Phase transition or phase separation occurs in cells and tissues in many physiological events, such as protein granules (P granules) in early C. elegans development. Inappropriate phase transition is often associated with pathologic processes such as RNA-protein complex (RNP) and FUS-mutation-associated diseases. Given its ubiquity, phase transition has been considered a new frontier for comprehending physiological processes and pathological diseases. However, molecular and cellular mechanisms of phase transition in situ remain poorly described. Combining histochemistry with polarization analysis and biochemical thin-layer chromatography, we identified a massive phase transition change during the development of Taihe fowl (Gallus gallus domesticus Brisson). During embryonic day 12 (E12), the livers of these Silkie chicken demonstrated a sudden massive transition from hepatic lipid droplets (HLD) into hepatic liquid crystal droplets (HLCDs). We identified these changes by characterizing the sudden appearance of birefringent Maltese crosses (MCs) typical to liquid crystals (LC) where non-birefringent lipid droplets used to reside within hepatic cells. LC status was confirmed by fluidity with shape-changing and in vitro thermal phase transition tests. These HLCDs were present consistently until the early postnatal days after hatching. Using thin-layer chromatography combined with X-ray diffraction analysis, we determined that these HLCDs were composed of cholesterol, cholesterol ester and lecithin, which are the same as the components of cytoplasmic membrane. There was no change in the quantity of lipid components during liver development to suggest a critical mass of components triggering these changes. However, expressions of membrane-associated autophagy markers LC3A and Beclin 1 increased dramatically during this HLD to HLCD transition. Increases in membrane-associated LC3A and Beclin 1 are localized with massive increases in membrane lipid components of HLCDs. Areas with enhanced LC3A and Beclin 1 signaling have been associated with liquid crystal MCs to the thickness of 69 Å (Bragg d value). These associations indicate the possible regulatory role autophagy plays during liquid crystal phase transition in embryonic liver development. Reactivation of this autophagy pathway may be a possible mechanism behind the development of non-alcoholic fatty liver disease in adulthood.

Atherosclerosis, a chronic inflammatory disease characterized by lipid accumulation and immune cell infiltration, is linked to plaque formation and cardiovascular events. While traditionally associated with lipid metabolism and endothelial dysfunction, recent research highlights the roles of autophagy and clonal hematopoiesis (CH) in its pathogenesis. Autophagy, a cellular process crucial for degrading damaged components, regulates macrophage homeostasis and inflammation, both of which are pivotal in atherosclerosis. In macrophages, autophagy influences lipid metabolism, cytokine regulation, and oxidative stress, helping to prevent plaque instability. Defective autophagy exacerbates inflammation, impairs cholesterol efflux, and accelerates disease progression. Additionally, autophagic processes in endothelial cells and smooth muscle cells further contribute to atherosclerotic pathology. Recent studies also emphasize the interplay between autophagy and CH, wherein somatic mutations in genes like TET2, JAK2, and DNMT3A drive immune cell expansion and enhance inflammatory responses in atherosclerotic plaques. These mutations modify macrophage function, intensifying the inflammatory environment and accelerating atherosclerosis. Chaperone-mediated autophagy (CMA), a selective form of autophagy, also plays a critical role in regulating macrophage inflammation by degrading pro-inflammatory cytokines and oxidized low-density lipoprotein (ox-LDL). Impaired CMA activity leads to the accumulation of these substrates, activating the NLRP3 inflammasome and worsening inflammation. Preclinical studies suggest that pharmacologically activating CMA may mitigate atherosclerosis progression. In animal models, reduced CMA activity accelerates plaque instability and increases inflammation. This review highlights the importance of autophagic regulation in macrophages, focusing on its role in inflammation, plaque formation, and the contributions of CH. Building upon current advances, we propose a hypothesis in which autophagy, programmed cell death, and clonal hematopoiesis form a critical intrinsic axis that modulates the fundamental functions of macrophages, playing a complex role in the development of atherosclerosis. Understanding these mechanisms offers potential therapeutic strategies targeting autophagy and inflammation to reduce the burden of atherosclerotic cardiovascular disease.

