Pathological Changes Research Articles

Synoviocyte detachment: an overlooked yet crucial histological aspect in rheumatoid arthritis

ObjectiveRheumatoid arthritis (RA) is a prevalent autoimmune disorder that leads to chronic joint inflammation, deformity, disability, and systemic complications. This study aimed to analyze the clinical characteristics and synovial pathology of RA patients with synoviocyte detachment, and explore the factors associated with this phenomenon.MethodsThis was a retrospective cohort study included RA patients who underwent synovial biopsy at our center from April to September 2023. Demographic, clinical, laboratory, and synovial histological data were retrospectively collected from medical records at the time of joint synovial biopsy in patients. Microscopic examination of hematoxylin and eosin (HE)-stained synovial tissue sections categorized the samples into synoviocyte detachment and no-synoviocyte detachment groups. Clinical characteristics and synovial pathological changes were compared between the two groups, and the factors associated with synoviocyte detachment were explored through logistic regression analysis.ResultsFifty-five RA patients were enrolled; 45 were females, and the mean age was 53.4 ± 11.8 years. Nine RA patients exhibited synoviocyte detachment. A total of 46 RA patients in the no-synoviocyte detachment group (15 with a normal lining layer and 31 with synovial cell proliferation) were included. Compared with the no-synoviocyte detachment group, the synoviocyte detachment group presented higher RF, ESR, CRP and DAS28-CRP levels (P < 0.05). The synoviocyte detachment group exhibited more prominent neovascularization (P < 0.05). ESR, DAS28-CRP and synovial neovascularization were risk factors associated with synoviocyte detachment in RA patients.ConclusionRA patients with synoviocyte detachment exhibit elevated clinical disease activity, marked by pronounced synovial pathology featuring increased neovascularization and less inflammatory cell infiltration. A significant reduction in lymphocyte count compared with patients with synovial cell proliferation was also observed.

Amyloid-β (Aβ) immunotherapy induced microhemorrhages are linked to vascular inflammation and cerebrovascular damage in a mouse model of Alzheimer’s disease

BackgroundAnti-amyloid-β (Aβ) immunotherapy trials have revealed amyloid-related imaging abnormalities (ARIA) as the most prevalent and serious adverse events linked to pathological changes in cerebral vasculature. Recent studies underscore the critical involvement of perivascular macrophages and the infiltration of peripheral immune cells in regulating cerebrovascular damage. Specifically, Aβ antibodies engaged at cerebral amyloid angiopathy (CAA) deposits trigger perivascular macrophage activation and the upregulation of genes associated with vascular permeability. Nevertheless, further research is needed to understand the immediate downstream consequences of macrophage activation, potentially exacerbating CAA-related vascular permeability and microhemorrhages linked to Aβ immunotherapy.MethodsThis study investigates immune responses induced by amyloid-targeting antibodies and CAA-induced microhemorrhages using RNA in situ hybridization, histology and digital spatial profiling in an Alzheimer's disease (AD) mouse model of microhemorrhage.ResultsIn the present study, we have demonstrated that bapineuzumab murine surrogate (3D6) induces profound vascular damage, leading to smooth muscle cell loss and blood–brain barrier (BBB) breakdown. In addition, digital spatial profiling (DSP) reveals that distinct immune responses contribute to vascular damage with peripheral immune responses and perivascular macrophage activation linked to smooth muscle cell loss and vascular fibrosis, respectively. Finally, RNA in situ hybridization identifies two distinct subsets of Trem2+ macrophages representing tissue-resident and monocyte-derived macrophages around vascular amyloid deposits. Overall, these findings highlight multifaceted roles of immune activation and vascular damage in driving the development of microhemorrhage.ConclusionsIn summary, our study has established a significant link between CAA-Aβ antibody immune complex formation, immune activation and vascular damage leading to smooth muscle cell loss. However, the full implications of this cascade on the development of microhemorrhages requires further exploration. Additional investigations are warranted to unravel the precise molecular mechanisms leading to microhemorrhage, the interplay of diverse immune populations and the functional roles played by various Trem2+ macrophage populations in response to Aβ immunotherapy.

