluated and compared before and after revascularization for functional, neuropsychological, and radiologic status. RESULTS: Postoperative functional outcome in terms of modified Rankin Scale score showed improvement in 33.33% of cases (P = 0.0769). An overall improving trend was observed in different neuropsychological domains in both adult and pediatric age groups. However, the trend of neuropsychological improvement was better in adults compared with pediatric patients. Radiologic outcome in the form of the Angiographic Outcome Score (AOS) significantly improved after revascularization (P = 0.0001). There was a trend toward improvement in magnetic resonance imaging (MRI) perfusion in the middle cerebral artery and anterior cerebral artery territories, 4.7% (P = 0.075) and 9.33% (P = 0.058) respectively, compared with preoperative MRI perfusion. CONCLUSIONS: After revascularization, significant improvement occurred in functional and neuropsychological status. This result was also shown radiologically as evidenced by improvement in MRI perfusion and cerebral angiography.

Exercise reduces pro-inflammatory lipids and preserves resolution mediators that calibrate macrophage-centric immune metabolism in spleen and heart following obesogenic diet in aging mice.

The study investigated the role of volunteer exercise and an obesogenic diet (OBD) in mice, focusing on the splenocardiac axis and inflammation-resolution signaling. Male C57BL/6J mice (2 months old) were assigned to control (CON) or OBD groups for ten months, then randomized into sedentary (Sed) or exercise (Exe) groups for two weeks. Leukocytes, heart function, structure, and spleen tissue examined for inflammation-resolution mediators and macrophage-centric gene transcripts. After two weeks of volunteer exercise, cardiac function shows limited changes, but structural changes were notable in the heart and spleen. Exercise induced cardiac nuclear hyperplasia observed in both CON and OBD groups. OBD-Sed mice showed splenic changes and increased neutrophils, whereas increased neutrophils were noted in the CON post exercise. OBD-Sed increased pro-inflammatory lipid mediators in the heart, reduced by exercise in OBD-Exe, while CON-Exe preserved resolution mediators. Chronic OBD-Sed depletes long chain fatty acids (DHA/EPA) in the heart and spleen, while exercise independently regulates lipid metabolism genes in both organs, affecting macrophage-centric lipid and lipoprotein pathways. Chronic obesity amplified cardiac inflammation, countered by exercise that lowered pro-inflammatory bioactive lipid mediators in the heart. OBD sustained inflammation in the heart and spleen, while exercise conserved resolution mediators in CON mice. In summary, these findings emphasize the interplay of diet with exercise and highlight the intricate connection of diet, exercise, inflammation-resolution signaling in splenocardiac axis and immune health.

Association of Common Foods with Inflammation and Mortality: Analysis from a Large Prospective Cohort Study.

Some dietary patterns are associated with inflammation, while others lower inflammation and improve health. However, many people cannot follow a complete, healthy diet. Therefore, this study's aim was to identify specific foods associated chronic inflammation and mortality. The study used Multi-Ethnic Study of Atherosclerosis (MESA) research materials from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center. Three plant-based and three animal-based MESA food categories were chosen based on perceived availability in the western diet. The assessed food categories were avocado, ham, sausage, eggs, greens, and broccoli. Inflammatory markers assessed were interleukin-6 (IL-6), fibrinogen antigen, C-reactive protein, D-Dimer, interleukin-2, matrix metalloproteinase 3, necrosis factor-a soluble receptors, oxidized LDL (oxLDL), and total homocysteine. The primary outcome was the multivariable association of foods and inflammatory markers with all-cause mortality. All inflammatory makers, except oxLDL, were associated with mortality in univariate analysis. The effect was largest with IL-6 and D-dimer. The category of broccoli had the most consistent association in univariate analyses with lower inflammation and lower mortality odds. Low and high broccoli consumption versus no consumption were associated with lower mortality odds in the multivariable models with IL-6 and D-dimer. Consumption of the MESA-defined food category "broccoli" (i.e., broccoli, cabbage, cauliflower, brussels sprouts, sauerkraut, and kimchee) was associated with lower inflammation and lower mortality odds. These findings should be validated in randomized controlled trials testing a "food is medicine" approach to identify which, if any, of these foods may have potential as an herbal therapeutic for chronic inflammation.

Gut Microbiome and Polycystic Ovary Syndrome: Interplay of Associated Microbial-Metabolite Pathways and Therapeutic Strategies.