Metabolic cardiomyopathy, encompassing diabetic and obese cardiomyopathy, is an escalating global health concern, driven by the rising prevalence of metabolic disorders such as insulin resistance, type 1 and type 2 diabetes, and obesity. These conditions induce structural and functional alterations in the heart, including left ventricular dysfunction, fibrosis, and ultimately heart failure, particularly in the presence of coronary artery disease or hypertension. Autophagy, a critical cellular process for maintaining cardiac homeostasis, is frequently disrupted in metabolic cardiomyopathy. This review explores the role of autophagy in the pathogenesis of high-fat diet (HFD) and streptozotocin (STZ)-induced metabolic cardiomyopathy, focusing on non-selective and selective autophagy pathways, including mitophagy, ER-phagy, and ferritinophagy. Key proteins and genes such as PINK1, Parkin, ULK1, AMPK, mTOR, ATG7, ATG5, Beclin-1, and miR-34a are central to the regulation of autophagy in metabolic cardiomyopathy. Dysregulated autophagic flux impairs mitochondrial function, promotes oxidative stress, and drives fibrosis in the heart. Additionally, selective autophagy processes such as lipophagy, regulated by PNPLA8, and ferritinophagy, modulated by NCOA4, play pivotal roles in lipid metabolism and iron homeostasis. Emerging therapeutic strategies targeting autophagy, including plant extracts (e.g., curcumin, dihydromyricetin), endogenous compounds (e.g., sirtuin 3, LC3), and lipid/glucose-lowering drugs, offer promising avenues for mitigating the effects of metabolic cardiomyopathy. Despite recent advances, the precise mechanisms underlying autophagy in this context remain poorly understood. A deeper understanding of autophagy’s regulatory networks, particularly involving these critical genes and proteins, may lead to novel therapeutic approaches for treating metabolic cardiomyopathy.

As a highly conserved cellular process, autophagy has been the focus of extensive research due to its critical role in maintaining cellular homeostasis and its implications in cardiovascular pathogenesis. The decline in muscular function, along with the neuronal system, and increased sensitivity to stress have been recognized in multiple animal models. Autophagic defects in cardiovascular architecture and cellular dysfunction have been linked to both physiological and pathological conditions of the heart in mammals and Drosophila. In this review, we systematically analyze the autophagy-associated pathways in the hearts of fruit flies and aim to provide a comprehensive understanding for developing potential treatments for patients and effective strategies for agricultural applications. This analysis elucidates the molecular mechanisms of autophagy in cardiovascular function under both physiological and pathological conditions in Drosophila, offering significant insights into the development of cardiovascular diseases. The loss of key autophagy-associated proteins, including the transmembrane protein Atg9 and its partners Atg2 or Atg18, along with DmSestrin, leads to cardiac hypertrophy and structural abnormalities in Drosophila, resembling the age-dependent deterioration of cardiac function. Members of the autophagy-related (Atg) gene family, cellular or nuclear skeletal lamins, and the mechanistic or mammalian target of rapamycin (mTOR) signaling pathways are critically influential in heart function in Drosophila, with autophagy activation shown to suppress cardiac laminopathy. The mTORC1/C2 complexes, along with axis of Atg2-AMPK/Sirt1/PGC-1α pathway, are essential in the hearts of both mammals and fruit flies, governing cardiac development, growth, maturation, and the maintenance of cardiac homeostasis. The beneficial effects of several interventions that enhance cardiac function, including exercise and cold stress, can influence autophagy-dependent TOR activity of the serine/threonine protein kinase signaling in both mammals and Drosophila. Exercise has been shown to increase autophagy when it is deficient and to inhibit it when it is excessive, highlighting the dual role of autophagy in cardiac health. This review evaluates the functional significance of autophagy in the heart, particularly in the context of Drosophila, in relation to mTORC-associated autophagy and the axis of Atg2-AMPK/Sirt1/PGC-1α pathways. It systematically contrasts the molecular mechanisms underlying autophagy-related cardiovascular physiological and pathological conditions in both fruit flies and mammals. The evolutionary conservation of autophagy underscores the value of Drosophila as a model for understanding broader mechanisms of autophagy across species. This study not only deepens our understanding of autophagy’s role in cardiovascular function but also provides a theoretical foundation for the potential application of autophagy in agricultural pest control.