Intervention effects of Naoxintong capsules on psychological and cardiac status in depressed rats after heart failure

Abstract Background Depression is a common clinical phenomenon in the patients with heart failure (HF). In traditional Chinese medicine (TCM), diseases in the brain and heart are thought to be correlated and interact. Naoxintong capsules (NXT) has been used for treating cardio-cerebrovascular diseases, while its therapeutic effect on depression after HF remains unclear. Objective The aim of the study is to evaluate the intervention effect of NXT on depression after HF. Methods Sprague-Dawley rats were assigned into the following 5 groups: sham, model, NXT (250, 1000 mg/kg), and valsartan (8 mg/kg). Coronary artery occlusion was performed to induce HF and subsequent depression in rats. The cardiac function was evaluated by echocardiography, hematoxylin-eosin staining, and Masson trichrome staining. The sucrose preference test and Morris water maze test were carried out to assess the depressive behaviors in rats. The ultrastructure of hippocampal CA1 neurons was observed and the levels of corticotropin-releasing hormone in the hypothalamus, brain-derived neurotrophic factor in the cortex, and adrenocorticotropic hormone (ACTH) in the plasma were determined by enzyme-linked immunosorbent assay. The levels of dopamine, 5-hydroxytryptamine, norepinephrine, and γ-aminobutyric acid in the hippocampus were measured by UPLC-QQQ-MS. Results NXT reduced myocardial injury and pathological changes in the cardiac tissue and increased the left ventricular ejection fraction, left ventricular fractional shortening, and cardiac output. NXT increased the sugar preference rate and number of crossings and shortened the escape latency. Furthermore, the NXT treatment restored the levels of corticotropin-releasing hormone, adrenocorticotropic hormone, brain-derived neurotrophic factor, dopamine, and γ-aminobutyric acid to the baseline values. Conclusions NXT not only demonstrates cardioprotective effect but also attenuates depression in the rats after HF. It may exert the antidepressant effect by inhibiting the hyperactivity of the hypothalamic-pituitary-adrenal axis and recovering the levels of neurotrophic factors and neurotransmitters.

Apigenin as a Promising Agent for Enhancing Female Reproductive Function and Treating Associated Disorders.

Apigenin is an organic flavonoid abundant in some plants such as parsley, chamomile, or celery. Recently, it has been investigated for several of its pharmacological characteristics, such as its ability to act as an antioxidant, reduce inflammation, and inhibit the growth of cancer cells. The purpose of this review is to provide a summary of the existing knowledge regarding the effects of apigenin on female reproductive systems and its dysfunctions. Apigenin can influence reproductive processes by regulating multiple biological events, including oxidative processes, cell proliferation, apoptosis, cell renewal and viability, ovarian blood supply, and the release of reproductive hormones. It could stimulate ovarian folliculogenesis, as well as ovarian and embryonal cell proliferation and viability, which can lead to an increase in fertility and influence the release of reproductive hormones, which may exert its effects on female reproductive health. Furthermore, apigenin could inhibit the activities of ovarian cancer cells and alleviate the pathological changes in the female reproductive system caused by environmental pollutants, harmful medications, cancer, polycystic ovarian syndrome, ischemia, as well as endometriosis. Therefore, apigenin may have potential as a biostimulator for female reproductive processes and as a therapeutic agent for certain reproductive diseases.

