This article is a review of published materials on Alexander Stanislavovich Dogiel, a prominent Russian histologist and founder of the journal "Morphology" (Russian Archives of Anatomy, Histology, and Embryology). It provides biographical information about A.S. Dogiel, discusses his contributions to various fields of neurohistology and histologic technique, his distinctive theoretical views, and his later cytological work. Particular attention is paid to the scientific and educational activities of A.S. Dogel and his role in foundation the oldest morphological journal in modern Russia. In addition to highlighting key publications on all of the above topics, the article provides the first complete bibliography of A.S. Dogiel's published works, verified against primary sources.

The FLAD1 gene codes for flavin adenine dinucleotide (FAD) synthase. FAD is a cofactor for many redox enzymes involved in vital processes from respiration to signal transduction. In this work, we described a clinical case of 2 siblings carrying compound heterozygous mutations in the FLAD1 gene resulting in the substitutions A418V and R542* at the protein level. The patients demonstrate adrenal insufficiency, which has not previously been associated with FLAD1 protein defects. To verify that adrenal insufficiency is caused by FLAD1 mutations, we created a personalized mouse model carrying the mutations found in the patients. The mutation in the FLAD1 gene, leading to the A418V substitution, appeared viable in the homozygous state, with minimal difference from the WT. The FLAD1 gene mutation leading to the R542* truncation is lethal when homozygous. The mouse model of the compound heterozygous FLAD1 A418V/R542* mutations recapitulated the physiological, biochemical, and endocrine manifestations of FLAD1 mutations in patients. The mouse model created demonstrates the causal effect of FLAD1 mutations on the described pathology and potentially paves the way for understanding the disease’s molecular mechanism and developing better therapies.

Caloric restriction (CR) is known to activate a broad spectrum of cytoprotective signaling pathways and enhance tissue tolerance to various stressors, including those associated with the cytotoxic effects of pharmaceutical agents. Nephrotoxic drugs, such as aminoglycoside antibiotics, remain a major clinical concern due to their frequent use and potential to cause acute kidney injury (AKI), for which effective preventive strategies are still limited. In this study, we investigated whether CR applied for 5 weeks (4-week pretreatment + 1-week concurrent with AKI induction) can alleviate AKI triggered by the antibiotic gentamicin, with a focus on evaluating changes in antioxidant-related parameters and autophagy-associated signaling during CR-mediated nephroprotection. CR’s nephroprotective effects were evaluated using diagnostic assays, Western blotting, and histological analysis. Additionally, oxidative stress markers and mitochondrial integrity were assessed to analyze the impact of CR on antioxidant-related pathways. CR significantly improved renal function and structure, with reduced kidney injury markers (KIM-1, NGAL) and alleviated histological damage. Critically, CR mitigated oxidative stress, evidenced by decreased thiobarbituric acid reactive substances (TBARS) and protein carbonylation, as well as increased levels of the reduced form of glutathione and activity of glutathione peroxidase (GPx). A lowered Bcl-XL/XS ratio was consistent with reduced apoptotic signaling, while reduced leukocyte infiltration reflected attenuated renal inflammation. Additionally, a reduction in mitochondrial DNA (mtDNA) lesions suggested that CR was associated with modulation of mitochondrial and metabolism-related pathways, with concurrent improvements in mitochondrial stability. Our findings demonstrate that CR attenuated gentamicin-induced AKI and was associated with changes in antioxidant-related parameters, reduced mtDNA damage, a decrease in inflammatory cell infiltration, and modulation of autophagy-related signaling.

The RNA methyltransferase NSUN7 has been reported to be involved in the regulation of longitudinal columns positioning in sperm flagella, but its catalytic mechanism remains unclear. In this study, we investigated the functional role of NSUN7's methylation in the longitudinal column positioning by generating a mouse strain with a substitution of the putative catalytic cysteine in motif IV to alanine (Nsun7C382A). Contrary to predictions based on the typical reaction mechanism of NOP2/Sun family methyltransferases, Nsun7C382A mice did not exhibit any phenotypical characteristics of knockouts and had normal fertility, sperm motility, and longitudinal column positioning, similar to wild-type mice. Structural modelling suggests that NSUN7 possesses an unusual catalytic site composition, including three highly conserved cysteines from motifs IV, VI and VIII. The distance between the canonical catalytic cysteines in motifs IV and VI is significantly greater than in related methyltransferases, while a cysteine from motif VIII is positioned closer to motif VI. These findings allow us to assume that NSUN7 may have an essential function in the spermatogenesis of mice independent on its methyltransferase activity.

