Organ Homeostasis Research Articles

Disorders in Amino Acid Metabolism Associated with Seizures

Seizures are a common presenting manifestation in children with amino acid metabolism disorders such as maple syrup urine disease (MSUD), nonketotic hyperglycinemia, sulfite oxidase deficiency, serine deficiency, and GABA-related disorders. In monoamine biosynthesis disorders, seizures are rare, but paroxysmal dystonia is often misdiagnosed as seizures. Metabolic changes, including amino acid turnover, have been noted during epileptogenesis and chronic epilepsy. Autophagy, a catabolic pathway crucial for maintaining tissue and organism homeostasis, is influenced by amino acids and plays a role in brain physiology and pathology, including epileptic disorders. Amino acid synthesis defects can cause neurological symptoms such as early-onset seizures, mental disability, and skin disorders. Besides neurological symptoms, amino acid metabolism disorders can impact other organ systems, resulting in various clinical manifestations. Early recognition and proper management of these disorders are vital for preventing long-term complications and enhancing patient outcomes. Ongoing research into the complex relationship between amino acid metabolism and neurological function may offer new insights into the pathogenesis of seizures and other neurological disorders.

SMAD2/3-SMYD2 and developmental transcription factors cooperate with cell cycle inhibitors to guide tissue formation.

Tissue formation and organ homeostasis is achieved by precise coordination of proliferation and differentiation of stem cells and progenitors. While deregulation of these processes can result in degenerative disease or cancer, their molecular interplays remain unclear. Here we show that the switch of human pluripotent stem cell (hPSC) self-renewal to differentiation is associated with the induction of distinct cyclin dependent kinase inhibitors (CDKIs). In hPSCs, Activin/Nodal/TGFβ signalling maintains CDKIs in a poised state via SMAD2/3-NANOG-OCT4-EZH2-SNON transcriptional complex. Upon gradual differentiation, CDKIs are induced by successive transcriptional complexes between SMAD2/3-SMYD2 and developmental regulators such as EOMES, thereby lengthening the G1 phase. This, in turn, induces SMAD2/3 transcriptional activity by blocking its linker phosphorylation. Such SMAD2/3-CDKI positive feedback loops drive the exit from pluripotency and stepwise cell fate specification that could be harnessed for producing cells for therapeutic applications. Our study uncovers fundamental mechanisms how cell fate specification is interconnected to cell cycle dynamics and provides insight to autonomous circuitries governing tissue self-formation.

Loss of the DNA-binding domain of the farnesoid X receptor gene causes severe liver and kidney injuries

Farnesoid X receptor (FXR) regulates bile acid synthesis, lipid metabolism, and glucose homeostasis in metabolic organs. FXR-knockout (FXR-KO) mice lacking the last exon of the FXR gene develop normally and display no prenatal and early postnatal lethality, whereas human patients with mutations in the DNA-binding domain of the FXR gene develop severe hepatic dysfunction. In this study, we generated novel FXR-KO mice lacking the DNA-binding domain of the FXR gene using CRISPR–Cas9 technology and evaluated their phenotypes. Similar to the aforementioned FXR-KO mice, our novel mice showed elevated serum levels of total bile acids and total cholesterol. However, they were obviously short-lived, showing severe liver and renal pathologies at an early age. These results indicate that FXR, including its unknown isoforms, has more significant functions in multiple organs than previously reported. Thus, the novel FXR-KO mice could lead to a new aspect that requires reworking of previous knowledge of FXR in the liver and renal function.

Leveraging the Fragment Molecular Orbital and MM-GBSA Methods in Virtual Screening for the Discovery of Novel Non-Covalent Inhibitors Targeting the TEAD Lipid Binding Pocket.

The Hippo pathway controls organ size and homeostasis and is linked to numerous diseases, including cancer. The transcriptional enhanced associate domain (TEAD) family of transcription factors acts as a receptor for downstream effectors, namely yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which binds to various transcription factors and is essential for stimulated gene transcription. YAP/TAZ-TEAD facilitates the upregulation of multiple genes involved in evolutionary cell proliferation and survival. TEAD1-4 overexpression has been observed in different cancers in various tissues, making TEAD an attractive target for drug development. The central drug-accessible pocket of TEAD is crucial because it undergoes a post-translational modification called auto-palmitoylation. Crystal structures of the C-terminal TEAD complex with small molecules are available in the Protein Data Bank, aiding structure-based drug design. In this study, we utilized the fragment molecular orbital (FMO) method, molecular dynamics (MD) simulations, shape-based screening, and molecular mechanics-generalized Born surface area (MM-GBSA) calculations for virtual screening, and we identified a novel non-covalent inhibitor-BC-001-with IC50 = 3.7 μM in a reporter assay. Subsequently, we optimized several analogs of BC-001 and found that the optimized compound BC-011 exhibited an IC50 of 72.43 nM. These findings can be used to design effective TEAD modulators with anticancer therapeutic implications.