Although highly active antiretroviral therapy (HAART) has changed infection with human immunodeficiency virus (HIV) from a diagnosis with imminent mortality to a chronic illness, HIV positive patients who do not develop acquired immunodeficiency syndrome (AIDs) still suffer from a high rate of cardiac dysfunction and fibrosis. Regardless of viral load and CD count, HIV-associated cardiomyopathy (HIVAC) still causes a high rate of mortality and morbidity amongst HIV patients. While this is a well characterized clinical phenomena, the molecular mechanism of HIVAC is not well understood. In this review, we consolidate, analyze, and discuss current research on the intersection between autophagy and HIVAC. Multiple studies have linked dysregulation in various regulators and functional components of autophagy to HIV infection regardless of mode of viral entry, i.e., coronary, cardiac chamber, or pericardial space. HIV proteins, including negative regulatory factor (Nef), glycoprotein 120 (gp120), and transactivator (Tat), have been shown to interact with type II microtubule-associated protein-1 β light chain (LC3-II), Rubiquitin, SQSTM1/p62, Rab7, autophagy-specific gene 7 (ATG7), and lysosomal-associated membrane protein 1 (LAMP1), all molecules critical to normal autophagy. HIV infection can also induce dysregulation of mitochondrial bioenergetics by altering production and equilibrium of adenosine triphosphate (ATP), mitochondrial reactive oxygen species (ROS), and calcium. These changes alter mitochondrial mass and morphology, which normally trigger autophagy to clear away dysfunctional organelles. However, with HIV infection also triggering autophagy dysfunction, these abnormal mitochondria accumulate and contribute to myocardial dysfunction. Likewise, use of HAART, azidothymidine and Abacavir, have been shown to induce cardiac dysfunction and fibrosis by inducing abnormal autophagy during antiretroviral therapy. Conversely, studies have shown that increasing autophagy can reduce the accumulation of dysfunctional mitochondria and restore cardiomyocyte function. Interestingly, Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has also been shown to reduce HIV-induced cytotoxicity by regulating autophagy-related proteins, making it a non-antiviral agent with the potential to treat HIVAC. In this review, we synthesize these findings to provide a better understanding of the role autophagy plays in HIVAC and discuss the potential pharmacologic targets unveiled by this research.

Genetics evidences have long linked mosaic loss of Y-chromosome (mLOY) in peripheral leukocytes with a wide range of male age-associated diseases. However, a lack of cellular and molecular mechanistic explanations for this link has limited further investigation into the relationship between mLOY and male age-related disease. Excitingly, Sano et al. have provided the first piece of evidence directly linking mLOY to cardiac fibrosis through mLOY enriched profibrotic transforming growth factor β1 (TGF-β1) regulons in hematopoietic macrophages along with suppressed interleukin-1β (IL-1β) proinflammatory regulons. The results of this novel finding can be extrapolated to other disease related to mLOY, such as cancer, cardiac disease, and age-related macular degeneration. Sano et al. used a CRISPR-Cas9 gRNAs gene editing induced Y-chromosome ablation mouse model to assess results of a UK biobank prospective analysis implicating the Y-chromosome in male age-related disease. Using this in vivo model, Sano et al. showed that hematopoietic mLOY accelerated cardiac fibrosis and heart failure in male mice through profibrotic pathways. This process was linked to monocyte-macrophage differentiation during hematopoietic development. Mice confirmed to have mLOY in leukocytes, by loss of Y-chromosome genes Kdm5d, Uty, Eif2s3y, and Ddx3y, at similar percentages to the human population were shown to have accelerated rates of interstitial and perivascular fibrosis and abnormal echocardiograms. These mice also recovered poorly from the transverse aortic constriction (TAC) model of heart failure and developed left ventricular dysfunction at higher rates. This was attributed to aberrant proliferation of cardiac MEF-SK4 + fibroblasts promoted by mLOY macrophages enriched in profibrotic regulons and lacking in proinflammatory regulons. These pro-fibrotic macrophages localized to heart and eventually resulted in cardiac fibrosis via enhanced TGF-β1 and suppressed IL-1β signaling. Furthermore, treatment of mLOY mice with TGFβ1 neutralizing antibody was able to improve their cardiac function. This study by Sano et al. was able to provide a causative link between the known association between mLOY and male cardiac disease morbidity and mortality for the first time, and thereby provide a new target for improving human health. Using a CRISPR-Cas9 induced Y-chromosome ablation mouse model, Sano et al. has proven mosaic loss of Y-chromosome in peripheral myeloid cells to have a causative effect on male mobility and mortality due to male age-related cardiac disease. They traced the mechanism of this effect to hyper-expression of the profibrotic TGF-β1 and reduced pro-inflammatory IL-1β signaling, attenuation of which could provide another potential strategy in improving outcomes against age-related diseases in men.