Spermatozoid's flagella assemble in transcriptionally silent spermatids and thus depend on posttranscriptional regulation of gene expression. Mutations in Nsun7 gene are known to cause male infertility in human and mice. We identified m5C-specific NSUN7 RNA methyltransferase as a protein present in elongated spermatids and interacting with RNAs specific for this type of spermatozoid's precursor cells. Inactivation of the Nsun7 gene in mice leads to upregulation of its RNA interactors, thus indicating that NSUN7 downregulates a set of RNAs in the elongated spermatids. A physiologic consequence of Nsun7 gene knockout is male infertility, which is mechanistically explained by the observed mispositioning of longitudinal columns relative to the axonemal microtubular doublets leading to a motility defect.

Renocardiac syndrome type 4 (RCS4) is a common comorbid pathology, but the mechanisms of kidney dysfunction-induced cardiac remodeling and the involvement of cardiac progenitor cells (CPCs) in this process remain unclear. The aim of this study was to investigate the structural and functional changes in the cardiac muscle in RCS4 induced by unilateral ureteral obstruction (UUO) and the role of nestin+ CPCs in these. Heart function and localization of nestin+ cells in the myocardium were assessed using nestin-GFP transgenic mice subjected to UUO for 14 and 28 days. UUO resulted in cardiac hypertrophy, accompanied by an elongation of the QRS wave on the ECG, decreased expression of Cxcl1, Cxcl9, and Il1b, reduced the number of CD11b+ cells, and increased in titin isoform parameters, such as T1/MHC and TT/MHC ratios, without changes in fibrosis markers. The number of nestin+ cells increased in the myocardium with increased duration of UUO and displayed an SCA-1+TBX5+ phenotype, consistent with CPCs. Thus, cardiac pathology in RCS4 was manifested by cardiomyocyte hypertrophy with changes in the electrophysiological phenotype of the heart, not accompanied by fibrosis or inflammation. Nestin+ cardiac cells retained the CPC phenotype during UUO, and their number increased, which suggests their participation in regenerative processes in the heart.

Spermiogenesis requires extensive molecular and structural remodeling to produce motile sperm. Mutations in the testis-specific RNA methyltransferase NSUN7 are associated with defective fibrous sheath, impaired sperm motility, and male infertility. However, the underlying molecular mechanisms remain poorly understood. Here, we performed proteomic profiling of sorted, elongated, and round spermatids, as well as mature spermatozoa from Nsun7 knockout mice. We showed that NSUN7 is present at all stages of spermiogenesis and is most abundant in round spermatids, which corresponds to the formation of the flagellum and fibrous sheath assembly. Loss of NSUN7 altered the abundance of proteins essential for dynein arm assembly (PIH1D3, CCDC103, CCDC40), intraflagellar transport (IFT122), and fibrous sheath organization (AKAP3, AKAP4, ROPN1L). We also showed that the previously detected impaired retention of cytoplasm in elongated spermatids may be caused by plectin accumulation. Interestingly, no statistically significant changes were found in mature sperm proteomes upon Nsun7 inactivation. Our findings support a model in which NSUN7 primarily stabilizes protein complexes and coordinates flagellar assembly. This indicates that NSUN7 is a critical regulator of spermiogenesis, and its malfunction is a contributing factor to male infertility.

CDK8 and CDK19 paralogs are regulatory kinases associated with the transcriptional Mediator complex. We have generated mice with the systemic inducible Cdk8 knockout on the background of Cdk19 constitutive knockout. Cdk8/19 double knockout (iDKO) males, but not single Cdk8 or Cdk19 KO, had an atrophic reproductive system and were infertile. The iDKO males lacked postmeiotic spermatids and spermatocytes after meiosis I pachytene. Testosterone levels were decreased whereas the amounts of the luteinizing hormone were unchanged. Single-cell RNA sequencing showed marked differences in the expression of steroidogenic genes (such as Cyp17a1, Star, and Fads ) in Leydig cells concomitant with alterations in Sertoli cells and spermatocytes, and were likely associated with an impaired synthesis of steroids. Star and Fads were also downregulated in cultured Leydig cells after iDKO. The treatment of primary Leydig cell culture with a CDK8/19 inhibitor did not induce the same changes in gene expression as iDKO, and a prolonged treatment of mice with a CDK8/19 inhibitor did not affect the size of testes. iDKO, in contrast to the single knockouts or treatment with a CDK8/19 kinase inhibitor, led to depletion of cyclin C (CCNC), the binding partner of CDK8/19 that has been implicated in CDK8/19-independent functions. This suggests that the observed phenotype was likely mediated through kinase-independent activities of CDK8/19, such as CCNC stabilization.

