Mitochondrial Function and Dysfunction in White Adipocytes and Therapeutic Implications.

For a long time, white adipocytes were thought to function as lipid storages due to the sizeable unilocular lipid droplet that occupies most of their space. However, recent discoveries have highlighted the critical role of white adipocytes in maintaining energy homeostasis and contributing to obesity and related metabolic diseases. These physiological and pathological functions depend heavily on the mitochondria that reside in white adipocytes. This article aims to provide an up-to-date overview of the recent research on the function and dysfunction of white adipocyte mitochondria. After briefly summarizing the fundamental aspects of mitochondrial biology, the article describes the protective role of functional mitochondria in white adipocyte and white adipose tissue health and various roles of dysfunctional mitochondria in unhealthy white adipocytes and obesity. Finally, the article emphasizes the importance of enhancing mitochondrial quantity and quality as a therapeutic avenue to correct mitochondrial dysfunction, promote white adipocyte browning, and ultimately improve obesity and its associated metabolic diseases. © 2024 American Physiological Society. Compr Physiol 14:5581-5640, 2024.

Repeatability and agreement of two swept-source optical coherence tomographers and scheimpflug imaging for measurements of corneal curvature.

PURPOSE: To evaluate the repeatability and agreement of two swept-source optical coherence tomographers and Scheimpflug imaging for corneal curvature in healthy subjects to obtain data on the clinical application of a new device. METHODS: This prospective study was conducted in January and February 2021 with 100 healthy subjects at the Eye Hospital of Wenzhou Medical University. Simulated keratometry (Sim-K), posterior keratometry (Kp), total corneal power (TCP), and total corneal astigmatism (TCA) were measured with CASIA2, Anterion, and Pentacam. Within-subject standard deviation (Sw), repeatability coefficient (RC), coefficient of variation (CoV), and intraclass correlation coefficient (ICC) were used to assess inter-device repeatability. Bland-Altman analysis was performed to determine inter-device agreement. RESULTS: The three devices showed good repeatability for Sim-K, Kp, and TCP with all ICC > 0.980. Pentacam showed the highest repeatability (ICC ≥ 0.993; ICC ≥ 0.993) while the CASIA2 demonstrated the lowest repeatability (ICC: ≥ 0.986; ICC: ≥ 0.985) for Sim-K and TCP. Anterion and CASIA2 revealed better repeatability (ICC ≥ 0.998; ICC ≥ 0.981) for Kp than Pentacam (ICC ≥ 0.980). Pentacam and Anterion showed good repeatability for TCA (ICC: 0.935 and 0.916), whereas the CASIA2 showed moderate repeatability (ICC: 0.836). Three instruments demonstrated good agreement with the maximum absolute 95% Limits of agreement (LoA) of 1.00 D for Sim-K, Kp, and TCP. Wide LoA were found for TCA with the maximum absolute 95% LoA ≥ 0.66 D between the three devices. CONCLUSIONS: In healthy subjects, the three devices (Pentacam, Anterion and CASIA2) displayed comparable repeatability and accuracy for SimK, Kp, and TCP, and could be used interchangeably for these parameters. However, TCA measured by the three devices was not interchangeable. TRIAL REGISTRATION: Chinese Clinical Trial Registry Center (10/10/2020, ChiCTR2000038959).

Experimental Model of Cerebral Arterial Air Embolism in Conscious Rats.

In this work, an optimal air supply mode was selected to create a model of cerebral arterial air embolism (CAAE) on conscious male Sprague-Dawley rats (n=49). The efficacy of the selected model (administration of 100 µl/kg of air at a rate of 10 µl/min with an infusion pump) was determined by changes in serum biochemical parameters (cholesterol, alkaline phosphatase, inorganic phosphates, AST, and triglycerides), impaired motor functions in the Rotarod test, and visual assessment of the ischemic foci (staining of frontal sections with 1% triphenyltetrazolium chloride solution) at different terms after AAE. The model of AAE created by us confirmed impairment of coordination and motor function in conscious animals and reproduced the lethal consequences of this condition. The obtained results can serve as the basis for drug testing and the development of new approaches to the treatment of ischemic stroke.