Polycystic ovary syndrome (PCOS) is a multifaceted disease with an intricate etiology affecting reproductive-aged women. Despite attempts to unravel the pathophysiology, the molecular mechanism of PCOS remains unknown. There are no effective or suitable therapeutic strategies available to ameliorate PCOS; however, the symptoms can be managed. In recent years, a strong association has been found between the gut microbiome and PCOS, leading to the formulation of novel ideas on the genesis and pathological processes of PCOS. Further, gut microbiome dysbiosis involving microbial metabolites may trigger PCOS symptoms via many mechanistic pathways including those associated with carbohydrates, short-chain fatty acids, lipopolysaccharides, bile acids, and gut-brain axis. We present the mechanistic pathways of PCOS-related microbial metabolites and therapeutic opportunities available to treat PCOS, such as prebiotics, probiotics, and fecal microbiota therapy. In addition, the current review highlights the emerging treatment strategies available to alleviate the symptoms of PCOS.

UBE2J1 is the E2 ubiquitin-conjugating enzyme regulating androgen receptor degradation and antiandrogen resistance.

Prostate cancer (PCa) is primarily driven by aberrant Androgen Receptor (AR) signaling. Although there has been substantial advancement in antiandrogen therapies, resistance to these treatments remains a significant obstacle, often marked by continuous or enhanced AR signaling in resistant tumors. While the dysregulation of the ubiquitination-based protein degradation process is instrumental in the accumulation of oncogenic proteins, including AR, the molecular mechanism of ubiquitination-driven AR degradation remains largely undefined. We identified UBE2J1 as the critical E2 ubiquitin-conjugating enzyme responsible for guiding AR ubiquitination and eventual degradation. The absence of UBE2J1, found in 5-15% of PCa patients, results in disrupted AR ubiquitination and degradation. This disruption leads to an accumulation of AR proteins, promoting resistance to antiandrogen treatments. By employing a ubiquitination-based AR degrader to adeptly restore AR ubiquitination, we reestablished AR degradation and inhibited the proliferation of antiandrogen-resistant PCa tumors. These findings underscore the fundamental role of UBE2J1 in AR degradation and illuminate an uncharted mechanism through which PCa maintains heightened AR protein levels, fostering resistance to antiandrogen therapies.

Evaluating physiochemical properties of FDA-approved orally administered drugs.

INTRODUCTION: Analyses of orally administered FDA-approved drugs from 1990 to 1993 enabled the identification of a set of physiochemical properties known as Lipinski's Rule of Five (Ro5). The original Ro5 and extended versions still remain the reference criteria for drug development programs. Since many bioactive compounds do not conform to the Ro5, we validated the relevance of and adherence to these rulesets in a contemporary cohort of FDA-approved drugs. AREAS COVERED: The authors noted that a significant proportion of FDA-approved orally administered parent compounds from 2011 to 2022 deviate from the original Ro5 criteria (~38%) or the Ro5 with extensions (~53%). They then evaluated if a contemporary Ro5 criteria (cRo5) could be devised to better predict oral bioavailability. Furthermore, they discuss many case studies showcasing the need for and benefit of increasing the size of certain compounds and cover several evolving strategies for improving oral bioavailability. EXPERT OPINION: Despite many revisions to the Ro5, the authors find that no single proposed physiochemical rule has universal concordance with absolute oral bioavailability. Innovations in drug delivery and formulation have dramatically expanded the range of physicochemical properties and the chemical diversity for oral administration.

Clinical and CT Scan Evaluation of Outcomes of Modified SARPE Using a Bone-Borne Hyrax Appliance in Unilateral Posterior Crossbite.

Objective: The objective of this study was to evaluate, using clinical and computed tomography, outcomes of unilateral SARPE with a bone-borne hyrax appliance in case of unilateral crossbite and to assess the correlations between hyrax appliance opening and post-SARPE skeletal changes. Materials and Methods: Two patients of unilateral crossbite underwent Unilateral SARPE and post-surgical expansion of maxilla using a bone-borne hyrax appliance. Computed tomography was used to make comparative linear and angular measurements of the anterior, intermediate, and posterior portions of the maxilla. The correlation between maxillary expansion and appliance opening was also investigated. Results: Significant overall expansion was observed with maximum expansion in the anterior and inferior portions of the maxilla. The degree of appliance opening was significantly greater than that of the skeletal expansion. Comparative CAD measurements showed maximum increase in interdental width at the second premolar level. Conclusion: The transverse expansion of the maxilla obtained with a bone-borne hyrax is less than uniform. The lack of linear correlation between appliance opening and skeletal expansion is attributable to multiple factors, including those related to the device, the surgical technique, and the craniofacial deformity itself.

