Fundamental Pathological Processes Research Articles

Unraveling the proteomic landscape of fibrosis in lupus nephritis through CI-based analysis.

The underlying mechanism by which lupus nephritis (LN) progresses to chronic kidney disease remains elusive. Fibrosis is a hallmark feature of chronic kidney disease, including LN. The chronicity index (CI) score, which incorporates glomerular sclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis, summarizes the extent of kidney tissue fibrosis. In this study, we employed label-free quantitative proteomics based on mass spectrometry to generate kidney protein profiles with varying CI scores. A total of 98 proteins exhibiting linear correlation with CI scores were initially screened out by linear model (CI linearly related proteins), and subsequently, 12 key proteins were derived based on the CI linearly related proteins using Cytohubba. LN patients were stratified into two subtypes based on CI scores and epithelial-mesenchymal transition (EMT) characteristics. These subtypes exhibited significant disparities in immune infiltration and molecular pathways. The high EMT group exhibited heightened activation of immune cells, such as memory B cells, gamma delta T cells, and resting mast cells. Gene Set Enrichment Analysis (GSEA) uncovered substantial dysregulation in critical biological processes and signaling pathways, including NF-κB, JNK, PI3K/AKT/mTOR signaling pathway, lipoprotein biosynthetic process, and endocytosis, in both subgroups. In conclusion, this study establishes molecular subgroups based on the CI score, providing novel insights into the molecular mechanisms governing chronicity in the kidneys of diverse LN patients. Key Points • Fibrosis is a fundamental and characteristic pathological process underlying the NIH-CI in LN. • Different EMT status presented variant clinical characteristics, immune features in LN.

Comprehensive Screening and Evaluation of Anti-gout Activity of Plantago asiatica L. through Integrated In vivo and In vitro Methodologies

Abstract Objective: This study aimed to elucidate the active components and mechanisms of Plantago asiatica L. (PAL) in the treatment of gout. Materials and Methods: Based on its polarity, PAL was partitioned into three parts, P1, P2, and P3, through gradient elution using AB-8 macroporous resin columns. The primary constituents of these fractions include iridoids, phenylethanoid glucosides, and flavonoids. Subsequently, a comprehensive in vitro and in vivo screening and evaluation model was developed considering the fundamental pathological processes of gout, including the inhibition of uric acid (UA) production, augmentation of UA excretion, and anti-inflammatory effects. This model was used to analyze the anti-gout activity of P1, P2, P3, and the overall extracts derived from PAL. Results: All the PAL parts exhibited specific therapeutic properties as part of gout therapy. Specifically, the P2 part demonstrated the ability to diminish interleukin-1 beta levels, lower UA concentrations, suppress joint inflammation in rats, and restore abnormal parameters associated with gout, such as creatinine and urea nitrogen. These findings highlight the significant effect of P2 on gout treatment. Conclusions: Following a thorough assessment of the outcomes derived from diverse anti-gout experiments, P2 exhibited superior anti-gout properties compared to the remaining parts. P2 demonstrated a restorative effect on the aberrant parameters associated with gout, thereby comprehensively elucidating the therapeutic mechanism of P2 against gout. This study provides substantial evidence and serves as a reference for future investigations regarding the material foundation of PAL in gout treatment.

4-Phenylbutyric Acid Treatment Reduces Low-Molecular-Weight Proteinuria in a Clcn5 Knock-in Mouse Model for Dent Disease-1.

Dent disease-1 (DD-1) is a rare X-linked tubular disorder characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrolithiasis and nephrocalcinosis. This disease is caused by inactivating mutations in the CLCN5 gene which encodes the voltage-gated ClC-5 chloride/proton antiporter. Currently, the treatment of DD-1 is only supportive and focused on delaying the progression of the disease. Here, we generated and characterized a Clcn5 knock-in mouse model that carries a pathogenic CLCN5 variant, c. 1566_1568delTGT; p.Val523del, which has been previously detected in several DD-1 unrelated patients, and presents the main clinical manifestations of DD-1 such as high levels of urinary b2-microglobulin, phosphate and calcium. Mutation p.Val523del causes partial ClC-5 retention in the endoplasmic reticulum. Additionally, we assessed the ability of sodium 4-phenylbutyrate, a small chemical chaperone, to ameliorate DD-1 symptoms in this mouse model. The proposed model would be of significant value in the investigation of the fundamental pathological processes underlying DD-1 and in the development of effective therapeutic strategies for this rare condition.