Hypoxia signaling in the adipose tissue.

Obesity per se is rapidly emerging all over the planet and further accounts for many other life-threatening conditions, such as diabetes, cardiovascular diseases, and cancers. Decreased oxygen supply or increased relative oxygen consumption in the adipose tissue results in adipose tissue hypoxia, which is a hallmark of obesity. This review aims to provide an up-to-date overview of the hypoxia signaling in the adipose tissue. First, we summarize literature evidence to demonstrate that hypoxia is regularly observed during adipose tissue remodeling in human and rodent models of obesity. Next, we discuss how hypoxia-inducible factors (HIFs) are regulated and how adipose tissues behave in response to hypoxia. Then, the differential roles of adipose HIF-1α and HIF-2α in adipose tissue biology and obesity pathology are highlighted. Finally, the review emphasizes the importance of modulating adipose hypoxia as a therapeutic avenue to assist adipose tissues in functionally adapting to hypoxic conditions, ultimately promoting adipose health and improving outcomes due to obesity.

Light-Activatable, Cell-Type Specific Labeling of the Nascent Proteome.

Elucidating the mechanisms by which protein synthesis contributes to complex biological processes has remained a challenging endeavor. This is particularly true in the field of neuroscience, where multiple, tightly regulated periods of new protein synthesis in different cell-types are thought to facilitate intricate neurological functions, such as memory formation. Current methods for labeling the de novo proteome have lacked the spatial and temporal resolution to accurately discriminate these overlapping and often competing windows of mRNA translation. To address this technological limitation, here we describe a novel, light-inducible specific method for labeling newly synthesized proteins within a targeted cell-type.By developing Opto-ANL, a photocaged version of the nonendogenous amino acid azidonorleucine (ANL), we can selectively label newly synthesized proteins in specific cell-types through the targeted expression of a mutant methionyl-tRNA synthetase (L274G-MetRS). We demonstrate that Opto-ANL can be rapidly uncaged by UV light treatment in both cell culture and mouse brain slices, with Opto-ANL labeled proteins being able to be visualized via fluorescent noncanonical amino acid tagging. We also reveal that pretreatment with Opto-ANL not only allows for the period of de novo proteomic labeling to be tightly controlled, but also improves labeling efficiency compared to regular ANL. To demonstrate the potential applications of this novel technique, we use Opto-ANL to detect insulin-induced increases in protein synthesis and to label the excitatory neuronal de novo proteome in mouse brain slices. We believe that this application of photopharmacology will allow researchers to generate novel insights into how the translational landscape is altered across cell-types during complex neurological phenomena such as memory formation.

Evaluation of the Effect of Dibornol on the Level of DNA Damage in the DNA Comet Test In Vivo.

In male C57BL/6 mice (8-12 weeks) and male Wistar rats (12 weeks), the effect of dibornol (2,6-diisobornyl-4-methylphenol) on the level of spontaneous DNA damage in cells of the bone marrow, liver, kidneys, and rectum of mice (series I) and genotoxic effects in rat testicular cells after administration of cytostatic drugs with different mechanisms of action (series II) were studied using the DNA comet assay. In series I, dibornol was intragastrically administered to mice once at doses of 200, 400, and 2000 mg/kg; in series II, dibornol was intragastrically administered to rats at a dose of 10 mg/kg for 5 days before and 5 days after the cytostatic treatment (methotrexate, doxorubicin). It was found that dibornol in all studied doses did not produce the genotoxic (carcinogenic) effect and reduced the level of spontaneous DNA damage in the bone marrow. After combined administration of cytostatic drugs (doxorubicin, methotrexate) and dibornol, the level of DNA breaks was reduced to 38.5 and 49% of the control, respectively.

Therapeutic Effects of Bacteroides fragilis Vesicles in a Model of Chemically Induced Colitis in Rats.