The Role of Low Mineral Water Consumption in Reducing the Mineral Density of Bones and Teeth: A Narrative Review.

Low mineral water has gained increasing attention due to its potential health implications concerning bone mineral density (BMD) and dental health. Reverse osmosis (RO) systems to purify water are in use extensively, and these systems, in addition to removing impurities from water, also remove 92-99% of beneficial minerals like calcium, lead, fluoride, magnesium, and iron. These minerals are essential for maintaining optimal mineral density of teeth and bones, thereby preserving bone and teeth health. Most of these mineral components are physically larger than water molecules and are trapped by the semi-permeable membrane of RO filters when drinking water is filtered through it. The resultant water is of very poor mineral content, and studies have shown that this water, when consumed, can absorb minerals from the body and eliminate the same through urine. The combined synergistic effect of consumption of low mineral water along with minerals being excreted has been shown to cause demineralization of bones and teeth, increasing the risk of osteoporosis and dental caries. This review tries to address the ill effects of consuming low mineral water along with preventive strategies to overcome its much-concealed adverse effects.

Direct ionic stress sensing and mitigation by the transcription factor NFAT5.

Homeostatic control of intracellular ionic strength is essential for protein, organelle and genome function, yet mechanisms that sense and enable adaptation to ionic stress remain poorly understood in animals. We find that the transcription factor NFAT5 directly senses solution ionic strength using a C-terminal intrinsically disordered region. Both in intact cells and in a purified system, NFAT5 forms dynamic, reversible biomolecular condensates in response to increasing ionic strength. This self-associative property, conserved from insects to mammals, allows NFAT5 to accumulate in the nucleus and activate genes that restore cellular ion content. Mutations that reduce condensation or those that promote aggregation both reduce NFAT5 activity, highlighting the importance of optimally tuned associative interactions. Remarkably, human NFAT5 alone is sufficient to reconstitute a mammalian transcriptional response to ionic or hypertonic stress in yeast. Thus NFAT5 is both the sensor and effector of a cell-autonomous ionic stress response pathway in animal cells.

Transposable Elements Are Co-opted as Oncogenic Regulatory Elements by Lineage-Specific Transcription Factors in Prostate Cancer.

Transposable elements hold regulatory functions that impact cell fate determination by controlling gene expression. However, little is known about the transcriptional machinery engaged at transposable elements in pluripotent and mature versus oncogenic cell states. Through positional analysis over repetitive DNA sequences of H3K27ac chromatin immunoprecipitation sequencing data from 32 normal cell states, we report pluripotent/stem and mature cell state-specific "regulatory transposable elements." Pluripotent/stem elements are binding sites for pluripotency factors (e.g., NANOG, SOX2, OCT4). Mature cell elements are docking sites for lineage-specific transcription factors, including AR and FOXA1 in prostate epithelium. Expanding the analysis to prostate tumors, we identify a subset of regulatory transposable elements shared with pluripotent/stem cells, including Tigger3a. Using chromatin editing technology, we show how such elements promote prostate cancer growth by regulating AR transcriptional activity. Collectively, our results suggest that oncogenesis arises from lineage-specific transcription factors hijacking pluripotent/stem cell regulatory transposable elements. SIGNIFICANCE: We show that oncogenesis relies on co-opting transposable elements from pluripotent stem cells as regulatory elements altering the recruitment of lineage-specific transcription factors. We further discover how co-option is dependent on active chromatin states with important implications for developing treatment options against drivers of oncogenesis across the repetitive DNA. This article is featured in Selected Articles from This Issue, p. 2293.

Riluzole Suppresses Growth and Enhances Response to Endocrine Therapy in ER+ Breast Cancer.