Transgenic expression of Cre recombinase driven by a specific promoter is normally used to conditionally knockout a gene in a tissue- or cell-type-specific manner. In αMHC-Cre transgenic mouse model, expression of Cre recombinase is controlled by the myocardial-specific α-myosin heavy chain (αMHC) promoter, which is commonly used to edit myocardial-specific genes. Toxic effects of Cre expression have been reported, including intro-chromosome rearrangements, micronuclei formation and other forms of DNA damage, and cardiomyopathy was observed in cardiac-specific Cre transgenic mice. However, mechanisms associated with Cardiotoxicity of Cre remain poorly understood. In our study, our data unveiled that αMHC-Cre mice developed arrhythmias and died after six months progressively, and none of them survived more than one year. Histopathological examination showed that αMHC-Cre mice had aberrant proliferation of tumor-like tissue in the atrial chamber extended from and vacuolation of ventricular myocytes. Furthermore, the αMHC-Cre mice developed severe cardiac interstitial and perivascular fibrosis, accompanied by significant increase of expression levels of MMP-2 and MMP-9 in the cardiac atrium and ventricular. Moreover, cardiac-specific expression of Cre led to disintegration of the intercalated disc, along with altered proteins expression of the disc and calcium-handling abnormality. Comprehensively, we identified that the ferroptosis signaling pathway is involved in heart failure caused by cardiac-specific expression of Cre, on which oxidative stress results in cytoplasmic vacuole accumulation of lipid peroxidation on the myocardial cell membrane. Taken together, these results revealed that cardiac-specific expression of Cre recombinase can lead to atrial mesenchymal tumor-like growth in the mice, which causes cardiac dysfunction, including cardiac fibrosis, reduction of the intercalated disc and cardiomyocytes ferroptosis at the age older than six months in mice. Our study suggests that αMHC-Cre mouse models are effective in young mice, but not in old mice. Researchers need to be particularly careful when using αMHC-Cre mouse model to interpret those phenotypic impacts of gene responses. As the Cre-associated cardiac pathology matched mostly to that of the patients, the model could also be employed for investigating age-related cardiac dysfunction.

MG53 is an essential component of the cell membrane repair machinery, participating in the healing of dermal wounds. Here we develop a novel delivery system using recombinant human MG53 (rhMG53) protein and a reactive oxygen species (ROS)-scavenging gel to treat diabetic wounds. Mice with ablation of MG53 display defective hair follicle structure, and topical application of rhMG53 can promote hair growth in the mg53(-/-) mice. Cell lineage tracing studies reveal a physiological function of MG53 in modulating the proliferation of hair follicle stem cells (HFSCs). We find that rhMG53 protects HFSCs from oxidative stress-induced apoptosis and stimulates differentiation of HSFCs into keratinocytes. The cytoprotective function of MG53 is mediated by STATs and MAPK signaling in HFSCs. The thermosensitive ROS-scavenging gel encapsulated with rhMG53 allows for sustained release of rhMG53 and promotes healing of chronic cutaneous wounds and hair follicle development in the db/db mice. These findings support the potential therapeutic value of using rhMG53 in combination with ROS-scavenging gel to treat diabetic wounds.