Role of the caudal Nucleus Tractus Solitarius and the Postinspiratory Complex in swallow production

The production of swallowing and its coordination with breathing is essential for homeostasis in most organisms. The postinspiratory complex (PiCo) is thought to regulate the transition between swallowing and breathing. Activation of PiCo triggers swallow production and stimulates laryngeal activation in a respiratory phase specific manner. However, little is known about PiCo’s role in swallow generation, which is thought to be controlled by the caudal portion of the Nucleus Tractus Solitarius (cNTS), presumably the swallow pattern generator (SPG). We hypothesize the cNTS is necessary for PiCo to trigger a swallow. Using both male and female Vglut2cre mice, a cre-dependent ChR2 AAV was bilaterally injected into PiCo and a cre-dependent inhibitory DREADD was bilaterally injected into the cNTS, specifically targeting the interstitial (SolI) and intermediate (SolIM) solitary nucleus. Twenty-one days after injection, using our freely breathing urethane anesthetized mouse model, swallows were stimulated by 1) injection of water into the oral cavity and 2) optogenetic stimulation of PiCo neurons; before and after DREADD activator, clozapine-N-oxide (CNO). Swallow and laryngeal activity were measured via monopolar suction electrodes of the hypoglossal (XII) and vagus (X) nerves as well as bipolar electromyogram (EMG) of the submental, laryngeal complex and costal diaphragm muscles. Post-hoc histological analysis was done to confirm areas of interest were targeted. We found that after activation of the inhibitory DREADD, located in the cNTS, swallow was not evoked by water stimulation nor optogenetic stimulation. We propose that PiCo relies on direct feedback from the cNTS in order to trigger swallow production. NIH F32 HL160102. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Aquaporins: Navigating the channels of cellular hydration

Aquaporin’s are water channel proteins found in all plasma membrane of various cells in all forms of life from bacteria to mammals. Around 17 mammalian aquaporin’s have been identified till date, which are classified into 3 subcategories based on their permeability. In normal physiology, AQPs serve as essential modulators of fluid transport and homeostasis in multiple organs and tissues. Altered expression of aquaporin’s is linked to numerous pathologies including fluid dysregulation, tumor metastasis and traumatic injury. Although some potential AQP modulators have been identified, challenges associated with the development of better modulators, include the suitability of the assay methods used to identify modulators and the drug ability of the target. The present review focus on aquaporin types and their altered conditions along with role of aquaporin’s in cancer and other diseases.

Progress in extracellular vesicle homeostasis as it relates to cardiovascular diseases.

Extracellular vesicles (EVs) are involved in both physiological and pathological processes in many organ systems and are essential in mediating intercellular communication and maintaining organismal homeostasis. It is helpful to propose new strategies for disease treatment by elucidating the mechanisms of EV release and sorting. An increasing number of studies have shown that there is specific homeostasis in EVs, which is helpful for the human body to carry out physiological activities. In contrast, an EV homeostasis im-balance promotes or accelerates disease onset and development. Alternatively, regulating the quality of EVs can maintain homeostasis and even achieve the purpose of treating conditions. An analysis of the role of EV homeostasis in the onset and development of cardiovascular disease is presented in this review. This article also summarizes the methods that regulate EV homeostasis and their application in cardiovascular diseases. In particular, this study focuses on the connection between EV steady states and the cardiovascular system and the potential value of EVs in treating cardiovascular diseases.

Exploring exercise-driven exerkines: unraveling the regulation of metabolism and inflammation.

Exercise has many beneficial effects that provide health and metabolic benefits. Signaling molecules are released from organs and tissues in response to exercise stimuli and are widely termed exerkines, which exert influence on a multitude of intricate multi-tissue processes, such as muscle, adipose tissue, pancreas, liver, cardiovascular tissue, kidney, and bone. For the metabolic effect, exerkines regulate the metabolic homeostasis of organisms by increasing glucose uptake and improving fat synthesis. For the anti-inflammatory effect, exerkines positively influence various chronic inflammation-related diseases, such as type 2 diabetes and atherosclerosis. This review highlights the prospective contribution of exerkines in regulating metabolism, augmenting the anti-inflammatory effects, and providing additional advantages associated with exercise. Moreover, a comprehensive overview and analysis of recent advancements are provided in this review, in addition to predicting future applications used as a potential biomarker or therapeutic target to benefit patients with chronic diseases.