The Use of "Acellbia"-A Biosimilar of Rituximab in Systemic Sclerosis.

The possibilities of modern therapy for systemic sclerosis (SSc) remains limited, since most of the used drugs do not have a disease-modifying effect. This encourages the study of new approaches that potentially affect the fundamental pathological processes underlying the disease. One example is anti-B-cell therapy, in particular rituximab (RTX). Until now RTX does not have a registration for the treatment of SSc, but there is a large positive experience of its use, which is reflected in recent meta-analyses and clinical recommendations. Complicated and expensive methods for obtaining genetically engineered biological drugs (biologics) have contributed to the emergence of more accessible biosimilars, one of which is the RTX biosimilar, Acellbia (Biocad, Russian Federation). The ''biosimilar'' versions of RTX might reduce the cost of therapy and increase patients accessibility to this treatment option. The RTX biosimilar Acellbia (ACB) has received approval in Russian Federation in 2014 for all indications held by reference RTX (including rheumatoid arthritis and ANCA-associated vasculitis).

Systemic cellular migration: The forces driving the directed locomotion movement of cells.

Directional motility is an essential property of cells. Despite its enormous relevance in many fundamental physiological and pathological processes, how cells control their locomotion movements remains an unresolved question. Here, we have addressed the systemic processes driving the directed locomotion of cells. Specifically, we have performed an exhaustive study analyzing the trajectories of 700 individual cells belonging to three different species (Amoeba proteus, Metamoeba leningradensis, and Amoeba borokensis) in four different scenarios: in absence of stimuli, under an electric field (galvanotaxis), in a chemotactic gradient (chemotaxis), and under simultaneous galvanotactic and chemotactic stimuli. All movements were analyzed using advanced quantitative tools. The results show that the trajectories are mainly characterized by coherent integrative responses that operate at the global cellular scale. These systemic migratory movements depend on the cooperative nonlinear interaction of most, if not all, molecular components of cells.

Wnt/β-catenin signaling pathway in liver biology and tumorigenesis.

The Wnt/β-catenin pathway is an evolutionarily conserved signaling pathway that controls fundamental physiological and pathological processes by regulating cell proliferation and differentiation. The Wnt/β-catenin pathway enables liver homeostasis by inducing differentiation and contributes to liver-specific features such as metabolic zonation and regeneration. In contrast, abnormalities in the Wnt/β-catenin pathway promote the development and progression of hepatocellular carcinoma (HCC). Similarly, hepatoblastoma, the most common childhood liver cancer, is frequently associated with β-catenin mutations, which activate Wnt/β-catenin signaling. HCCs with activation of the Wnt/β-catenin pathway have unique gene expression patterns and pathological and clinical features. Accordingly, they are highly differentiated with retaining hepatocyte-like characteristics and tumorigenic. Activation of the Wnt/β-catenin pathway in HCC also alters the state of immune cells, causing "immune evasion" with inducing resistance to immune checkpoint inhibitors, which have recently become widely used to treat HCC. Activated Wnt/β-catenin signaling exhibits these phenomena in liver tumorigenesis through the expression of downstream target genes, and the molecular basis is still poorly understood. In this review, we describe the physiological roles of Wnt/b-catenin signaling and then discuss their characteristic changes by the abnormal activation of Wnt/b-catenin signaling. Clarification of the mechanism would contribute to the development of therapeutic agents in the future.

Plasma p‐tau181 levels in Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB)