Abstract Background Age-related macular degeneration (AMD) is the leading cause of severe vision loss in patients over 55 years old in the industrialized world. In the past 20 years, approximately 288 million patents have been affected by this disease. Despite this high prevalence, the molecular mechanism for AMD remains unclear, and there remains no effective treatment for this disease. The mosaic loss of Y chromosome (mLOY) has been identified as a common phenomenon in multiple age-related disease (i.e., oncogenesis and cardiovascular disease) has recently been identified by genome-wide analysis to be linked to AMD as well. As the Y chromosome mainly possesses three genomic functions, sister chromatin cohesion, cell cycle mitosis, and apoptotic signaling, here we characterize the Y chromosome euchromatic genes and non-chromosome AMD genes in relevance to cellular proliferation and apoptotic signaling of leukocytes. Results Using STRING, a publically available database of all protein–protein interaction, Grassmann et al. found the genes on the Y chromosome is mainly believed to take part in three major cellular genomic functions- sister chromatin cohesion, cell cycle mitosis, and apoptotic signaling. Based on data from the Ensembl Genome database, we focus on our discussion on coding genes found in the euchromatins but not the PAR1 and PAR2 regions of the Y chromosomes. All 14 known euchromatic genes on the Y chromosome short arm and all 31 known euchromatic genes on the Y chromosome long arm (Yq) are directly or indirectly involved in the cell cycle (meiosis and mitosis) and proliferation. We sorted non-Y chromosome AMD associated genes into these three categories to identify signaling pathways that may compound with cellular dysregulation due to mLOY. Of the genes associated with AMD, complement pathway genes such as C2, C9 and CFH/ARMD4 are associated with proliferation, receptor-mediated endocytosis genes such as APOE, DAB2 and others associated with apoptotic signaling. Because nucleated cells found in peripheral circulation are mainly composed of leukocytes with reduced expression of CD99, a protein essential for leukocytes adhesion, translocation, and function, mLOY in these cells likely affect retinal degeneration through altered immunological surveillance. In fact, there is precedence that circulating macrophage can stabilize and modify the cardiac rhythm and contractility post ischemic damage. Therefore, the most likely mechanism through which peripheral mLOY affects AMD development in men is through the role affected leukocytes play in retinal proliferation and apoptosis. Conclusions mLOY in peripheral blood is newly discovered in AMD by Grassmann et al. as it is a common phenomenon in oncogenesis and cardiac dysfunction. Here the recent data conclude the possible mechanism for the newly identified link between mLOY and AMD, and provide support that mLOY in circulating macrophage-monocyte of affected male patients promotes AMD by targeting the retina and causing macular degeneration.

Liver hepatocellular carcinoma (LIHC) remains a global health challenge with poor prognosis and high mortality. FKBP1A was first discovered as a receptor for the immunosuppressant drug FK506 in immune cells and is critical for various tumors and cancers. However, the relationships between FKBP1A expression, cellular distribution, tumor immunity, and prognosis in LIHC remain unclear. Here, we investigated the expression level of FKBP1A and its prognostic value in LIHC via multiple datasets including ONCOMINE, TIMER, GEPIA, UALCAN, HCCDB, Kaplan–Meier plotter, LinkedOmics, and STRING. Human liver tissue microarray was employed to analyze the characteristics of FKBP1A protein including the expression level and pathological alteration in cellular distribution. FKBP1A expression was significantly higher in LIHC and correlated with tumor stage, grade and metastasis. The expression level of the FKBP1A protein was also increased in LIHC patients along with its accumulation in endoplasmic reticulum (ER). High FKBP1A expression was correlated with a poor survival rate in LIHC patients. The analysis of gene co-expression and the regulatory pathway network suggested that FKBP1A is mainly involved in protein synthesis, metabolism and the immune-related pathway. FKBP1A expression had a significantly positive association with the infiltration of hematopoietic immune cells including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Moreover, M2 macrophage infiltration was especially associated with a poor survival prognosis in LIHC. Furthermore, FKBP1A expression was significantly positively correlated with the expression of markers of M2 macrophages and immune checkpoint proteins such as PD-L1, CTLA-4, LAG3 and HAVCR2. Our study demonstrated that FKBP1A could be a potential prognostic target involved in tumor immune cell infiltration in LIHC.

Under natural conditions, injured cells can be repaired rapidly through inherent biological processes. However, in the case of diabetes, cardiovascular disease, muscular dystrophy, and other degenerative conditions, the natural repair process is impaired. Repair of injury to the cell membrane is an important aspect of physiology. Inadequate membrane repair function is implicated in the pathophysiology of many human disorders. Recent studies show that Mitsugumin 53 (MG53), a TRIM family protein, plays a key role in repairing cell membrane damage and facilitating tissue regeneration. Clarifying the role of MG53 and its molecular mechanism are important for the application of MG53 in regenerative medicine. In this review, we analyze current research dissecting MG53′s function in cell membrane repair and tissue regeneration, and highlight the development of recombinant human MG53 protein as a potential therapeutic agent to repair multiple-organ injuries.