The anti-inflammatory properties of Bacteroides fragilis vesicles were studied in a rat model of dextran sodium sulfate-induced colitis. According to the histology results, addition of B. fragilis vesicles to the therapy promoted colon repair. Evaluation of the disease activity index confirms the high rate of colon recovery: against the background of vesicle administration, the absence of blood in stool, normal stool consistency, and body weight normalization were observed.

Modeling of Cerebral Ischemic Stroke in Conscious Rats via Arterial Air Embolization.

The etiological factor of cerebral ischemia in the vast majority of cases is vascular embolism. In the present study we investigated embolism caused by atmospheric air bubbles injected into the internal carotid artery of conscious rats. Immediately after embolism modeling, behavioral abnormalities were observed in the animals, and after 24 h, foci of brain damage were detected. The death of animals was observed within 5 days after embolism. The proposed experimental model of cerebral ischemia in conscious rats is more relevant and better corresponds to real conditions than the model on narcotized animals and allows to perform physiological tests immediately after modeling.

[Expedited program and utilization for anticancer drug approval in China and the United States].

Objective: To systematically summarize and comparatively analyze the development, establishment and usage of oncology drugs speedy review approaches in China and in the United States between 2012 and 2021. Methods: Based on National Medical Products Administration (NMPA) and Food and Drug Administration (FDA) websites, the development and current status of the speedy review approaches were consulted and summarized. Approved oncology drugs in China and in the United States (87 in China, 118 in the United States) over the past decade were analyzed using chi-square test for group comparison. Results: Five speedy approaches have been established in China and in the United States, three of which are the same, priority review, conditional approval or accelerated approval and breakthrough therapy. The rest two are special review and approval, special examination and approval in China, and fast track and real-time oncology review in the United States. Compared to the United States, speedy review approaches in China set up late (1992 vs. 2005). The overall utilization rates of the oncology drugs speedy review approaches were similar between the China and United States (90.8% vs. 92.4%, P=0.800) in the previous 10 years, and priority review have highest utilization rates in both China and the United States without significant group difference (77.0% vs. 82.2%, P=0.381); relatively low utilization rates of conditional approval (31.0% vs. 44.9%, P=0.041) and breakthrough therapy (2.3% vs. 50.0%, P＜0.001) were seen in China. 52.9% of new drugs applied for special examination and approval in China and 40.7% of new drugs applied for fast track in the United States. Overall, the priority review both in China and the United States are stable, with a similar average annual utilization rate (84.8% vs. 83.7%); accelerated approval and breakthrough therapies in the United States fluctuate wildly, but the situation is tending towards stability in the last 3 years. Conclusions: Both China and the United States have established a relatively complete accelerated review system, with an overall utilization rate over 90%; China's accelerated review started late, although the overall utilization rate is close to that of the United States. The utilization rates of conditional approval and breakthrough therapy are still relatively low. Flexible usage of speedy review approaches, gaining regulatory recognition to use alternative endpoints, achieving real-time review and guidance are keys to accelerate new drug development in China.

LaFe1-xNixO3 perovskites in the catalytic reaction of high-temperature decomposition of nitrous oxide.

The catalytic performance of LaFe1-xNixO3 perovskites prepared by the Pechini method was studied in the high-temperature decomposition reaction of nitrous oxide at temperatures of 750-900 °C. The samples were characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), transmission electron microscopy (TEM), adsorption (Sbet) and hydrogen thermo-programmed reduction (H2-TPR) methods. The prepared single-phase solids with specific surface areas of 4.7-8.4 m2 g-1 are porous particles (aggregates) of 10-100 µm composed of microblock crystallites. The surface of all samples is enriched with lanthanum. Increasing the Ni content increases the normalized per m2 catalytic activity of LaFe1-xNixO3 perovskites, their reducibility in hydrogen, the ratio of Fe + Ni/La and the content of low bond oxygen forms on the sample surface. The correlation of activity and low bond oxygen forms was revealed, which is consistent with the mechanism of reaction of nitrous oxide decomposition. For future industrial applications the LaFe0.4Ni0.6O3 perovskite is proposed due to its higher stability in the reaction medium as compared with samples with x > 0.6.