Autonomous circadian rhythms in the human hepatocyte regulate hepatic drug metabolism and inflammatory responses.

Critical aspects of physiology and cell function exhibit self-sustained ~24-hour variations termed circadian rhythms. In the liver, circadian rhythms play fundamental roles in maintaining organ homeostasis. Here, we established and characterized an in vitro liver experimental system in which primary human hepatocytes display self-sustained oscillations. By generating gene expression profiles of these hepatocytes over time, we demonstrated that their transcriptional state is dynamic across 24 hours and identified a set of cycling genes with functions related to inflammation, drug metabolism, and energy homeostasis. We designed and tested a treatment protocol to minimize atorvastatin- and acetaminophen-induced hepatotoxicity. Last, we documented circadian-dependent induction of pro-inflammatory cytokines when triggered by LPS, IFN-β, or Plasmodium infection in human hepatocytes. Collectively, our findings emphasize that the phase of the circadian cycle has a robust impact on the efficacy and toxicity of drugs, and we provide a test bed to study the timing and magnitude of inflammatory responses over the course of infection in human liver.

Recent Advances in the Biomedical Applications of Copper Nanomaterial‐Mediated Cuproptosis

Nanomedicine‐induced cancer cell death has become a prominent area of research in the life sciences field in recent years. The concept of cuproptosis was first proposed in 2022. Copper homeostasis in organisms is tightly regulated by protein transporters and molecular chaperones. Disruptions in copper homeostasis can adversely affect mitochondrial respiration and disrupt other physiological processes, leading to cytotoxicity. Therefore, researchers have designed and refined copper‐based nanomaterials to induce cuproptosis and assess their effects on cancer treatment. While several reviews on cuproptosis exist, they primarily delve into its molecular mechanisms. This review begins with elucidating the metabolism and homeostasis of copper in the body. Subsequently, the latest advancements in copper nanomaterial‐induced cuproptosis for cancer treatment and antimicrobial purposes is summarized. Finally, a comprehensive summary and outlook on the subject is provided. The goal with this review is to assist researchers in gaining a deeper understanding of the interaction between nanomaterials and cuproptosis, thereby offering new perspectives for designing novel nanomaterials to induce cuproptosis.

The Impact of Curcumin, Resveratrol, and Cinnamon on Modulating Oxidative Stress and Antioxidant Activity in Type 2 Diabetes: Moving beyond an Anti-Hyperglycaemic Evaluation.

Research indicates that up to half of the population resorts to dietary supplements for managing diseases such as type 2 diabetes rather than changing their nutritional habits. These supplements not only aim to have an anti-hyperglycaemic effect but also seek to reduce oxidative stress to prevent diabetes complications. This systematic literature systematic review aims to evaluate the efficacy of curcumin, resveratrol, and cinnamon in modulating oxidative stress and antioxidant activity in individuals with type 2 diabetes. Data were collected from PubMed, Web of Sciences, and Scopus databases regarding the impact of curcumin, resveratrol, and cinnamon on total antioxidant capacity (TAC), malondialdehyde (MDA), tumour necrosis factor α (TNF-α), interleukin 6 (IL-6), and high-sensitivity C-reactive protein (hs-CRP) levels for this review. Effect sizes for each study were calculated using Cohen's or Hedges's d coefficient. Parameters of oxidative stress and inflammatory status, such as TAC, MDA, TNF-α, IL-6, and hs-CRP, improved following phytochemicals. Additionally, curcumin, resveratrol, and cinnamon exhibited regulatory effects on carbohydrate metabolism by reducing glucose, insulin, and glycated haemoglobin concentrations and lipid metabolism by lowering total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides (TG) and increasing high-density lipoprotein (HDL). Incorporating curcumin, resveratrol, and cinnamon into diets may be beneficial for maintaining organism homeostasis and improving metabolic control in individuals with type 2 diabetes. However, the conflicting results reported in the literature highlight the need for further detailed investigations into the effectiveness of phytochemical use for type 2 diabetes.

Copper Homeostasis in the Model Organism C. elegans.

