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The sodium-glucose cotransporter 2 (SGLT2) is a glucose transporter that is located within the proximal tubule of the kidney’s nephrons. While it is typically associated with the kidney, it was later identified in various areas of the central nervous system, including areas modulating cardiorespiratory regulation like blood pressure. In the kidney, SGLT2 functions by reabsorbing glucose from the nephron’s tubule into the bloodstream. SGLT2 inhibitors are medications that hinder the function of SGLT2, thus preventing the absorption of glucose and allowing for its excretion through the urine. While SGLT2 inhibitors are not the first-line choice, they are given in conjunction with other pharmaceutical interventions to manage hyperglycemia in individuals with diabetes mellitus. SGLT2 inhibitors also have a surprising secondary effect of decreasing blood pressure independent of blood glucose levels. The implication of SGLT2 inhibitors in lowering blood pressure and its presence in the central nervous system brings to question the role of SGLT2 in the brain. Here, we evaluate and review the function of SGLT2, SGLT2 inhibitors, their role in blood pressure control, the future of SGLT2 inhibitors as antihypertensive agents, and the possible mechanisms of SGLT2 blood pressure control in the central nervous system.

Avian Influenza A(H5N1) Infection in a Farm WorkerA highly pathogenic avian influenza A(H5N1) virus infection was identified in a dairy farm worker in Texas. This pathogen has been reported in multiple dairy herds in several states.

Pre-existing mental disorders are linked to COVID-19-related outcomes. However, the findings are inconsistent and a thorough analysis of a broader spectrum of outcomes such as COVID-19 infection severity, morbidity, and mortality is required. We investigated whether the presence of psychiatric diagnoses and/or the use of antidepressants influenced the severity of the outcome of COVID-19. This retrospective cohort study evaluated electronic health records from the INSIGHT Clinical Research Network in 116,498 individuals who were diagnosed with COVID-19 between March 1, 2020, and February 23, 2021. We examined hospitalization, intubation/mechanical ventilation, acute kidney failure, severe sepsis, and death as COVID-19-related outcomes. After using propensity score matching to control for demographics and medical comorbidities, we used contingency tables to assess whether patients with (1) a history of psychiatric disorders were at higher risk of more severe COVID-19-related outcomes and (2) if use of antidepressants decreased the risk of more severe COVID-19 infection. Pre-existing psychiatric disorders were associated with an increased risk for hospitalization, and subsequent outcomes such as acute kidney failure and severe sepsis, including an increased risk of death in patients with schizophrenia spectrum disorders or bipolar disorders. The use of antidepressants was associated with significantly reduced risk of sepsis ( p  = 0.033), death ( p  = 0.026). Psychiatric disorder diagnosis prior to a COVID-19-related healthcare encounter increased the risk of more severe COVID-19-related outcomes as well as subsequent health complications. However, there are indications that the use of antidepressants might decrease this risk. This may have significant implications for the treatment and prognosis of patients with COVID-19.

Pyrogallol[4]arenes are polyhydroxylated compounds obtained by condensation between pyrogallol and different aldehydes. Depending on both the type of aldehyde (aromatic or aliphatic) and the reaction time, these compounds can be obtained in different conformations, the most common being the crown and chair conformations. Using the conventional synthesis method, it is possible to obtain, in addition to the chair or crown conformers, other molecular associations, such as dimer capsules. The research in this study focuses on the synthesis products obtained from the condensation between pyrogallol and propanal. These products were characterized using spectroscopic methods, revealing that it is possible to obtain, in addition to the crown conformation, the dimer capsule of the macrocycle. Finally, the volumetric properties of these conformers were evaluated in dimethyl sulfoxide (DMSO) solution at several temperatures.