AbstractBackgroundThe fundamental pathological process in AD involves amyloid(Aβ) deposition and Tau hyperphosphorylation (ptau). Plasma ptau has been proven as more accessible and less invasive biomarker than CSF for the assessment of AD pathological features. DLB is another common cause of dementia in the elderly and has overlapping features with AD. Thus, the detection of Alzheimer’s biomarkers might be useful for distinguishing the underlying pathology of AD from other concurrent pathologic processes. In this study, we compared the plasma levels of p‐tau181 in patients with clinically diagnosed DLB and AD.MethodWe examined EDTA plasma samples of patients assessed at the UBC Hospital Clinic for AD. The cohort was clinically characterized as control (n = 89) if no significant cognitive impairment was found, AD (n = 195) if they fulfill the NIA‐AA criteria (McKhann 2011), and DLB (n = 39) if they fulfill the consensus criteria for DLB (McKeith 2005; McKeith 2017). The samples were analyzed by a p‐tau181‐specific Simoa assay.ResultThe mean age of the cohort is 69.2 ± 10.3 with the control 63.4 ± 8.7, AD 70.1 ±9.9 and DLB 77.8 ± 8. There are 74.2% females in the controls, 52.8% in AD, and 35.9% in DLB.).The patients with DLB were older than the cases of AD and controls (p<0.001) and there was no significant effect of age on plasma ptau‐181 concentrations (p = 0.65). There were more females in the controls and AD groups compared to DLB (p<0.001), however, there was no significant correlation between sex and plasma ptau‐181 (p = 0.24). While the plasma p‐tau181 concentrations of cases with AD (74.1 ± 35.6 pg/ml) were slightly higher than DLB (73.2 ± 44.4 pg/ml), they were not significantly different. However, they were significantly higher than the control group (26.5 ± 23 pg/ml) (p < 0.001).ConclusionIn current study, plasma p‐tau181 levels did not differentiate the DLB group from the AD, but both groups were significantly higher than controls. This suggests that DLB often have co‐existing AD pathology, making their p‐tau measurements like the AD group. Further studies with autopsy‐defined samples will be needed to clarify the role of plasma p‐tau181 in DLB.

Candida albicans Adhesion Measured by Optical Nanomotion Detection

Cellular adhesion plays an important role in numerous fundamental physiological and pathological processes. Its measurement is relatively complex, requires sophisticated equipment, and, in most cases, cannot be carried out without breaking the links between the studied cell and its target. In this contribution, we propose a novel, nanomotion-based, technique that overcomes these drawbacks. The applied force is generated by the studied cell itself (nanomotion), whereas cellular movements are detected by traditional optical microscopy and dedicated software. The measurement is non-destructive, single-cell sensitive, and permits following the evolution of the adhesion as a function of time. We applied the technique on different strains of the fungal pathogen Candida albicans on a fibronectin-coated surface. We demonstrated that this novel approach can significantly simplify, accelerate, and make more affordable living cells–substrate adhesion measurements.

Modern concept of autoimmunity in rheumatology

Two fundamental pathologic processes are central to the spectrum of chronic inflammation mechanisms: autoimmunity and autoinflammation. Autoimmunity and autoinflammation are mutually potent pathologic processes; their development is considered within the framework of the “immunoinflammatory” continuum, reflecting the close relationship between innate and acquired types of immune response. Autoimmunity is the leading mechanism of pathogenesis of a large group of chronic inflammatory human diseases, defined as autoimmune diseases, the frequency of which in the population exceeds 10%. Advances in molecular biology, pharmacogenetics and bioinformatics have created prerequisites for individualization of therapy of autoimmune rheumatic diseases within the concept of personalized medicine. The study of immunopathogenesis mechanisms, improvement of diagnostics, deciphering the nature of molecular taxonomy, development of approaches to prevention and personalized therapy of human autoimmune diseases is among the priority directions of medicine of the 21st century.