Obstructive nephropathy is a common clinical condition caused by urinary retention. After urine flow is restored, kidney function is recovered. However, the effectiveness of this process can be influenced by many factors, including the age of the patient. In this study, we analyzed the following parameters in young and old rats subjected to a 3-day reversible unilateral ureteral obstruction (R-UUO): AKI severity, renal tissue proliferation and histology, inflammatory and fibrosis marker expression, as well as autophagosomal-lysosomal and mitochondrial function. Compared to old rats, young animals exhibited more pronounced renal tissue proliferation and higher expression of profibrotic markers (Col1a1, Fn1, Tgfb1, MMP2), but diminished expression of pro-inflammatory markers (Il1b, Tnfa, Cd32) in response to R-UUO. Additionally, young rats showed more pronounced activity of autophagy, as indicated by increased beclin-1 levels. R-UUO induced severe damage to the mitochondrial respiratory chain in old animals, as indicated by reduced complex I, IV, cytochrome c, VDAC protein levels, and impaired mitochondrial biogenesis (associated with decreased Pgc1a mRNA expression). Thus, we demonstrated that despite restored urine outflow, kidneys exhibited autophagy activation, inflammatory response, and mitochondrial dysfunction after R-UUO. Negative alterations in the kidney were age-dependent indicating necessity for therapeutic strategies optimization for patients of different ages.

The aim of this work was to test whether we can treat cholestasis with dietary approaches applied after the onset of the disease. The effects of intermittent fasting and dietary restriction on liver damage caused by common bile duct ligation (BDL) in rats were studied, with particular attention paid to changes in the activity of enzymes of energy metabolism and antioxidant protection. Morphological changes in liver tissue and serum markers of liver damage were assessed in rats with BDL kept for one month on ad libitum diet, intermittent fasting, or 35% dietary restriction. We studied parameters of glucose metabolism (activity of glycolysis and gluconeogenesis enzymes), TCA cycle, and indicators of oxidative stress and redox status of the liver tissue. Dietary restriction resulted in an increase in gluconeogenesis activity, antioxidant capacity, and autophagy activation. When implemented after BDL, none of the dietary restriction protocols reduced the level of oxidative stress, detrimental morphological and biochemical alterations, or the fibrosis progression. Thus, under severe damage and oxidative stress developing in cholestasis, dietary restrictions are not hepatoprotective and can only be used in a pre-treatment mode.

Over the past decades, an unimaginably large number of attempts have been made to restore the structure of mammalian organs after injury by introducing stem cells into them. However, this procedure does not lead to full recovery. At the same time, it is known that complete regeneration (restitution without fibrosis) is possible in organs with proliferating parenchymal cells. An analysis of such models allows to conclude that the most important condition for the repair of histological structures of an organ (in the presence of stem cells) is preservation of the collagen frame structures in it, which serve as “guide rails” for proliferating and differentiating cells. An alternative condition for complete reconstruction of organ structures is the presence of a free “morphogenetic space” containing a gel-like matrix of the embryonic-type connective tissue, which exists during embryonal development of organs in mammals or during complete regeneration in amphibians. Approaches aimed at preserving frame structures or creating a “morphogenetic space” could radically improve the results of organ regeneration using both local and exogenous stem cells.