Cellular and organismic copper (Cu) homeostasis is regulated by Cu transporters and Cu chaperones to ensure the controlled uptake, distribution and export of Cu ions. Many of these processes have been extensively investigated in mammalian cell culture, as well as in humans and in mammalian model organisms. Most of the human genes encoding proteins involved in Cu homeostasis have orthologs in the model organism, Caenorhabditis elegans (C. elegans). Starting with a compilation of human Cu proteins and their orthologs, this review presents an overview of Cu homeostasis in C. elegans, comparing it to the human system, thereby establishing the basis for an assessment of the suitability of C. elegans as a model to answer mechanistic questions relating to human Cu homeostasis.

Mesenchymal stem cells in autoimmune disease: A systematic review and meta-analysis of pre-clinical studies

Mesenchymal Stem Cells (MSCs) are of interest in the clinic because of their immunomodulation capabilities, capacity to act upstream of inflammation, and ability to sense metabolic environments. In standard physiologic conditions, they play a role in maintaining the homeostasis of tissues and organs; however, there is evidence that they can contribute to some autoimmune diseases. Gaining a deeper understanding of the factors that transition MSCs from their physiological function to a pathological role in their native environment, and elucidating mechanisms that reduce their therapeutic relevance in regenerative medicine, is essential. We conducted a Systematic Review and Meta-Analysis of human MSCs in preclinical studies of autoimmune disease, evaluating 60 studies that included 845 patient samples and 571 control samples. MSCs from any tissue source were included, and the study was limited to four autoimmune diseases: multiple sclerosis, rheumatoid arthritis, systemic sclerosis, and lupus. We developed a novel Risk of Bias tool to determine study quality for in vitro studies. Using the International Society for Cell & Gene Therapy's criteria to define an MSC, most studies reported no difference in morphology, adhesion, cell surface markers, or differentiation into bone, fat, or cartilage when comparing control and autoimmune MSCs. However, there were reported differences in proliferation. Additionally, 308 biomolecules were differentially expressed, and the abilities to migrate, invade, and form capillaries were decreased. The findings from this study could help to explain the pathogenic mechanisms of autoimmune disease and potentially lead to improved MSC-based therapeutic applications.

Metformin modulates autophagic pathway in renal fibrosis induced by carbon tetrachloride in adult male albino rats

ABSTRACT Backgrounds Chronic kidney disease (CKD) is a global public health problem. All progressive chronic kidney disease (CKD) is characterized by tubulointerstitial fibrosis. Exposure to high concentrations of carbon tetrachloride (including vapor) can destroy the kidneys. Autophagy played an important role in maintaining the homeostasis of organs. Impaired autophagy was frequently associated with renal damage and fibrosis. Recent data suggests that metformin protects against a variety of kidney disorders. Aim To investigate the protective role of metformin on carbon tetrachloride induced renal damage via autophagy pathway. Materials and Methods Forty adult male albino rats were divided into four equal groups (10 rats, each); Group 1: control group. Group 2: olive oil group received olive oil 1.5 mg/kg twice weekly S.C for 12 weeks. Group 3: The ccl4 group, the rats were received ccl4 1.5 mg/kg twice weekly S.C for 12 weeks. Group 4: CCL4 and Metformin group received concomitant treatment of CCL4, 1.5 mg/kg twice weekly S.C and 100 mg/kg/day Metformin orally for 12 weeks. After sacrifice, kidneys were taken from all animal groups and processed for light and electron microscopy, immunological studies and biochemical tests. Statistical analysis was done. Results Administration of ccl4 resulted in histopathological changes in the kidney tissue in the form of areas of tissue destruction, inflammatory cell infiltration, congestion and fibrosis. Ultrastructurally, irregular thickening of GBM was observed. Improvement was noticed with concomitant treatment of ccl4 with metformin. Conclusion Metformin administration can modulate histological and biochemical effects in the renal tissue induced by of ccl4.

Unveiling the Potential of Extracellular Vesicles as Biomarkers and Therapeutic Nanotools for Gastrointestinal Diseases.

