The serotonin (5-hydroxytryptamine; 5-HT) 2A receptor is a cell surface class A G protein-coupled receptor that regulates a multitude of physiological functions of the body and is a target for antipsychotic drugs. Here we found by means of fluorescence resonance energy transfer and immunoprecipitation studies that the 5-HT 2A -receptor homodimerized in live cells, which we linked with its antagonist-dependent fingerprint in both binding and receptor signaling. Some antagonists, like the atypical antipsychotics clozapine and risperidone, differentiate themselves from others, like the typical antipsychotic haloperidol, antagonizing these 5-HT 2A receptor-mediated functions in a pathway-specific manner, explained here by a new model of multiple active interconvertible conformations at dimeric receptors.
Studies have reported the importance of mitochondria in sperm functionality. However, for some species, the glycolytic pathway appears to be as important as oxidative phosphorylation in ATP synthesis and sperm kinetics. These mechanisms have not been fully elucidated for bovine spermatozoa. Therefore, the aim of this study was to evaluate the role of mitochondria and the glycolytic pathway in ATP synthesis, sperm movement patterns, and oxidative homeostasis of epididymal spermatozoa in bovine specimens. We observed that mitochondrial uncoupling with protonophores significantly reduced ATP levels. However, these levels were reestablished after stimulation of the glycolytic pathway. We verified the same pattern of results for sperm kinetic variables and the production of reactive oxygen species (ROS). Thus, we suggest that, after its appropriate stimulation, the glycolytic pathway is capable of maintaining ATP levels, sperm kinetic patterns, and oxidative balance of bovine epididymal spermatozoa submitted to mitochondrial uncoupling.
Background SARS‐CoV‐2 virus requires host proteases to cleave its spike protein to bind to its ACE2 target through a two‐step furin‐mediated entry mechanism. Aprotinin is a broad‐spectrum protease inhibitor that has been employed as antiviral drug for other human respiratory viruses. Also, it has important anti‐inflammatory properties for inhibiting the innate immunity contact system. Methods This was a multicentre, double‐blind, randomized trial performed in four Spanish hospitals comparing standard treatment versus standard treatment + aprotinin for patients with COVID‐19 between 20 May 2020 and 20 October 2021. The primary efficacy outcomes were length of hospital stay and ICU admission. The secondary endpoints were each of the primary efficacy outcomes and a composite of oxygen therapy, analytical parameters and death. Safety outcomes included adverse reactions to treatment during a 30‐day follow‐up period. Treatment was given for 11 days or till discharge. Results With almost identical analytical profiles, significant differences were observed in treatment time, which was 2 days lower in the aprotinin group (p = .002), and length of hospital admission, which was 5 days shorter in the aprotinin group (p = .003). The incidence of discharge was 2.19 times higher (HR: 2.188 [1.182–4.047]) in the aprotinin group than in the placebo group (p = .013). In addition, the aprotinin‐treated group required less oxygen therapy and had no adverse reactions or side effects. Conclusion Inhaled aprotinin may improve standard treatment and clinical outcomes in hospitalized patients with COVID‐19, resulting in a shorter treatment time and hospitalization compared with the placebo group. The administration of aprotinin was safe.
For the last two decades, most efforts on new drug development to treat Alzheimer's disease have been focused to inhibit the synthesis of amyloid beta (Aβ), to prevent Aβ deposition, or to clear up Aβ plaques from the brain of Alzheimer's disease (AD) patients. Other pathogenic mechanisms such as the hyperphosphorylation of the microtubular tau protein (that forms neurofibrillary tangles) have also been addressed as, for instance, with inhibitors of the enzyme glycogen synthase-3 kinase beta (GSK3β). However, in spite of their proven efficacy in animal models of AD, all these compounds have so far failed in clinical trials done in AD patients. It seems therefore desirable to explore new concepts and strategies in the field of drug development for AD. We analyze here our hypothesis that a trifunctional chemical entity acting on the L subtype of voltage-dependent Ca 2+ channels (VDCCs) and on the mitochondrial Na + /Ca 2+ exchanger (MNCX), and having additional antioxidant properties, may efficiently delay or stop the death of vulnerable neurons in the brain of AD patients. In recent years, evidence has accumulated indicating that enhanced neuronal Ca 2+ cycling (NCC) and futile mitochondrial Ca 2+ cycling (MCC) are central stage in activating calpain and calcineurin, as well as the intrinsic mitochondrial pathway for apoptosis, leading to death of vulnerable neurons. An additional contributing factor to neuronal death is the excess free radical production linked to distortion of Ca 2+ homeostasis. We propose that an hybrid compound containing a dihydropyridine moiety (to block L channels and mitigate Ca 2+ entry) and a benzothiazepine moiety (to block the MNCX and slow down the rate of Ca 2+ efflux from the mitochondrial matrix into the cytosol), as well as a polyphenol moiety (to sequester excess free radicals) could break down the pathological enhanced NCC and MCC, thus delaying the initiation of apoptosis and the death of vulnerable neurons. In so doing, such a trifunctional compound could eventually become a neuroprotective medicine capable of delaying disease progression in AD patients.
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