The use of “Acellbia” – a biosimilar of rituximab in systemic sclerosis

Introduction. The possibilities of modern therapy for systemic sclerosis (SSc) remains limited, since most of the used drugs do not have a diseasemodifying effect. This encourages the study of new approaches that potentially affect the fundamental pathological processes underlying the disease. One example is anti-B cell therapy, in particular rituximab (RTX). Until now RTX do not have a registration for the treatment of SSc, but there is a large positive experience of its use, which is reflected in recent meta-analyses and clinical recommendations. Complicated and expensive methods for obtaining genetically engineered biological preparations have contributed to the emergence of more accessible biosimilars, one of which is the RTX biosimilar, Acellbia (Biocad, Russian Federation). The “biosimilar” versions of RTX might reduce the cost of therapy and increase patients accessibility to this treatment option. The RTX biosimilar Acellbia (ACB) has received approval in Russian Federation in 2014 for all indications held by reference RTX (including rheumatoid arthritis and ANCA-associated vasculitis).The aim of this study was to investigate the efficacy and safety of Acellbia in patients with systemic sclerosis.Material and methods. Our prospective uncontrolled study included 20 patients (14 women) aged 50±14 years, with a disease duration of 3.5±2.7 years. Indications for the prescribing of ACB were high disease activity and the presence of risk factors for progression. All patients had radiological signs of interstitial lung disease, 13 (65%) were positive for antibodies to topoisomerase 1. None of the patients had previously been treated with biological therapy. All patients received glucocorticoids in low doses and 15 (75%) patients were not on concomitant immunosuppressants during the study. ACB was administered in doses of 2 g (two doses of 1 g with a weekly interval) at inclusion of the study and after 6–8 months according to the same scheme, cumulative dose – 4 g. An assessment of basic measurements was obtained at baseline (Point 0), before the second course (after 7.2±1.7 mo, Point 1) and at the end of follow-up (13.4±1.6 mo, Point 2). The results are presented in the form of mean values and standard deviations.Results. There was a positive effect on the main manifestations of the disease, which accompanied by stable depletion of CD19+ B lymphocytes in the peripheral blood. At the intermediate assessment (between points 0–1), no significant changes were observed, with the exception of the skin score. At the end of the study, most of the parameters showed a significant improvement between points 0–2. The activity of the disease (EScSG-AI) decreased, and the skin score decreased from 12.8±11 to 6.2±5.6 (p=0.002). The forced vital capacity (% of predicted) increased from 89±18.2 to 98.26±16.13% (p=0.0002), and the diffusion capacity of the lungs (% of predicted) increased from 56.8±15.7 to 61.9±17.2% (p<0.019). A significant decrease in CRP, antitopoisomerase-1 antibodies, as well as IgG (from 12.6±2.6 to 10.2±2.2 g/l) was noted. Repopulation to normal level of B lymphocytes did not occur in any case, and complete depletion of B lymphocytes at the end of the study was maintained in 83% of patients (15 of 18). The quality of life questionnaire SHAQ improved (p=0.0001), and the average dose of prednisolone was reduced from 11.0±2.7 to 9.4±2.3 mg/day (p=0.03). Positive changes according to HRCT was evident in 9 (45%) patients due to a decrease in ground glass opacity. The frequency and spectrum of adverse events (AEs) corresponded to those already known for RTX. Of the 20 patients who received 2 courses of ACB, two withdrew from the evaluation at Point 2 due to pregnancy (1) and lung cancer (1). A total of 11 (55%) AEs were reported in 9 (45%) patients, most of them were classified as mild. Infectious complications developed in 7 (35%) patients: respiratory infections of the upper respiratory tract (4), positivity in the TB skin test (2), otitis (1), cystitis (1) and cholecystitis (1). One patient developed calf vein thrombosis and lung cancer was diagnosed in one case.Conclusion. Our data suggest that Acellbia could be used for the treatment of SSc. A short-term, prospective, uncontrolled study showed good efficacy and acceptable safety of the ACB biosimilar in SSc. A significant decrease of skin fibrosis and improvement of lung functions have been proven. The clinical effect of ACB manifested by the 6th month from the start of therapy and reached its maximum one year after its initiation. Due to the positive efficacy of ACB, it can be prescribed for the patients with SSc with ineffectiveness and/or intolerance to immunosuppressants, and could be considered as a first-line therapy. Our data should be confirmed by the results of controlled clinical trials.

Pan-cancer analyses of classical protein tyrosine phosphatases and phosphatase-targeted therapy in cancer.

Protein tyrosine phosphatases function in dephosphorylating target proteins to regulate signaling pathways that control a broad spectrum of fundamental physiological and pathological processes. Detailed knowledge concerning the roles of classical PTPs in human cancer merits in-depth investigation. We comprehensively analyzed the regulatory mechanisms and clinical relevance of classical PTPs in more than 9000 tumor patients across 33 types of cancer. The independent datasets and functional experiments were employed to validate our findings. We exhibited the extensive dysregulation of classical PTPs and constructed the gene regulatory network in human cancer. Moreover, we characterized the correlation of classical PTPs with both drug-resistant and drug-sensitive responses to anti-cancer drugs. To evaluate the PTP activity in cancer prognosis, we generated a PTPscore based on the expression and hazard ratio of classical PTPs. Our study highlights the notable role of classical PTPs in cancer biology and provides novel intelligence to improve potential therapeutic strategies based on pTyr regulation.