Background Vascular calcification is a closely linked to cardiovascular diseases, such as atherosclerosis, chronic kidney disease, diabetes, hypertension and aging. The extent of vascular calcification is closely correlate with adverse clinical events and cardiovascular all-cause mortality. The role of autophagy in vascular calcification is complex with many mechanistic unknowns. Methods In this review, we analyze the current known mechanisms of autophagy in vascular calcification and discuss the theoretical advantages of targeting autophagy as an intervention against vascular calcification. Results Here we summarize the functional link between vascular calcification and autophagy in both animal models of and human cardiovascular disease. Firstly, autophagy can reduce calcification by inhibiting the osteogenic differentiation of VSMCs related to ANCR, ERα, β-catenin, HIF-1a/PDK4, p62, miR-30b, BECN1, mTOR, SOX9, GHSR/ERK, and AMPK signaling. Conversely, autophagy can induce osteoblast differentiation and calcification as mediated by CREB, degradation of elastin, and lncRNA H19 and DUSP5 mediated ERK signaling. Secondly, autophagy also links apoptosis and vascular calcification through AMPK/mTOR/ULK1, Wnt/β-catenin and GAS6/AXL synthesis, as apoptotic cells become the nidus for calcium-phosphate crystal deposition. The failure of mitophagy can activate Drp1, BNIP3, and NR4A1/DNA‑PKcs/p53 mediated intrinsic apoptotic pathways, which have been closely linked to the formation of vascular calcification. Additionally, autophagy also plays a role in osteogenesis by regulating vascular calcification, which in turn regulates expression of proteins related to bone development, such as osteocalcin, osteonectin, etc. and regulated by mTOR, EphrinB2 and RhoA. Furthermore, autophagy also promotes vitamin K2-induced MC3T3 E1 osteoblast differentiation and FGFR4/FGF18- and JNK/complex VPS34–beclin-1-related bone mineralization via vascular calcification. Conclusion The interaction between autophagy and vascular calcification are complicated, with their interaction affected by the disease process, anatomical location, and the surrounding microenvironment. Autophagy activation in existent cellular damage is considered protective, while defective autophagy in normal cells result in apoptotic activation. Identifying and maintaining cells at the delicate line between these two states may hold the key to reducing vascular calcification, in which autophagy associated clinical strategy could be developed.

BACKGROUND & AIMS:Drug-induced liver injury (DILI) remains challenging to treat and is still a leading cause of acute liver failure. MG53 is a muscle-derived tissue-repair protein that circulates in the bloodstream and whose physiological role in protection against DILI has not been examined. METHODS:Recombinant MG53 protein (rhMG53) was administered exogenously, using mice with deletion of Mg53 or Ripk3. Live-cell imaging, histological, biochemical, and molecular studies were used to investigate the mechanisms that underlie the extracellular and intracellular action of rhMG53 in hepatoprotection. RESULTS:Systemic administration of rhMG53 protein, in mice, can prophylactically and therapeutically treat DILI induced through exposure to acetaminophen, tetracycline, concanavalin A, carbon tetrachloride, or thioacetamide. Circulating MG53 protects hepatocytes from injury through direct interaction with MLKL at the plasma membrane. Extracellular MG53 can enter hepatocytes and act as an E3-ligase to mitigate RIPK3-mediated MLKL phosphorylation and membrane translocation. CONCLUSIONS:Our data show that the membrane-delimited signaling and cytosolic dual action of MG53 effectively preserves hepatocyte integrity during DILI. rhMG53 may be a potential treatment option for patients with DILI. LAY SUMMARY:Interventions to treat drug-induced liver injury and halt its progression into liver failure are of great value to society. The present study reveals that muscle-liver cross talk, with MG53 as a messenger, serves an important role in liver cell protection. Thus, MG53 is a potential treatment option for patients with drug-induced liver injury.