Circadian fluctuations in physiological setpoints are determined by the suprachiasmatic nucleus (SCN) which exerts control over many target structures within and beyond the hypothalamus via projections. The SCN, or central pacemaker, orchestrates synchrony between the external environment and the internal circadian mechanism. The resulting cycles in hormone levels and autonomic nervous system (ANS) activity provide precise messages to specific organs, adjusting, for example, their sensitivity to approaching hormones or metabolites. The SCN responds to both photic (light) and non-photic input. Circadian patterns are found in both heart rate and blood pressure, which are linked to daily variations in activity and autonomic nervous system activity. Variations in blood pressure are of great interest as several cardiovascular diseases such as stroke, arrhythmias, and hypertension are linked to circadian rhythm dysregulation. The disruption of normal day-night cycles, such as in shift work, social jetlag, or eating outside of normal hours leads to desynchronization of the central and peripheral clocks. This desynchronization leads to disorganization of the cellular processes that are normally driven by the interactions of the SCN and photic input. Here, we review autonomic system function and dysfunction due to regulation and interaction between different cardiorespiratory brain centers and the SCN, as well as social, lifestyle, and external factors that may impact the circadian control of blood pressure.

Remdesivir is a leading therapy in patients with moderate to severe coronavirus 2 (SARS-CoV-2) infection; the majority of whom are older individuals. Remdesivir is a nucleoside analog that incorporates into nascent viral RNA, inhibiting RNA-directed RNA polymerases, including that of SARS-CoV-2. Less is known about remdesivir’s effects on mitochondria, particularly in older adults where mitochondria are known to be dysfunctional. Furthermore, its effect on age-induced mitochondrial mutations and copy number has not been previously studied. We hypothesized that remdesivir adversely affects mtDNA copy number and deletion mutation frequency in aged rodents. To test this hypothesis, 30-month-old male F333BNF1 rats were treated with remdesivir for three months. To determine if remdesivir adversely affects mtDNA, we measured copy number and mtDNA deletion frequency in rat hearts, kidneys, and skeletal muscles using digital PCR. We found no effects from three months of remdesivir treatment on mtDNA copy number or deletion mutation frequency in 33-month-old rats. These data support the notion that remdesivir does not compromise mtDNA quality or quantity at old age in mammals. Future work should focus on examining additional tissues such as brain and liver, and extend testing to human clinical samples.

The retromer is a cellular structure that recruits and recycles proteins inside the cell. In mammalian and yeast, the retromer components have been widely studied, but very little in parasites. In yeast, it is formed by a SNX-BAR membrane remodeling heterodimer and the cargo selecting complex (CSC), composed by three proteins. One of them, the Vps26 protein, possesses a flexible and intrinsically disordered region (IDR), that facilitates interactions with other proteins and contributes to the retromer binding to the endosomal membrane. In Entamoeba histolytica , the protozoan parasite responsible for human amoebiasis, the retromer actively participates during the high mobility and phagocytosis of trophozoites, but the molecular details in these events, are almost unknown. Here, we studied the EhVps26 role in phagocytosis. Bioinformatic analyses of EhVps26 revealed a typical arrestin folding structure of the protein, and a long and charged IDR, as described in other systems. EhVps26 molecular dynamics simulations (MDS) allowed us to predict binding pockets for EhVps35, EhSNX3, and a PX domain-containing protein; these pockets were disorganized in a EhVps26 truncated version lacking the IDR. The AlphaFold2 software predicted the interaction of EhVps26 with EhVps35, EhVps29 and EhSNX3, in a model similar to the reported mammalian crystals. By confocal and transmission electron microscopy, EhVps26 was found in the trophozoites plasma membrane, cytosol, endosomes, and Golgi-like apparatus. During phagocytosis, it followed the erythrocytes pathway, probably participating in cargoes selection and recycling. Ehvps26 gene knocking down evidenced that the EhVps26 protein is necessary for efficient phagocytosis.