Inflammatory Immune-Associated eRNA: Mechanisms, Functions and Therapeutic Prospects.

The rapid development of multiple high-throughput sequencing technologies has made it possible to explore the critical roles and mechanisms of functional enhancers and enhancer RNAs (eRNAs). The inflammatory immune response, as a fundamental pathological process in infectious diseases, cancers and immune disorders, coordinates the balance between the internal and external environment of the organism. It has been shown that both active enhancers and intranuclear eRNAs are preferentially expressed over inflammation-related genes in response to inflammatory stimuli, suggesting that enhancer transcription events and their products influence the expression and function of inflammatory genes. Therefore, in this review, we summarize and discuss the relevant inflammatory roles and regulatory mechanisms of eRNAs in inflammatory immune cells, non-inflammatory immune cells, inflammatory immune diseases and tumors, and explore the potential therapeutic effects of enhancer inhibitors affecting eRNA production for diseases with inflammatory immune responses.

Regenerating Damaged Myocardium: A Review of Stem-Cell Therapies for Heart Failure.

Cardiovascular disease (CVD) is one of the contributing factors to more than one-third of human mortality and the leading cause of death worldwide. The death of cardiac myocyte is a fundamental pathological process in cardiac pathologies caused by various heart diseases, including myocardial infarction. Thus, strategies for replacing fibrotic tissue in the infarcted region with functional myocardium have long been a goal of cardiovascular research. This review begins by briefly discussing a variety of somatic stem- and progenitor-cell populations that were frequently studied in early investigations of regenerative myocardial therapy and then focuses primarily on pluripotent stem cells (PSCs), especially induced-pluripotent stem cells (iPSCs), which have emerged as perhaps the most promising source of cardiomyocytes for both therapeutic applications and drug testing. We also describe attempts to generate cardiomyocytes directly from cardiac fibroblasts (i.e., transdifferentiation), which, if successful, may enable the pool of endogenous cardiac fibroblasts to be used as an in-situ source of cardiomyocytes for myocardial repair.

Small-Molecule Fluorogenic Probe for the Detection of Mitochondrial Temperature In Vivo.

Mitochondria, as energy factories, participate in many metabolic processes and play vital roles in cell life. Most human diseases are caused by mitochondrial dysfunction, and mitochondrial temperature is an important indicator of mitochondrial function. Despite the biological importance of mitochondria, there are few tools for detecting changes in mitochondrial temperature in living organisms. Here, we report on a thermosensitive rhodamine B (RhB)-derived fluorogenic probe (RhBIV) that enables fluorescent labeling of cell mitochondria at concentrations as low as 1 μM. We demonstrate that this probe exhibits a temperature-dependent response in cell mitochondria. Furthermore, in mice, it has a long half-life (t1/2) and is primarily enriched in the liver. This unique thermosensitive probe offers a simple, nondestructive method for longitudinal monitoring of mitochondrial temperature both in vitro and in vivo to elucidate fundamental physiological and pathological processes related to mitochondrial function.

Effect of Uncaria rhynchophylla against Thioacetamide-Induced Acute Liver Injury in Rat.

Both oxidative stress (OS) and inflammation are two fundamental pathological processes of acute liver injury (ALI). The current work is to investigate the effect and possible mechanism of Uncaria rhynchophylla (UR) on thioacetamide- (TAA-) induced ALI in rats. UR (100 and 200 mg/kg) was orally administrated with TAA (200 mg/kg of bodyweight, intraperitoneal injection) for 3 consecutive days. ALI was confirmed using histological examination and the factors associated with OS and liver function activity measured in serum. Moreover, expressions of inflammation and collagen-related proteins were measured by the Western blot analysis. Myeloperoxidase (MPO), which mediates OS in the ALI control group, was manifested by a significant rise compared with the normal group. UR significantly reduced AST, ALT, and ammonia levels in serum. The nuclear factor-κB (NF-κB) activation induced by TAA led to increase both inflammatory mediators and cytokines. Whereas, UR administration remarkably suppressed such an overexpression. UR supplementation improved matrix metalloproteinases (MMPs) such as MMP-1, -2, and -8. In contrast, tissue inhibitors of metalloproteinases- (TIMP-) 1 level increased significantly by UR treatment. In addition, the histopathological analysis showed that the liver tissue lesions were improved obviously by UR treatment. UR may ameliorate the effects of TAA-induced ALI in rats by suppressing both OS through MPO activation and proinflammatory factors through NF-κB activation. In conclusion, UR exhibited a potent hepatoprotective effect on ALI through the suppression of OS.