Obogashchenie sredy obitaniya zhivushchih v nevole gryzunov Heterocephalus glaber (golyh zemlekopov), pozvolivshee im realizovat' vrozhdennyj povedencheskij pattern ryt'ya plotnogo grunta, neizvestnym obrazom privelo k poyavleniyu v kolonii neobychnyh zhivotnyh s priznakami kaheksii, otlichavshihsya ot ostal'nyh zhivotnyh snizhennym indeksom massy tela na fone umen'sheniya doli podkozhnogo zhira. Sami zhivotnye demonstrirovali pri etom agressivnoe pishchevoe povedenie, no ne nabirali vesa dazhe posle prekrashcheniya ryt'ya pri otsoedinenii kamery s gruntom. Cel'yu raboty bylo vyyasnit' patogeneticheskij mekhanizm nablyudaemogo yavleniya. Dlya etogo iz kolonii iz"yali zhivotnyh s priznakami kaheksii (odna samka i dva samca vozrastom 4–5 let), a takzhe zhivotnyh, ne imeyushchih dannyh priznakov (dve samki i odin samec vozrastom 4–5 let) v kachestve kontrol'nyh. Pri gistologicheskom analize tkanej byli vyyavleny gipertrofiya serdca i giperlipofuscinoz pecheni. Na gipetrofiyu serdca takzhe ukazyvali rezul'taty bioinformaticheskogo analiza sekvenirovaniya mikroRNK serdca zhivotnyh, kotoryj pokazal povyshennyj uroven' mikroRNK, otvetstvennyh za povyshenie aktivnosti deleniya kletok, i snizhenie aktivnosti apoptoza v serdce. Eti dannye svidetel'stvuyut o tom, chto zhivotnye, nahodyas' v srede obitaniya s povyshennym dlya nih soderzhaniem kisloroda (21% protiv 8% v estestvennoj srede obitaniya pod zemlej), pri vypolnenii fizicheskih nagruzok ispytali sil'nyj okislitel'nyj stress, chto privelo k narusheniyu raboty regulyatornyh sistem organizma, pod"emu metabolizma v pokoe, peregruzke raboty serdechno-sosudistoj sistemy i povrezhdeniyu organov i tkanej. Takim obrazom, golye zemlekopy mogut vesti normal'nuyu dlya nih fizicheskuyu aktivnost' tol'ko v usloviyah nizkogo soderzhaniya kisloroda.

The development of drugs for the treatment of acute kidney injury (AKI) that could suppress the excessive inflammatory response in damaged kidneys is an important clinical challenge. Recently, synaptamide (N-docosahexaenoylethanolamine) has been shown to exert anti-inflammatory and neurogenic properties. The aim of this study was to investigate the anti-inflammatory effect of synaptamide in ischemic AKI. For this purpose, we analyzed the expression of inflammatory mediators and the infiltration of different leukocyte populations into the kidney after injury, evaluated the expression of the putative synaptamide receptor G-protein-coupled receptor 110 (GPR110), and isolated a population of CD11b/c+ cells mainly representing neutrophils and macrophages using cell sorting. We also evaluated the severity of AKI during synaptamide therapy and the serum metabolic profile. We demonstrated that synaptamide reduced the level of pro-inflammatory interleukins and the expression of integrin CD11a in kidney tissue after injury. We found that the administration of synaptamide increased the expression of its receptor GPR110 in both total kidney tissue and renal CD11b/c+ cells that was associated with the reduced production of pro-inflammatory interleukins in these cells. Thus, we demonstrated that synaptamide therapy mitigates the inflammatory response in kidney tissue during ischemic AKI, which can be achieved through GPR110 signaling in neutrophils and a reduction in these cells’ pro-inflammatory interleukin production.

A small protein, Mitoregulin (Mtln), localizes in mitochondria and contributes to oxidative phosphorylation and fatty acid metabolism. Mtln knockout mice develop obesity on a high-fat diet, demonstrating elevated cardiolipin damage and suboptimal creatine kinase oligomerization in muscle tissue. Kidneys heavily depend on the oxidative phosphorylation in mitochondria. Here we report kidney-related phenotypes in aged Mtln knockout mice. Similar to Mtln knockout mice muscle mitochondria, those of the kidney demonstrate a decreased respiratory complex I activity and excessive cardiolipin damage. Aged male mice carrying Mtln knockout demonstrated an increased frequency of renal proximal tubules' degeneration. At the same time, a decreased glomerular filtration rate has been more frequently detected in aged female mice devoid of Mtln. An amount of Mtln partner protein, Cyb5r3, is drastically decreased in the kidneys of Mtln knockout mice.

Small peptides compose a large share of the mitochondrial proteome. Mitoregulin (Mtln) is a mitochondrial peptide known to contribute to the respiratory complex I functioning and other processes in mitochondria. In our previous studies, we demonstrated that Mtln knockout mice develop obesity and accumulate triglycerides and other oxidation substrates in serum, concomitant with an exhaustion of tricarboxylic acids cycle intermediates. Here we examined the functional role of Mtln in skeletal muscles, one of the major energy consuming tissues. We observed reduced muscle strength for Mtln knockout mice. Decrease of the mitochondrial cardiolipin and concomitant increase in monolysocardiolipin concentration upon Mtln inactivation is likely to be a consequence of imbalance between oxidative damage and remodeling of cardiolipin. It is accompanied by the mitochondrial creatine kinase octamer dissociation and suboptimal respiratory chain performance in Mtln knockout mice.