Proliferative Diabetic Retinopathy Microenvironment Drives Microglial Polarization and Promotes Angiogenesis and Fibrosis via Cyclooxygenase-2/Prostaglandin E2 Signaling

Diabetic retinopathy (DR) is the leading cause of visual impairment, particularly in the proliferative form (proliferative DR [PDR]). The impact of the PDR microenvironment on microglia, which are the resident immune cells in the central nervous system, and the specific pathological changes it may induce remain unclear. This study aimed to investigate the role of microglia in the progression of PDR under hypoxic and inflammatory conditions. We performed a comprehensive gene expression analysis using human-induced pluripotent stem cell-derived microglia under different stimuli (dimethyloxalylglycine (DMOG), lipopolysaccharide (LPS), and DMOG + LPS) to mimic the hypoxic inflammatory environment characteristic of PDR. Principal component analysis revealed distinct gene expression profiles, with 76 genes synergistically upregulated under combined stimulation. Notably, prostaglandin-endoperoxide synthase 2 (encoding cyclooxygenase (COX)-2) exhibited the most pronounced increase, leading to elevated prostaglandin E2 (PGE2) levels and driving pathological angiogenesis and inflammation via the COX-2/PGE2/PGE receptor 2 signaling axis. Additionally, the upregulation of the fibrogenic genes snail family transcriptional repressor 1 and collagen type I alpha 1 chain suggested a role for microglia in fibrosis. These findings underscore the critical involvement of microglia in PDR and suggest that targeting both the angiogenic and fibrotic pathways may present new therapeutic strategies for managing this condition.

Ouabain Ameliorates Alzheimer’s Disease-Associated Neuropathology and Cognitive Impairment in FAD4T Mice

Background: Alzheimer’s disease (AD) is a common clinical neurodegenerative disorder, primarily characterized by progressive cognitive decline and behavioral abnormalities. The hallmark pathological changes of AD include widespread neuronal degeneration, plaques formed by the deposition of amyloid β-protein (Aβ), and neurofibrillary tangles (NFTs). With the acceleration of global aging, the incidence of AD is rising year by year, making it a major global public health concern. Due to the complex pathology of AD, finding effective interventions has become a key focus of research. Ouabain (OUA), a cardiac glycoside, is well-known for its efficacy in treating heart disease. Recent studies have also indicated its potential in AD therapy, although its exact mechanism of action remains unclear. Methods: This study integrates bioinformatics, multi-omics technologies, and in vivo and in vitro experiments to investigate the effects of OUA on the pathophysiological changes of AD and its underlying molecular mechanisms. Results: This study analyzed the expression of the triggering receptor expressed on myeloid cells 2 (TREM2) across different stages of AD using bioinformatics. Serum samples from patients were used to validate soluble TREM2 (sTREM2) levels. Using an Aβ1-42-induced microglial cell model, we confirmed that OUA enhances the PI3K/AKT signaling pathway activation by upregulating TREM2, which reduces neuroinflammation and promotes the transition of microglia from an M1 proinflammatory state to an M2 anti-inflammatory state. To evaluate the in vivo effects of OUA, we assessed the learning and memory capacity of FAD4T transgenic mice using the Morris water maze and contextual fear conditioning tests. We used real-time quantitative PCR, immunohistochemistry, and Western blotting to measure the expression of inflammation-associated cytokines and to assess microglia polarization. OUA enhances cognitive function in FAD4T mice and has been confirmed to modulate microglial M1/M2 phenotypes both in vitro and in vivo. Furthermore, through bioinformatics analysis, molecular docking, and experimental validation, TREM2 was identified as a potential target for OUA. It regulates PI3K/Akt signaling pathway activation, playing a crucial role in OUA-mediated M2 microglial polarization and its anti-inflammatory effects in models involving Aβ1-42-stimulated BV-2 cells and FAD4T mice. Conclusions: These findings indicate that OUA exerts anti-neuroinflammatory effects by regulating microglial polarization, reducing the production of inflammatory mediators, and activating the PI3K/Akt signaling pathway. Given its natural origin and dual effects on microglial polarization and neuroinflammation, OUA emerges as a promising therapeutic candidate for neuroinflammatory diseases such as AD.