Extracellular vesicles (EVs), acting as inherent nanocarriers adept at transporting a range of different biological molecules such as proteins, lipids, and genetic material, exhibit diverse functions within the gastroenteric tract. In states of normal health, they participate in the upkeep of systemic and organ homeostasis. Conversely, in pathological conditions, they significantly contribute to the pathogenesis of gastrointestinal diseases (GIDs). Isolating EVs from patients' biofluids facilitates the discovery of new biomarkers that have the potential to offer a rapid, cost-effective, and non-invasive method for diagnosing and prognosing specific GIDs. Furthermore, EVs demonstrate considerable therapeutic potential as naturally targeted physiological carriers for the intercellular delivery of therapeutic cargo molecules or as nanoscale tools engineered specifically to regulate physio-pathological conditions or disease progression. Their attributes including safety, high permeability, stability, biocompatibility, low immunogenicity, and homing/tropism capabilities contribute to their promising clinical therapeutic applications. This review will delve into various examples of EVs serving as biomarkers or nanocarriers for therapeutic cargo in the context of GIDs, highlighting their clinical potential for both functional and structural gastrointestinal conditions. The versatile and advantageous properties of EVs position them as promising candidates for innovative therapeutic strategies in advancing personalized medicine approaches tailored to the gastroenteric tract, addressing both functional and structural GIDs.

MST1/2 exerts a pivotal role in inducing neuroinflammation and Coxsackievirus-A10 replication by interacting with innate immunity

Coxsackievirus-A10 (CV-A10), responsible for the hand, foot and mouth disease (HFMD) pandemic, could cause serious central nervous system (CNS) complications. The underlying molecular basis of CV-A10 and host interactions inducing neuropathogenesis is still unclear. The Hippo signaling pathway, historically known for a dominator of organ development and homeostasis, has recently been implicated as an immune regulator. However, its role in host defense against CV-A10 has not been investigated. Herein, it was found that CV-A10 proliferated in HMC3 cells and promoted the release of inflammatory cytokines. Moreover, pattern recognition receptors (PRRs)-mediated pathways, including TLR3-TRIF-TRAF3-TBK1-NF-κB axis, RIG-I/MDA5-MAVS-TRAF3-TBK1-NF-κB axis and TLR7-MyD88-IRAK1/IRAK4-TRAF6-TAK1-NF-κB axis, were examined to be elevated under CV-A10 infection. Meanwhile, it was further uncovered that Hippo signaling pathway was inhibited in HMC3 cells with CV-A10 infection. Previous studies have been reported that there exist complex relations between innate immune and Hippo signaling pathway. Then, plasmids of knockdown and overexpression of MST1/2 were transfected into HMC3 cells. Our results showed that MST1/2 suppressed the levels of inflammatory cytokines via interacting with TBK1 and IRAK1, and also enhanced virus production via restricting IRF3 and IFN-β expressions. Overall, these data obviously pointed out that CV-A10 accelerated the formation of neuroinflammation by the effect of the Hippo pathway on the PRRs-mediated pathway, which delineates a negative immunoregulatory role for MST1/2 in CV-A10 infection and the potential for this pathway to be pharmacologically targeted to treat CV-A10.

Surviving the Storm: The Role of Poly- and Depolyploidization in Tissues and Tumors.

Polyploidization and depolyploidization are critical processes in the normal development and tissue homeostasis of diploid organisms. Recent investigations have revealed that polyaneuploid cancer cells (PACCs) exploit this ploidy variation as a survival strategy against anticancer treatment and for the repopulation of tumors. Unscheduled polyploidization and chromosomal instability in PACCs enhance malignancy and treatment resistance. However, their inability to undergo mitosis causes catastrophic cellular death in most PACCs. Adaptive ploid reversal mechanisms, such as multipolar mitosis, centrosome clustering, meiosis-like division, and amitosis, counteract this lethal outcome and drive cancer relapse. The purpose of this work is to focus on PACCs induced by cytotoxic therapy, highlighting the latest discoveries in ploidy dynamics in physiological and pathological contexts. Specifically, by emphasizing the role of "poly-depolyploidization" in tumor progression, the aim is to identify novel therapeutic targets or paradigms for combating diseases associated with aberrant ploidies.

Tissue adaptation of CD4 T lymphocytes in homeostasis and cancer.