[Laparoscopic preperitoneal and Lichtenstein inguinal hernia repair. What method is preferable?] / Laparoskopicheskaya predbryushinnaya plastika pakhovykh gryzh i gernioplastika po Likhtenshteinu. Kakoi metod predpochtitel'nee?

This review is devoted to laparoscopic preperitoneal and open Lichtenstein unguinal hernia repair. Considering the PubMed, Google, the Springer Link online library and the Cochrane Systematic Review databases, we analyzed the reviews, prospective and retrospective studies devoted to comparison of these most common methods of treating inguinal hernias. Indications and contraindications for endoscopic hernia repair, features of laparoscopic surgeries, causes of conversion to open interventions, early and long-term results of laparoscopic and open operations were estimated.

Apoptotic endonuclease EndoG induces alternative splicing of Caspase-2.

Caspase-2 (Casp-2) is an enzyme that regulates the development of apoptosis upon alternative splicing of its mRNA. The long form of Casp-2 (Casp-2L) promotes apoptosis while the short form (Casp-2S) has decreased enzymatic activity and inhibits the development of apoptotic processes. However, very little is known about the mechanism of Casp-2 alternative splicing. Several endonucleases are known to participate in this process. The aim of this study was to determine the role of EndoG in regulation of Casp-2 alternative splicing. Strong correlation between expression levels of EndoG and Casp-2 splice-variants was found in CD4⁺ and CD8⁺ human T lymphocytes. Such correlation increased after incubation of these cells with etoposide. Increased expression of Casp-2S was determined during EndoG over-expression in CD4⁺ T-cells, after EndoG treatment of cell cytoplasm and nuclei and after nuclei incubation with EndoG digested cell RNA. Casp-2 alternative splicing was induced by a 60-mer RNA oligonucleotide in naked nuclei and in cells after transfection. The identified long non-coding RNA of 1016 nucleotides is the precursor of the 60-mer RNA oligonucleotide. Based on the results the following mechanism has been proposed. Casp-2 pre-mRNA is transcribed from the coding DNA strand while long non-coding RNA is transcribed from the template strand of the Casp-2 gene. EndoG digests long non-coding RNA and produces the 60-mer RNA oligonucleotide complementary to the Casp-2 pre-mRNA exon 9 and intron 9 junction place. Interaction of the 60-mer RNA oligonucleotide and Casp-2 pre-mRNA causes alternative splicing.

[Bioacoustic correction in treatment of phantom pain syndrome. (Pilot study)]. / Bioakusticheskaya korrektsiya v terapii fantomno-bolevogo sindroma. (Pilotnoe issledovanie).

OBJECTIVE: To assess the severity of the phantom pain syndrome in patients with consequences of combat trauma before and after comprehensive therapy using the bioacoustic correction (BAC) method. MATERIAL AND METHODS: A number of male patients equal 15 aged 24-60 years with consequences of combat traumas and confirmed phantom pain syndrome were examined. Patients were given 10 BAC therapy procedures with an average duration of 20 minutes per day after a comprehensive diagnostic assessment of state. The dynamics of pain syndrome was evaluated by visual analogue scale. RESULTS: It has been shown that the BAC procedures contribute to a significant reduction of the phantom pain syndrome severity. The decrease of the phantom pain syndrome after the BAC procedures was maintained at least 6 months in the catamnesis. The probable mechanism of reducing the phantom pain syndrome in BAC procedures is adaptive reorganization of thalamocortical detectors of affected limbs by modulation of neuroplasticity processes. CONCLUSION: The conducted preliminary studies have shown that the BAC therapy contributes to the reduction of the phantom pain syndrome intensity.

Intraspecific Variation of Brown Rat Rattus norvegicus in Russia by D-Loop mtDNA Data.