Ponatinib exacerbate renal injury in systemic lupus erythematosus mouse model through PDGFR-PI3K/AKT pathway

Lupus nephritis (LN) is a common clinical complication of systemic lupus erythematosus (SLE). Proliferative lupus nephritis represents the gravest form of LN, and since effective drugs for its treatment are still lacking, tyrosine kinase inhibitors (TKIs) find extensive clinical utility due to their notable impact on suppressing cell proliferation and may serve as potential drugs for LN treatment. However, previous studies on the effects of TKI on LN have been controversial. Ponatinib, a third-generation TKI, lacks studies on its role in LN. This study aimed to investigate the impact of the ponatinib on LN. MRL/lpr mice were evaluated for renal function, autoimmune markers and histopathological changes after oral administration of ponatinib. RNA-seq analysis was performed to explore the molecular pathways involved in ponatinib-induced kidney injury. Ponatinib uniquely exacerbated renal damage in MRL/lpr mice, evidenced by a decline in renal function and acute pathological changes, without affecting lupus-related autoimmune markers. Differential expressed genes analysis and functional enrichment implicate ponatinib-induced renal damage in MRL/lpr mice associated with adiponectin. Furthermore, we verified ponatinib signaling the PI3K/AKT pathway through PDGFRα, potentially influencing high molecular weight adiponectin (HMW ADIPOQ) expression and exacerbating renal damage. In conclusion, this study demonstrates that ponatinib can up-regulate HMW ADIPOQ expression via the PI3K/AKT pathway by inhibiting PDGFRα phosphorylation, highlighting the potential nephrotoxic effects of ponatinib in lupus-prone mice, and underscoring the importance of monitoring renal function in systemic autoimmune diseases patients receiving ponatinib.

STATE OF CELLULAR IMMUNITY IN PURULENT CHOLANGITIS

Abstract. Objective: To study the state of the cellular link of immunity in acute and chronic cholangitis. Materials and methods. Cholangitis always worsens the condition of the biliary system. Depending on the magnitude of the pathological changes in the bile ducts, we distinguished three groups of patients. Group I – cholangitis caused by obstruction of the main extrahepatic bile ducts due to choledocholithiasis, group II – cholangitis in conditions of cicatricial strictures of the main bile ducts, and group III – cholangitis in conditions of already performed reconstruction of the duct system. The indicators of the cellular link of immunity were studied separately in each group. The results. The conducted studies indicate an imbalance of the immune system in patients with different courses of cholangitis. The presence of inflammation of a mild degree of severity causes stimulation of almost all links of the immune system, while the cellular branch reacts first. Conclusions. Long-term cholangitis was accompanied by suppression of the main markers of T-lymphocyte differentiation — CD2+, CD3+, CD4+ and CD8+, which take part in antigen presentation, signal transmission to other cells and affect their adhesive properties.

Macrophage-Derived Exosomes Promoted the Development and Stemness of Inflammatory Bowel Disease-Related Colorectal Cancer via nuclear paraspeckle assembly transcript 1-Mediated miRNA-34a-5p/phosphoprotein enriched in astrocytes 15 Axis.