The immune system is traditionally classified as a defense system that can discriminate between self and non-self or dangerous and non-dangerous situations, unleashing a tolerogenic reaction or immune response. These activities are mainly coordinated by the interaction between innate and adaptive cells that act together to eliminate harmful stimuli and keep tissue healthy. However, healthy tissue is not always the end point of an immune response. Much evidence has been accumulated over the years, showing that the immune system has complex, diversified, and integrated functions that converge to maintaining tissue homeostasis, even in the absence of aggression, interacting with the tissue cells and allowing the functional maintenance of that tissue. One of the main cells known for their function in helping the immune response through the production of cytokines is CD4+ T lymphocytes. The cytokines produced by the different subtypes act not only on immune cells but also on tissue cells. Considering that tissues have specific mediators in their architecture, it is plausible that the presence and frequency of CD4+ T lymphocytes of specific subtypes (Th1, Th2, Th17, and others) maintain tissue homeostasis. In situations where homeostasis is disrupted, such as infections, allergies, inflammatory processes, and cancer, local CD4+ T lymphocytes respond to this disruption and, as in the healthy tissue, towards the equilibrium of tissue dynamics. CD4+ T lymphocytes can be manipulated by tumor cells to promote tumor development and metastasis, making them a prognostic factor in various types of cancer. Therefore, understanding the function of tissue-specific CD4+ T lymphocytes is essential in developing new strategies for treating tissue-specific diseases, as occurs in cancer. In this context, this article reviews the evidence for this hypothesis regarding the phenotypes and functions of CD4+ T lymphocytes and compares their contribution to maintaining tissue homeostasis in different organs in a steady state and during tumor progression.

Abstract LT04: Dissecting Mediator Kinase Activity in Normal Tissue Homeostasis and Cancer

Abstract Cyclin-dependent kinase 8 (CDK8) and its paralog CDK19, collectively known as Mediator kinase, are part of the multimeric Mediator complex that fine-tune gene expression programs on multiple levels, most notably by controlling transcription factor (TF) activity at promoter- and enhancer regions as well as organising the chromatin landscape. While Mediator kinases have been predominantly studied as a therapeutic target in cancer cells, their functions in a physiologically relevant context remain poorly understood. To study in vivo functions of Mediator, we developed a comprehensive suite of genetically engineered mouse models (GEMMs), including conditional floxed alleles (Cdk8fl/fl/Cdk19fl/fl) and kinase-dead knock-ins (Cdk8D173A/fl/Cdk19D173A/fl), enabling the analysis of scaffolding and kinase-dependent functions of this critical transcriptional module. Herein, we show that Mediator kinase has distinct kinase-dependent functions in modulating homeostasis and tissue lineage specification in diverse organs. Moreover, using a proteo-genomic approach we show that the Mediator Kinase module functionally interacts with the SWI/SNF complex to mediate transcriptional output. Collectively, our work expands the understanding of how Mediator Kinase regulates tissue homeostasis and provides a framework for considering how Mediator Kinase inhibition may be effectively employed in the clinical setting. Citation Format: Marius Dannappel, Danxi Zhu, Claire Sun, Ron Firestein. Dissecting Mediator Kinase Activity in Normal Tissue Homeostasis and Cancer [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr LT04.

Ethyl alcohol. Influence on the dynamics of blood supply of skin and other soft tissues during their sudden cooling

It is shown that in norm (i.e. in sober people in the absence of ethyl alcohol in blood) sudden local cooling of skin and soft tissues of different parts of the body from +37 to +18 °С and below (but not below 0 °С) causes in the cooled tissues 2-phase change in the value of blood vessels tone, their blood filling, intensity of blood supply and feeling of painfulness. Thus from the first seconds of cooling the tone of blood vessels of muscular type begins to increase, their blood filling begins to decrease, skin color lightens and soon in the cooled area of the body there is a feeling of acute soreness. After a few tens of seconds of cooling, the spasm of blood vessels reaches maximum values, their filling with blood decreases to a minimum, the skin turns white, and the soreness reaches maximum values. These changes persist at their peak for a few minutes, after which they begin to disappear, despite the persisting hypothermia. But then, after 10-15 minutes of cooling, hyperemia inevitably develops in the hypothermia zone, as a result of which the soreness disappears and the skin reddens. It is established that in the norm, sudden cooling of tissues causes irritation of temperature receptors located in them. The resulting excitation of temperature receptors causes reflex spasm of blood vessels, which has an adaptive value, as it is evolutionarily developed for temperature homeostasis of warm-blooded organism. It has been found out that acute painfulness accompanying cold spasm of blood vessels arises due to mechanical squeezing of pain receptors located under the muscular layer in the wall of blood vessels. On the other hand, the presence of ethyl alcohol in the blood (the presence of alcohol intoxication) fundamentally changes the dynamics of blood supply of tissues at their sudden cooling: during cooling, blood vessels expand and overflow with blood without the initial phase of spasm and the appearance of a sense of pain. At the same time, hyperemia persists not only throughout the cooling period, but also after it. In other words, alcohol intoxication is manifested by the immediate development of hyperemia and redness of the skin in the cooled area of the body without the initial spasm of blood vessels, the appearance of a feeling of soreness and pallor of the skin in the area of cooling.