Abstract Background In the past 30 years, incidences of non-alcoholic fatty liver disease (NAFLD) has risen by 30%. However, there is still no clear mechanism or accurate method of anticipating liver failure. Here we reveal the phase transitions of liquid crystalline qualities in hepatic lipid droplets (HLDs) as a novel method of anticipating prognosis. Methods NAFLD was induced by feeding C57BL/6J mice on a high-fat (HiF) diet. These NAFLD livers were then evaluated under polarized microscopy, X-ray diffraction and small-angle scattering, lipid component chromatography analysis and protein expression analysis. Optically active HLDs from mouse model and patient samples were both then confirmed to have liquid crystal characteristics. Liver MAP1LC3A expression was then evaluated to determine the role of autophagy in liquid crystal HLD (LC-HLD) formation. Results Unlike the normal diet cohort, HiF diet mice developed NAFLD livers containing HLDs exhibiting Maltese cross birefringence, phase transition, and fluidity signature to liquid crystals. These LC-HLDs transitioned to anisotropic crystal at 0 °C and remain crystalline. Temperature increase to 42 °C causes both liquid crystal and crystal HLDs to convert to isotropic droplet form. These isotropic HLDs successfully transition to anisotropic LC with fast temperature decrease and anisotropic crystal with slow temperature decrease. These findings were duplicated in patient liver. Patient LC-HLDs with no inner optical activity were discovered, hinting at lipid saturation as the mechanism through which HLD acquire LC characteristics. Downregulation of MAP1LC3A in conjunction with increased LC-HLD also implicated autophagy in NAFLD LC-HLD formation. Conclusions Increasing concentrations of amphiphilic lipids in HLDs favors organization into alternating hydrophilic and hydrophobic layers, which present as LC-HLDs. Thus, evaluating the extent of liquid crystallization with phase transition in HLDs of NAFLD patients may reveal disease severity and predict impending liver damage.

Apicomplexan parasites have challenged researchers for nearly a century. A major challenge to developing efficient treatments and vaccines is the parasite’s ability to change its cellular and molecular makeup to develop intracellular and extracellular niches in its hosts. Ca 2+ signaling is an important messenger for the egress of the malaria parasite from the infected erythrocyte, gametogenesis, ookinete motility in the mosquito, and sporozoite invasion of mammalian hepatocytes. Calcium-dependent protein kinases (CDPKs) have crucial functions in calcium signaling at various stages of the parasite’s life cycle; this therefore makes them attractive drug targets against malaria. Here, we summarize the functions of the various CDPK isoforms in relation to the malaria life cycle by emphasizing the molecular mechanism of developmental progression within host tissues. We also discuss the current development of anti-malarial drugs, such as how specific bumped kinase inhibitors (BKIs) for parasite CDPKs have been shown to reduce infection in Toxoplasma gondii , Cryptosporidium parvum , and Plasmodium falciparum . Our suggested combinations of BKIs, artemisinin derivatives with peroxide bridge, and inhibitors on the Ca(2+)-ATPase PfATP6 as a potential target should be inspected further as a treatment against malaria.

最新研究表明,决定疾病相关表型的因素40％由基因决定,包括膳食、运动、心理和生活压力等环境因素决定25％的表型,作为连接环境因素(如环境和食品)和疾病的关键蛋白,钙协调蛋白DCK信号通路与许多疾病相关.基于钙协调蛋白的基本分子特性可组织分布特征,介绍了肌肉细胞中正常生理和病理的功能作用.在肌肉细胞中钙诱导的钙释放CICR中,DCK均是通过结合到CaV1.1和Ca1.2上从而间接调节RyR的功能.DCK-CaV调节RyRs和IP3Rs两个蛋白家族介导钙离子从内质网/肌浆网释放进入胞浆,在肌肉收缩、激素分泌、基因转录、蛋白折叠、程序凋亡以及坏死等一系列以细胞功能为基础的生理过程中起到了极其重要的作用.以上分析表明,作为外界环境影响基因表型的重要介质,钙协调蛋白DCK可能是通过钙信号通路来实现对基因表型的决定,以上研究结果为解决诸如肌肉萎缩等肌肉相关疾病提供重要信息和早期预警监控生物标记,同时也为研发该类疾病的治疗方案提供药物可能的药物靶点.