Inflammatory bowel disease (IBD) is closely associated with the development of colorectal cancer (CRC) due to the chronic inflammatory response. Macrophages play critical roles in regulating the microenvironment to facilitate tumor progression. Exosomes are key modulators for the communication between macrophages and tumor cells. The mechanism of macrophage-derived exosomes in IBD-related CRC development remains unclear. The macrophages were isolated using fluorescence activating cell sorter (FACS). The RNA and protein expressions in exosomes and CRC cells were examined by quantitative real-time polymerase chain reaction and western blot assays, respectively. CRC cell development was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, BrdU staining, Transwell assay, and spheroid formation assay. The level of stemness was determined by detecting the proportion of leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5)-positive CRC cells and the expression of LGR5, CD133, and CD44. Molecular interaction experiments were done using luciferase reporter assay and RNA immunoprecipitation assay. Xenograft tumor model in vivo and immunohistochemistry were used to observe the pathological changes. Macrophage-derived exosomes from IBD-related CRC tissues were enriched with nuclear paraspeckle assembly transcript 1 (NEAT1) and able to promote the progression and stemness of CRC both in vitro and in vivo. The exosomal NEAT1 could sponge miR-34a-5p, leading to the restoration of PEA15 expression in CRC cells and promoting the development of CRC. Inhibition of NEAT1 in exosomes could effectivity inhibit the tumor growth in the CRC xenograft model. These findings provide novel insights into how macrophages affect CRC development and highlight exosomal NEAT1 as a therapeutic target for CRC treatment.

Role of cuproptosis in mediating the severity of experimental malaria-associated acute lung injury/acute respiratory distress syndrome

BackgroundMalaria-associated acute lung injury/acute respiratory distress syndrome (MA-ALI/ARDS) is a fatal complication of Plasmodium falciparum infection that is partially triggered by macrophage recruitment and polarization. As reported, copper exposure increases the risk of malaria infection, and copper accumulation-induced cuproptosis triggers M1 macrophage polarization. It is thus hypothesized that cuproptosis could act as a critical mediator in the pathogenesis of MA-ALI/ARDS, but its underlying mechanism remains unclear. The present study aimed to explore the role of cuproptosis in the severity of murine MA-ALI/ARDS.MethodsWe utilized an experimental model of MA-ALI/ARDS using female C57BL/6 mice with P. berghei ANKA infection, and treated these animals with the potent copper ion carrier disulfiram (DSF) or copper ion chelator tetrathiomolybdate (TTM). The RAW 264.7 macrophages, which were stimulated with infected red blood cells (iRBCs) in vitro, were also targeted with DSF-CuCl2 or TTM-CuCl2 to further investigate the underlying mechanism.ResultsOur findings showed a dramatic elevation in the amount of copper and the expression of SLC31A1 (a copper influx transporter) and FDX1 (a key positive regulator of cuproptosis) but displayed a notable reduction in the expression of ATP7A (a copper efflux transporter) in the lung tissue of experimental MA-ALI/ARDS mice. Compared to the P. berghei ANKA-infected control group, mice that were administered DSF exhibited a remarkable increase in parasitemia/lung parasite burden, total protein concentrations in bronchoalveolar lavage fluid (BALF), lung wet/dry weight ratio, vascular leakage, and pathological changes in lung tissue. Strikingly, the experimental MA-ALI/ARDS mice with DSF treatment also demonstrated dramatically elevated copper levels, expression of SLC31A1 and FDX1, numbers of CD86+, CD68+, SLC31A1+-CD68+, and FDX1+-CD68+ macrophages, and messenger RNA (mRNA) levels of pro-inflammatory cytokines (tumor necrosis factor [TNF-α] and inducible nitric oxide synthase [iNOS]) in lung tissue, but showed a remarkable decrease in body weight, survival time, expression of ATP7A, number of CD206+ macrophages, and mRNA levels of anti-inflammatory cytokines (transforming growth factor beta [TGF-β] and interleukin 10 [IL-10]). In contrast, TTM treatment reversed these changes in the infected mice. Similarly, the in vitro experiment showed a notable elevation in the mRNA levels of SLC31A1, FDX1, CD86, TNF-α, and iNOS in iRBC-stimulated RAW 264.7 cells targeted with DSF-CuCl2, but triggered a remarkable decline in the mRNA levels of ATP7A, CD206, TGF-β, and IL-10. In contrast, TTM-CuCl2 treatment also reversed these trends in the iRBC-stimulated RAW 264.7 cells.ConclusionsOur data demonstrate that the activation of cuproptosis with DSF aggravated the severity of MA-ALI/ARDS by partially inducing M1 polarization of pulmonary macrophages, while inhibition of cuproptosis with TTM contrarily ameliorated the severity of MA-ALI/ARDS by promoting macrophage M2 polarization. Our findings suggest that blockage of cuproptosis could be a potential therapeutic strategy for treatment of MA-ALI/ARDS.Graphical