Background: Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a significant clinical problem. Riluzole is FDA-approved for the treatment of amyotrophic lateral sclerosis. A benzothiazole-based glutamate release inhibitor with several context-dependent mechanism(s) of action, riluzole has shown antitumor activity in multiple malignancies, including melanoma, glioblastoma, and breast cancer. We previously reported that the acquisition of tamoxifen resistance in a cellular model of invasive lobular breast cancer is accompanied by the upregulation of GRM mRNA expression and growth inhibition by riluzole. Methods: We tested the ability of riluzole to reduce cell growth, alone and in combination with endocrine therapy, in a diverse set of ER+ invasive ductal and lobular breast cancer-derived cell lines, primary breast tumor explant cultures, and the estrogen-independent, ESR1-mutated invasive lobular breast cancer patient-derived xenograft model HCI-013EI. Results: Single-agent riluzole suppressed the growth of ER+ invasive ductal and lobular breast cancer cell lines in vitro, inducing a histologic subtype-associated cell cycle arrest (G0-G1 for ductal, G2-M for lobular). Riluzole induced apoptosis and ferroptosis and reduced phosphorylation of multiple prosurvival signaling molecules, including Akt/mTOR, CREB, and Fak/Src family kinases. Riluzole, in combination with either fulvestrant or 4-hydroxytamoxifen, additively suppressed ER+ breast cancer cell growth in vitro. Single-agent riluzole significantly inhibited HCI-013EI patient-derived xenograft growth in vivo, and the combination of riluzole plus fulvestrant significantly reduced proliferation in ex vivo primary breast tumor explant cultures. Conclusion: Riluzole may offer therapeutic benefits in diverse ER+ breast cancers, including lobular breast cancer.

Comparison between ocular biometry parameters in patients with unilateral congenital glaucoma.

Purpose: To compare the axial length (AL) and corneal diameter between glaucomatous eye (GE) and fellow normal eye (NE) in patients with unilateral congenital glaucoma and to obtain a normative database for ocular growth among Indian children below 3 years of age. Methods: Retrospective longitudinal study. Patients who had a follow-up of 3 years from diagnosis with ocular biometry parameters being recorded at least thrice (once a year) and fellow eye being normal were included. Data collected were age, gender, intraocular pressure (IOP), AL, corneal diameter, optic disc findings, diagnosis, and surgery details. Results: Eleven patients were analyzed. All GE underwent combined trabeculotomy with trabeculectomy. Mean (SD) baseline IOP, AL, and corneal diameter were 17.1 (6.7) mmHg, 18.9 (1.1) mm and 12 (0.91) mm in GE, and 11.1 (3.8) mmHg, 17.8 (0.44) mm, and 10.5 (0.58) mm in NE, respectively. Increase in AL was 3.1 mm in the first year followed by 0.6 mm in second year and 0.4 mm in third year in GE compared to 2.6, 0.6, and 0.5 mm in NE, respectively. Corneal diameter increased by 1.1 mm in GE in the first year and remained stable thereafter compared to 0.7 mm in first year followed by 0.3 mm in second year and stable thereafter in NE. The percentage of success was 73% at 3 years. Conclusion: Axial length and corneal diameter were higher in GE than NE at all-time points. With prompt intervention, the growth curve of the GE was made parallel to that of NE.

Extrinsic and intrinsic modulators of inflammation-resolution signaling in heart failure.

Chronic and uncleared inflammation is the root cause of various cardiovascular diseases. Fundamentally, acute inflammation is supportive when overlapping with safe clearance of inflammation termed resolution; however, if the lifestyle-directed extrinsic factors such as diet, sleep, exercise, or physical activity are misaligned, that results in unresolved inflammation. Although genetics play a critical role in cardiovascular health, four extrinsic risk factors-unhealthy processed diet, sleep disruption or fragmentation, sedentary lifestyle, thereby, subsequent stress-have been identified as heterogeneous and polygenic triggers of heart failure (HF), which can result in several complications with indications of chronic inflammation. Extrinsic risk factors directly impact endogenous intrinsic factors, such as using fatty acids by immune-responsive enzymes [lipoxygenases (LOXs)/cyclooxygenases (COXs)/cytochromes-P450 (CYP450)] to form resolution mediators that activate specific resolution receptors. Thus, the balance of extrinsic factors such as diet, sleep, and physical activity feed-forward the coordination of intrinsic factors such as fatty acids-enzymes-bioactive lipid receptors that modulates the immune defense, metabolic health, inflammation-resolution signaling, and cardiac health. Future research on lifestyle- and aging-associated molecular patterns is warranted in the context of intrinsic and extrinsic factors, immune fitness, inflammation-resolution signaling, and cardiac health.