Non-alcoholic fatty liver disease (NAFLD), or metabolic (dysfunction)-associated fatty liver disease (MAFLD), is characterized by high global incidence and prevalence, a tight association with common metabolic comorbidities, and a substantial risk of progression and associated mortality. Despite the increasingly high medical and socioeconomic burden of NAFLD, the lack of approved pharmacotherapy regimens remains an unsolved issue. In this paper, we aimed to provide an update on the rapidly changing therapeutic landscape and highlight the major novel approaches to the treatment of this disease. In addition to describing the biomolecules and pathways identified as upcoming pharmacological targets for NAFLD, we reviewed the current status of drug discovery and development pipeline with a special focus on recent evidence from clinical trials.

Гипоксия представляет собой типовой патологический процесс, характеризующийся возникновением кислородного дефицита в тканях и клетках и сопровождающийся развитием немедленных и отсроченных компенсаторно-адаптационных реакций. Одним из основных регуляторных механизмов, обеспечивающих срочную адаптацию к гипоксии, является репрограммирование работы митохондриальной электронтранспортной цепи (ЭТЦ). Янтарная кислота, или сукцинат, принимает участие в этом процессе не только как один из интермедиатов цикла трикарбоновых кислот (ЦТК), но и как сигнальная молекула. В связи с этим целью данного обзора стала систематизация имеющихся данных о молекулярных механизмах развития гипоксии и адаптации к ней на участке сопряжения ЭТЦ и ЦТК, а также о роли янтарной кислоты в указанных процессах.

Alzheimer’s disease and cerebral ischemia are among the many causative neurodegenerative diseases that lead to disabilities in the middle-aged and elderly population. There are no effective disease-preventing therapies for these pathologies. Recent in vitro and in vivo studies have revealed the TRPC6 channel to be a promising molecular target for the development of neuroprotective agents. TRPC6 channel is a non-selective cation plasma membrane channel that is permeable to Ca²⁺. Its Ca²⁺-dependent pharmacological effect is associated with the stabilization and protection of excitatory synapses. Downregulation as well as upregulation of TRPC6 channel functions have been observed in Alzheimer’s disease and brain ischemia models. Thus, in order to protect neurons from Alzheimer’s disease and cerebral ischemia, proper TRPC6 channels modulators have to be used. TRPC6 channels modulators are an emerging research field. New chemical structures modulating the activity of TRPC6 channels are being currently discovered. The recent publication of the cryo-EM structure of TRPC6 channels should speed up the discovery process even more. This review summarizes the currently available information about potential drug candidates that may be used as basic structures to develop selective, highly potent TRPC6 channel modulators to treat neurodegenerative disorders, such as Alzheimer’s disease and cerebral ischemia.

The search for and development of new neuroprotective (or cerebroprotective) drugs, as well as suitable methods for their preclinical efficacy evaluation, are priorities for current biomedical research. Alpha-2 adrenergic agonists, such as mafedine and dexmedetomidine, are a highly appealing group of drugs capable of reducing neurological deficits which result from brain trauma and vascular events in both experimental animals and human patients. Thus, our aim was to assess the effects of mafedine and dexmedetomidine on the brain’s electrical activity in a controlled cortical-impact model of traumatic brain injury (TBI) in rats. The functional status of the animals was assessed by electrocorticography (ECoG), using ECoG electrodes which were chronically implanted in different cortical regions. The administration of intraperitoneal mafedine sodium at 2.5 mg∙kg⁻¹ at 1 h after TBI induction, and daily for the following 6 days, restored interhemispheric connectivity in remote brain regions and intrahemispheric connections within the unaffected hemisphere at post-TBI day 7. Animals that had received mafedine sodium also demonstrated an improvement in cortical responses to photic and somatosensory stimulation. Dexmedetomidine at 25 μg∙kg⁻¹ did not affect the brain’s electrical activity in brain-injured rats. Our results confirm the previously described neuroprotective effects of mafedine sodium and suggest that ECoG registration and analysis are a viable method evaluating drug efficacy in experimental animal models of TBI.

БИОЛОГИЧЕСКАЯ АКТИВНОСТЬ HYPERICUM PERFORATUM L. (HYPERICACEAE): ОБЗОР

Fixed-dose drug products as well as non-fixed hepatoprotective drug combinations are commonly used in modern clinical practice. Combined and concurrent drug use makes it possible to augment the pharmacological effects of individual agents, or extend the range of their potential indications. The drugs most commonly considered for combination therapy include essential phospholipids, glycyrrhizinic acid, ursodeoxycholic acid, silibinin, and S-adenosylmethionine. This paper discusses the rationale for combined use of liver-targeting drugs from a pathogenetic viewpoint, and provides a review of the evidence from clinical trials on combined pharmacotherapy for liver disease.