New capabilities of optical coherence tomography in the diagnostics of primary angle-closure glaucoma

INTRODUCTION. Recently, posterior vitreous detachment (PVD) was suggested as a fundamental pathologic process in primary angle-closure glaucoma (PACG) in morphologically predisposed patients with anatomically narrow anterior chamber angle.PURPOSE. To study the role of PVD in the development and clinical manifestation of PACG in anatomically predisposed eyes and to assess the capabilities of posterior segment optical coherence tomography (PS-OCT) in PACG diagnostics.MATERIALS AND METHODS. Thirty eyes with newly diagnosed stage I-II PACG and thirty eyes predisposed to PACG (with narrow anterior chamber angle without glaucoma signs) were enrolled in the study. All patients underwent ophthalmological examination, Hyams test, ocular ultrasound (OU) and PS-OCT.RESULTS. PVD with retrohyaloid space (RHS) formation was revealed in all PACG eyes. Positive Hyams test was in 86.67% eyes with PACG, and 13.33% were negative. All the eyes with PVD as a result of Hyams test experienced RHS enhancement correlating with IOP rise. Despite the negative results of Hyams test in some PACG eyes with PVD — glaucomatous optic neuropathy signs were present. Possible causes are discussed.PVD with RHS formation was revealed in 53.33% predisposed to PACG eyes — all with positive result of Hyams test. The other 46.67% eyes predisposed to PACG had negative Hyams test, no PVD and no RHS.CONCLUSION. Obtained results confirm a new theory of PACG etiopathogenesis suggesting PVD with PGS to be the essential mechanism of POAG development in morphologically predisposed eyes. PS-OCT appears to be crucial in PACG early diagnostics.

Sepsis-3: new edition — old problems. analysis from the perspective of general pathology

Sepsis-3 Guidelines defines sepsis as an organ dysfunction caused by dysregulated host response to infection. To record organ dysfunction, the SOFA/quick SOFA scales were recommended. In fact, in medical practice, sepsis is considered nothing more than a critical infection that requires intensive care. Therefore, sepsis is pathogenetically a nonhomogeneous condition manifested by diverse nosologies and syndromes. Unlike the previous two editions, Sepsis-1 and Sepsis-2 Guidelines, the formal criteria provided in the Sepsis-3 are closer to the de facto position, describe more specific, but less sensitive features to predict mortality. However, the initial, latent manifestations of critical conditions, which can be relatively effectively controlled by intensive therapy, remain outside the Sepsis-3 criteria. Not all signs of multiple organ dysfunctions (according to the Sepsis-3 criteria) will require intensive care. Hence, obviously the presence or absence of formal criteria of Sepsis-3 will not be always taken into account while verifying sepsis. The only relatively pathogenetically homogeneous definition in Sepsis-3 is “septic shock”. However, it also does not fully consider the staging (according to the degree of compensation of hemodynamic disturbances) and the phasing (according to the severity of the proinflammatory response) of the dynamics of the shock condition. From our point of view, a positive result of the Sepsis-3 consensus would be in transition of the systemic inflammatory response syndrome (SIRS) from the main to additional (optional) verifying sepsis criteria. We also believe that the weak side of the Sepsis-3 Guidelines is in underestimated mechanisms of systemic inflammation as a general pathological process in the genesis of developing critical conditions of various origins. From the perspective of general pathology, sepsis is a combination of the three common fundamental pathological processes: classical (canonical) and systemic inflammation (SI), as well as chronic systemic low-grade inflammation (parainflammation), the latter can be considered as an unfavorable background for development of the former two processes. All three processes are characterized by any SIR signs and require to be differentiated on the basis of integral criteria, which reflect specific blocks of the SI complex process. The pathogenesis of the SARS-CoV-2 infection (COVID-19) is a relevant example underlying inevitability of such approach. The systemic microvascular vasculitis, and its main clinical manifestations such as systemic microcirculatory disorders in the form of shockogenic conditions is the SI pathogenetic basis. Apparently, one of the modalities for further evolution of critical care medicine will be coupled to development of a more multilayered but effective methods for assessing pathogenesis of critical states and more differentiated methods of pathogenetic therapy. Therefore, it will require to modernize a number of fundamental premises in our knowledge about pathobiology, pathophysiology, and general pathology.