心脏心肌细胞和神经系统神经元细胞是人类及哺乳动物中最为重要的两类兴奋细胞,心脏心肌细胞为整个机体血液循环提供动力,将氧气和营养物质通过血液运输送至各组织,同时,将二氧化碳等有害气体和代谢废物带离各组织器官;而神经系统神经元细胞则为有机体生存的指挥体系,为生物的生存进化提供了可能.两类兴奋细胞均以RyRs、IP3R家族为主导,以及它们的重要调节蛋白DCK来协调,并借助钙诱导的钙释放CICR体系完成上述功能.DCK通过结合到CaV1.1和Ca1.2上,从而间接调节RyR的功能.DCK-CaV系统调节RyRs和IP3Rs两个蛋白家族介导钙离子从内质网/肌浆网释放进入胞浆,进而在心肌细胞肌肉收缩、突触神经冲动的传递、激素分泌、基因转录、蛋白折叠、程序性凋亡等以细胞功能为基础的生理过程中发挥非常重要的作用,DCK的突变及异常均会引起包括人类在内的相关疾病.DCK的基因调控作用会直接影响心脏传导系统,通过RyRs和IP3R以及这两个基因的构象改变,导致心律失常,比如儿茶酚胺能多态性心室心搏过速,乃至心脏突然死亡.同时,DCK基因的表达对神经元热感觉感知的调控也起到了重要作用,通过PKC联合调控SFO神经元血管紧张素II介导的钙瞬变来控制大脑相关功能的正常发挥.如果异常,则会导致大脑病理生理学的病变.

Background: The newly designated organ system consisting of the mesentery and peritoneum (MAP), is a thin, sheet-like membrane responsible for protecting the abdominal cavity, suspending and organizing abdominal viscera, and facilitating communication between these structures. Recognition of the mesentery as an organ has introduced a potential link between visceral obesity and systemic diseases such as cardiovascular disease and metabolic syndromes. Methods: Polarization macroscopy, small angle X-ray scattering (SAXS), X-ray diffraction (XRD) and histological analysis were deployed to study the movement of liquid crystal lipid droplets (LCLDs) in the chick yolk sac, mesentery, and peritoneum during the seven-to-ten-day yolk sac absorption process. Results: Nutrients in the yolk sac were visualized as liquid crystal lipid droplets and calcium carbonate vaterite crystal particles with polarized birefringence. During yolk sac absorption, these birefringent structures were distributed between the yolk sac and the yolk sac-Jejunum/Ileum (YC-JI) mesenteric complex. The latter is a mesenteric region enclosing the vitelline duct, vitelline artery, umbilical vein, and yolk sac, and extending into Jejunum/Ileum. LCLD nutrients were also distributed in the intra-mesentery-space (IMS) (i.e., the anatomical space between mesentery and enclosed viscera). Within the IMS they appeared to accumulate at a certain region, termed the mesenteric traffic center. We further found that the LCLDs were distributed throughout the mesentery in apposition with organs including the aorta and the pericardium and heart before being absorbed into their respective organs including heart, lung, and kidney. Conclusions: The distribution of birefringent LCLDs indicates that the mesentery provides a conduit for the distribution of nutrients from the yolk sac to viscera.

近20年以来病毒源性已经是第二次对人类发起致命的侵染攻击,已造成两次严重危害全球人类生命的重大疫情.考量如何研发最为有效的保护人类和限制和消灭新冠病毒的方案,是目前亟待解决的重要问题,目前新冠病毒席卷全球,现在也是细胞生物学和病毒分子生物学等基础科学应用于疫情病理研究的关键时刻.本文就新冠病毒有效侵染粘液上皮细胞和心血管的分子机理进行了介绍,对该病毒RNA基因组在细胞内的整合、复制和释放扩散过程进行了探讨.对新冠病毒通过血液再次感染内皮细胞而导致包括心肺肾关联心血管疾病深度感染的分析表明,感染使人体内启动的炎症风暴使得免疫系统对外部侵染的特异性抵御功能丧失,而变成对包括自身正常细胞在内的无差别免疫攻击.本文分析揭示了ACE2-S蛋白可能导致的血钙和细胞钙相关蛋白在靶向细胞和组织过程中发生改变的可能细胞分子作用机理,为尽快从细胞分子机理上认清和战胜新冠病毒,以致为未来能将危害人类生命健康的病毒源性侵染消灭于萌芽状态提供了有价值的信息.