Osteosarcoma is a bone cancer primarily affecting teenagers. It has a poor prognosis and diminished quality of life after treatment due to chemotherapy side effects, surgical complications and post-surgical osteoporosis risks. The sulphated polysaccharide fucoidan, derived from brown algae, has been a subject of interest for its potential anti-cancer properties and its impact on bone regeneration. This study explores the influence of crude, low-molecular-weight (LMW, 10–50 kDa), medium-molecular-weight (MMW, 50–100 kDa) and high-molecular-weight (HMW, >100 kDa) fractions from Sargassum filipendula, harvested from the Colombian sea coast, as well as crude fucoidan from Fucus vesiculosus, on a specific human osteoprogenitor cell type, human embryonic-derived mesenchymal stem cells. Fourier transform infrared spectroscopy coupled with attenuated total reflection (FTIR-ATR) results showed the highest sulphation levels and lowest uronic acid content in crude extract from F. vesiculosus. There was a dose-dependent drop in focal adhesion formation, proliferation and osteogenic differentiation of cells for all fucoidan types, but the least toxicity was observed for LMW and MMW. Transmission electron microscopy (TEM), JC-1 (5,50,6,60-tetrachloro-1,10,3,30-tetraethylbenzimi-dazolylcarbocyanine iodide) staining and cytochrome c analyses confirmed mitochondrial damage, swollen ER and upregulated autophagy due to fucoidans, with the highest severity in the case of F. vesiculosus fucoidan. Stress-induced apoptosis-like cell death by F. vesiculosus fucoidan and stress-induced necrosis-like cell death by S. filipendula fucoidans were also confirmed. LMW and MMW doses of <200 ng/mL were the least toxic and showed potential osteoinductivity. This research underscores the multifaceted impact of fucoidans on osteoprogenitor cells and highlights the delicate balance between potential therapeutic benefits and the challenges involved in using fucoidans for post-surgery treatments in patients with osteosarcoma.

Fucoidan is a brown algae-derived polysaccharide having several biomedical applications. This study simultaneously compares the anti-cancer activities of crude fucoidans from Fucus vesiculosus and Sargassum filipendula, and effects of low (LMW, 10–50 kDa), medium (MMW, 50–100 kDa) and high (HMW, >100 kDa) molecular weight fractions of S. filipendula fucoidan against osteosarcoma cells. Glucose, fucose and acid levels were lower and sulphation was higher in F. vesiculosus crude fucoidan compared to S. filipendula crude fucoidan. MMW had the highest levels of sugars, acids and sulphation among molecular weight fractions. There was a dose-dependent drop in focal adhesion formation and proliferation of cells for all fucoidan-types, but F. vesiculosus fucoidan and HMW had the strongest effects. G1-phase arrest was induced by F. vesiculosus fucoidan, MMW and HMW, however F. vesiculosus fucoidan treatment also caused accumulation in the sub-G1-phase. Mitochondrial damage occurred for all fucoidan-types, however F. vesiculosus fucoidan led to mitochondrial fragmentation. Annexin V/PI, TUNEL and cytochrome c staining confirmed stress-induced apoptosis-like cell death for F. vesiculosus fucoidan and features of stress-induced necrosis-like cell death for S. filipendula fucoidans. There was also variation in penetrability of different fucoidans inside the cell. These differences in anti-cancer activity of fucoidans are applicable for osteosarcoma treatment.

Hypertrophic cardiomyopathy (HCM) is a hereditary cardiac condition characterized by unexplained left ventricular hypertrophy without a hemodynamic cause. This condition is prevalent in the United States, resulting in various clinical manifestations, including diastolic dysfunction, left ventricular outflow obstruction, cardiac ischemia, and atrial fibrillation. HCM is associated with several genetic mutations, with sarcomeric mutations being the most common and contributing to a more complex disease course. Early diagnosis of HCM is essential for effective management, as late diagnosis often requires invasive treatments and creates a substantial financial burden. Disparities in HCM diagnosis and treatment exist between high-income and low-income countries. High-income countries have more resources to investigate and implement advanced diagnostic and treatment modalities. In contrast, low-income countries face challenges in accessing diagnostic equipment, trained personnel, and affordable medications, leading to a lower quality of life and life expectancy for affected individuals. Diagnostic tools for HCM include imaging studies such as 2D echocardiography, cardiovascular magnetic resonance (CMR), and electrocardiograms (ECGs). CMR is considered the gold standard but remains inaccessible to a significant portion of the world's population, especially in low-income countries. Genetics plays a crucial role in HCM, with numerous mutations identified in various genes. Genetic counseling is essential but often limited in low-income countries due to resource constraints. Disparities in healthcare access and adherence to treatment recommendations exist between high-income and low-income countries, leading to differences in patient outcomes. Addressing these disparities is essential to improve the overall management of HCM on a global scale. In conclusion, this review highlights the complex nature of HCM, emphasizing the importance of early diagnosis, genetic counseling, and access to appropriate diagnostic and therapeutic interventions. Addressing healthcare disparities is crucial to ensure that all individuals with HCM receive timely and effective care, regardless of their geographic location or socioeconomic status.