The beneficial effects of caloric restriction (CR) and a ketogenic diet (KD) have been previously shown when performed prior to kidney injury. We investigated the effects of CR and KD on fibrosis development after unilateral kidney ischemia/reperfusion (UIR). Post-treatment with CR significantly (p < 0.05) affected blood glucose (2-fold decrease), ketone bodies (3-fold increase), lactate (1.5-fold decrease), and lipids (1.4-fold decrease). In the kidney, CR improved succinate dehydrogenase and malate dehydrogenase activity by 2-fold each, but worsened fibrosis progression. Similar results were shown for the KD, which restored the post-UIR impaired activities of succinate dehydrogenase, malate dehydrogenase, and α-ketoglutarate dehydrogenase (which was decreased 2-fold) but had no effect on fibrosis progression. Thus, our study shows that the use of CR or KD after UIR did not reduce the development of fibrosis, as shown by hydroxyproline content, western-blotting, and RT-PCR, whereas it caused significant metabolic changes in kidney tissue after UIR.

Acute kidney injury (AKI) is a frequent pathology with a high mortality rate after even a single AKI episode and a great risk of chronic kidney disease (CKD) development. To get insight into mechanisms of the AKI pathogenesis, there is a need to develop diverse experimental models of the disease. Photothrombosis is a widely used method for inducing ischemia in the brain. In this study, for the first time, we described photothrombosis-induced kidney ischemia as an appropriate model of AKI and obtained comprehensive characteristics of the photothrombotic lesion using micro-computed tomography (micro-CT) and histological techniques. In the ischemic area, we observed destruction of tubules, the loss of brush border and nuclei, connective tissue fibers disorganization, leukocyte infiltration, and hyaline casts formation. In kidney tissue and urine, we revealed increased levels in markers of proliferation and injury. The explicit long-term consequence of photothrombosis-induced kidney ischemia was renal fibrosis. Thus, we establish a new low invasive experimental model of AKI, which provides a reproducible local ischemic injury lesion. We propose our model of photothrombosis-induced kidney ischemia as a useful approach for investigating AKI pathogenesis, studying the mechanisms of kidney regeneration, and development of therapy against AKI and CKD.

Metabolic chambers are routinely used for urine collection in rodents. In mice, due to small urination volume, evaporation in the metabolic chambers (≈50%) distorts diuresis and urinalysis parameters. We have developed a new technique of bladder catheterization enabling long-term accurate and contamination-free urine collection in awake male and female mice for 30 days or longer.Daily diuresis in catheterized mice was twice higher as compared to metabolic cages. The twofold difference in urine recovery was preserved when the circadian variation of diuresis, the effects of furosemide, desmopressin and water load were estimated using the two techniques. Urine osmolarity, urinalysis, and microbiological parameters evidence higher quality of the catheter-collected urine. Using phenol red, we demonstrate utility of our technique for pharmacokinetic studies. 30 days after the surgery the catheters were patent and had minimal impact on the animals' heath.Bladder catheterization is a useful tool for physiological, pharmacological, and toxicological studies.

Although the effects of amphetamine on food consumption and body weight in nondeprived animals are of interest for theoretical and clinical reasons, there are only a few studies on this topic in the literature. In Experiment 1, independent groups of nondeprived rats were given daily injections of 0, 1, 2, 5, or 10 mg/kg d-amphetamine sulfate shortly after light onset for 30 days. While drug treatment did not affect food consumption, all amphetamine-treated groups lost weight over the initial 12 days and then, over the final 18 days of treatment, gained weight at the same rate as controls. Experiment 2 assessed whether the effects of amphetamine on these measures are influenced by the timing of the daily injections relative to the light-dark cycle. As in Experiment 1, injections of amphetamine at light onset again produced weight loss while not affecting food consumption, whereas injections of the drug at light offset did not reliably affect either measure. Experiment 3 showed that the relationships among variables observed in nondeprived animals remain the same in animals restricted to 12 h of access to food each day and replicated the amphetamine-induced hyperphasia observed earlier by Jones and Caul (9).