For the first time in Russia, the intraspecific structure of the brown rat Rattus norvegicus was studied using the mitochondrial control region (D-loop) as a molecular marker. The mtDNA sequence was determined in brown rats from eight regions of European and Asian Russia. Three rat clades were identified, including one in European Russia and two in Asian Russia. The synanthropic subspecies R. n. norvegicus was found to have two, European and Asian, lineages. The European lineage included haplotypes from central and southern regions of Russia, and the Asian lineage included haplotypes from Eastern Siberia and the Russian Far East. The exoanthropic subspecies R. n. caraco from the Russian Far East formed a separate genetic lineage.

Point Mutations in the M Domain of PCID2 Impair Its Function in mRNA Export in Drosophila melanogaster.

The PCID2 protein is a component of the eukaryotic TREX-2 complex, which is responsible for mRNA export from the nucleus into the cytoplasm. We have previously shown that Drosophila melanogaster PCID2 is involved in specific mRNA recognition and identified the key amino acids responsible for its interaction with the ras2 RNA. In this work, point mutations of the amino acids were shown to disrupt the PCID2 interaction with cell RNAs and to distort the export of polyA-containing mRNAs from the nucleus into the cytoplasm in Drosophila cells.

[Posterior petrous meningioma with secondary trigeminal neuralgia: microsurgical resection after stereotactic radiosurgery (case report and literature review)]. / Meningioma zadnei poverkhnosti piramidy visochnoi kosti s vtorichnoi trigeminal'noi nevralgiei: mikrokhirurgicheskaya rezektsiya posle stereotaksicheskoi radiokhirurgii (klinicheskii sluchai i obzor literatury).

According to the literature, cerebellopontine angle tumors cause secondary trigeminal neuralgia and other symptoms of neurovascular compression in 1-9.9% of cases. We present a 58-year-old patient with left-sided secondary trigeminal neuralgia caused by ipsilateral posterior petrous meningioma. Stereotactic irradiation was followed by effective tumor growth control. However, residual trigeminal pain paroxysms significantly reduced the quality of life and required subsequent microsurgery. Trigeminal facial pain regressed after total resection of tumor. Considering this clinical case, we would like to discuss several issues: follow-up of meningioma requiring radiosurgery, course of secondary trigeminal neuralgia in a patient with apical petrous meningioma, characteristics of pain before and after radiosurgery, the best treatment option for these patients. Stereotactic radiosurgery seems unreasonable for CPA tumors with secondary trigeminal neuralgia. Indeed, persistent pain is possible even after tumor shrinkage. Moreover, primary stereotactic irradiation significantly complicates subsequent resection of tumor.

Factors that Determined a Positive Response to Resynchronization Therapy in Patients With Chronic Heart Failure and Cardiac Dyssynchrony. One Center Experience.

AIM: To evaluate the efficacy of cardiac resynchronization therapy (CRT) in patients with chronic heart failure (CHF) associated with cardiac dyssynchrony and to identify the factors that influence the CRT efficacy. MATERIAL AND METHODS: This retrospective study included 155 patients after implantation of CRT devices. The CRT devices with a built-in cardioverter-defibrillator (CRT-D) and without it (CRT-P) were implanted in 139 (89.7%) and 16 (10.3%) patients, respectively. The follow-up period was 52.37±35.94 months. Based on the study results, two groups of patients were formed depending on the presence of a clinical response to CRT, responders and non-responders. The factors that influenced the clinical response to CRT were studied. The effect of the baseline state of patients on the effect of therapy was assessed. The need for CRT optimization and a possibility of using electrocardiographic criteria for that purpose were studied. Modern devices and leads for CRT, their functional capabilities and their influence on the CRT efficacy were characterized. Statistical analysis was performed with an IBM SPSS Statistics 21.0 (Chicago, USA) package. RESULTS: CRT implantation with the left ventricular lead placement according to the traditional technique, through the coronary sinus, was successful in 130 (87.9%) patients. Difficulties with the left ventricular lead placement were noted in 13 (8.3%) patients when other techniques were used. After 6 months, a hemodynamic and clinical response was observed in 112 (72.2%) patients, and no positive response in 43 (27.8%). The increase in left ventricular ejection fraction in the responder group was more than 21.8±3.7%, which was associated with an improvement of the 6-minute walk test results. Th clinical response was significantly influenced by the possibility of stimulation from the basal parts of the heart; the use of more modern devices for CRT and quadripolar left ventricular leads; timely CRT optimization; and persistent dyssynchrony in non-responders. During the follow-up period, 34 (21.9%) patients died. The death rate in the non-responder group was significantly higher than in the responder group, 18 (41.3%) vs. 16 (14.3%), p=0.001. The main cause of death in the group of non-responders was CHF. Heart transplantation was performed in 3 (1.9%) patients. CONCLUSION: CRT increases the life span and improves the quality of life in patients with CHF and cardiac dyssynchrony. There was a group of patients with no benefit from CRT in this study. Modern devices allow increasing the number of patients who benefit from CRT. Periodic optimization of CRT is necessary. When optimizing CRT, it is possible to use electrocardiographic criteria of effectiveness: duration of the QRS complex and changes in the position of the electrical axis of the heart.