Differential microRNAs expression profiles in liver from three different lifestyle modification mice models

BackgroundMicroRNAs play an important role in many fundamental biological and pathological processes. Defining the microRNAs profile underlying the processes by beneficial and detrimental lifestyles, including caloric restriction (CR), exercise and high-fat diet (HF), is necessary for understanding both normal physiology and the pathogenesis of metabolic disease. We used the microarray to detect microRNAs expression in livers from CR, EX and HF mice models. After predicted potential target genes of differentially expressed microRNAs with four algorithms, we applied GO and KEGG to analyze the function of predicted microRNA targets.ResultsWe describe the overall microRNAs expression pattern, and identified 84 differentially expressed microRNAs changed by one or two or even all the three lifestyle modifications. The common and different enriched categories of gene function and main biochemical and signal transduction pathways were presented.ConclusionsWe provided for the first time a comprehensive and thorough comparison of microRNAs expression profiles in liver among these lifestyle modifications. With this knowledge, our findings provide us with an overall vision of microRNAs in the molecular impact of lifestyle on health as well as useful clues for future and thorough research of the role of microRNAs.

P2X7 Receptor Antagonist Attenuates Retinal Inflammation and Neovascularization Induced by Oxidized Low-Density Lipoprotein.

Age-related macular degeneration (AMD) is a common and severe blinding disease among people worldwide. Retinal inflammation and neovascularization are two fundamental pathological processes in AMD. Recent studies showed that P2X7 receptor was closely involved in the inflammatory response. Here, we aim to investigate whether A740003, a P2X7 receptor antagonist, could prevent retinal inflammation and neovascularization induced by oxidized low-density lipoprotein (ox-LDL) and explore the underlying mechanisms. ARPE-19 cells and C57BL/6 mice were treated with ox-LDL and A740003 successively for in vitro and in vivo studies. In this research, we found that A740003 suppressed reactive oxygen species (ROS) generation and inhibited the activation of Nod-like receptor pyrin-domain protein 3 (NLRP3) inflammasome and nuclear factor-κB (NF-κB) pathway. A740003 also inhibited the generation of angiogenic factors in ARPE-19 cells and angiogenesis in mice. The inflammatory cytokines and phosphorylation of inhibitor of nuclear factor-κB alpha (IKBα) were repressed by A740003. Besides, ERG assessment showed that retinal functions were remarkably preserved in A740003-treated mice. In summary, our results revealed that the P2X7 receptor antagonist reduced retinal inflammation and neovascularization and protected retinal function. The protective effects were associated with regulation of NLRP3 inflammasome and the NF-κB pathway, as well as inhibition of angiogenic factors.

A Fluorogenic Trehalose Probe for Tracking Phagocytosed Mycobacterium tuberculosis.

Tuberculosis (TB) disease is a global epidemic caused by the pathogenic Mycobacterium tuberculosis (Mtb). Tools that can track the replication status of viable Mtb cells within macrophages are vital for the elucidation of host-pathogen interactions. Here, we present a cephalosphorinase-dependent green trehalose (CDG-Tre) fluorogenic probe that enables fluorescence labeling of single live Bacille Calmette-Guérin (BCG) cells within macrophages at concentrations as low as 2 μM. CDG-Tre fluoresces upon activation by BlaC, the β-lactamase uniquely expressed by Mtb, and the fluorescent product is subsequently incorporated within the bacterial cell wall via trehalose metabolic pathway. CDG-Tre showed high selectivity for mycobacteria over other clinically prevalent species in the Corynebacterineae suborder. The unique labeling strategy of BCG by CDG-Tre provides a versatile tool for tracking Mtb in both pre- and postphagocytosis and elucidating fundamental physiological and pathological processes related to the mycomembrane.