[The actual issues of detection of risk factors and prevention of myocardium infarction in sailors].

In Russia, increases morbidity of myocardial infarction. The statistics of recent years demonstrate failure in meeting target indicators of national programs on reducing number of deaths from this disease. At that, able-bodied population is in high risk zone and their professional activity is under influence of large combination of risk factors of myocardial infarction. This risk area covers profession of seafarer that is characterized by irregular work schedule, high levels of stress and mental tension, low physical activity or, contrariwise, increased working loads, unbalanced diet, isotherm stress and interaction with harmful substances. Besides that, situation is aggravated by limited set of first medical aid measures at exacerbation of disease in view of remoteness from hospitalization centers. Thus, considering high mortality rate from myocardial infarction, it is extremely important for ship crews to have full and timely information about diagnostic, symptomatic and prevention of this disease. The article examines statistics data of morbidity and mortality of myocardial infarction in population of the Russian Federation on the basis of Rosstat data and target indicators of the National project "Health Care". The risk factors of myocardial infarction established by INTERHEART studies are analyzed. The specifics of work conditions of crew members of marine vessels are established. The collection of professional modifying risk factors was selected. The recommendations for their correction were developed to enhance efficiency of primary preventive measures and to decrease morbidity and mortality among seafarers.

Comparative Evaluation of the Radioprotective Properties of Copper Chlorophyllin, Trolox, and Indralin in an Experiment on Mice.

The radioprotective properties of copper chlorophyllin (100 and 150 µg/g), the standard antioxidant trolox (100 and 200 µg/g), and the standard radioprotector indralin (100 and 150 µg/g) were compared in male ICR mice (CD-1) subjected to whole-body irradiation (X-ray radiation) in doses of 6, 6.5, and 6.75 Gy. Animal survival was analyzed using the Kaplan-Meier method, and the significance of differences was evaluated using the log-rank test method. Dose change factors determined using the Phinney probit analysis were 1.1, 1.0, and 1.8 for chlorophyllin, trolox, and indralin at a dose of 100 µg/g body weight, respectively. The insignificant radioprotective properties of chlorophyllin and their absence in trolox when administered prophylactically do not rule out their possible radioprotective properties like a radiomodulator that protects the body after irradiation.

7-Methylguanine Inhibits Colon Cancer Growth in Vivo.

7-Methylguanine (7-MG) is a natural inhibitor of poly(ADP-ribose) polymerase 1 and tRNA-guanine transglycosylase, the enzymatic activity of which is central for the proliferation of cancer cells. Recently, a number of preclinical tests have demonstrated the safety of 7-MG and a regimen of intragastric administration was established in mice. In the present work, the pharmacological activity of 7-MG was studied in BALB/c and BALB/c nude mice with transplanted tumors. It was found that 7-MG effectively penetrates tumor tissue and suppresses colon adenocarcinoma growth in the Akatol model, as well as in a xenograft model with human HCT116 cells.