Organic mental illnesses are outlawed: farewell to Karl Bonhoeffer

The article analyzes the reasons for the deletion of the section “Organic mental disorders” from the psychiatric classifications (ICD-11, DSM-5) and its replacement by the sections “Neurocognitive disorders” and “Secondary mental and behavioral disorders associated with disorders and diseases classified in other chapters”. It is argued that at the present stage of development of psychiatry it has become clear that not only organic mental disorders are associated with impaired brain function, but also all others, e.g. the disorders of the schizophrenic spectrum. This leads to the conclusion that the term “organic” has become an anachronism and no longer reflects the essence of psychogenesis. As a result, changes in terminology in modern psychiatric classifications should be recognized as justified. However, the term “organic disorders” did not have a stigmatizing character, unlike, for example, “psychopathy”, “oligophrenia”, “hysteria” or “manic-depressive psychosis”. It undoubtedly had an indeterminate character, as it interpreted pathological changes in the brain broadly and was opposed to the concept of “functional disorders”. At the current stage of development of psychoneurology, organic causes are often found behind the functional. Exclusion of the term “organic” from the psychiatric lexicon, rejection of the Bonhoeffer approach, the Walter-Buell triad and the psychoorganic syndrome can be considered superfluous, since the introduction of the concept of “secondary mental disorders” in their place does not alter the process of understanding the nature of psychogenesis. It is concluded that the division of mental disorders into so-called primary and secondary disorders is no better than the opposition of functional and organic disorders, and that the “outdated” approach can be used in the training of young psychiatrists, emphasizing that the term “organic” can also be extended to mental disorders that used to be called endogenous.

Impact of Curcumin on the IL-17A-Mediated p53-Fibrinolytic System: Mouse Proteomics and Integrated Human Fibrosis scRNAseq Insights.

Acute lung injury (ALI) is primarily driven by an intense inflammation in the alveolar epithelium. Key to this is the pro-inflammatory cytokine, Interleukin 17 (IL-17), which influences pulmonary immunity and modifies p53 function. The direct role of IL-17A in p53-fibrinolytic system is still unclear, it is important to evaluate this mechanism to regulate the ALI progression to idiopathic pulmonary fibrosis (IPF). C57BL/6 mice, exposed to recombinant IL-17A protein and treated with curcumin, provided insight into IL-17A mechanisms and curcumin's potential for modulating early pulmonary fibrosis stages. A diverse methodology, including proteomics, single-cell RNA sequencing (scRNA-seq) integration, molecular, and Schroedinger approach were utilized. In silico approaches facilitated the potential interactions between curcumin, IL-17A, and apoptosis-related proteins. A notable surge in the expression levels of IL-17A, p53, and fibrinolytic components such as Plasminogen Activator Inhibitor-1 (PAI-I) was discerned upon the IL17A exposure in mouse lungs. Furthermore, the enrichment of pathways and differential expression of proteins underscored the significance of IL-17A in governing downstream regulatory pathways such as inflammation, NF-kappaB signaling, Mitogen-Activated Protein Kinases (MAPK), p53, oxidative phosphorylation, JAK-STAT, and apoptosis. The integration of scRNA-seq data from 20 IPF and 10 control lung specimens emphasized the importance of IL-17A mediated downstream regulation in PF patients. A potent immuno-pharmacotherapeutic agent, curcumin, demonstrated a substantial capacity to modulate the lung pathology and molecular changes induced by IL-17A in mouse lungs. Human IPF single cell data integration confirmed the effects of IL-17A mediated fibrinolytic components in ALI to IPF progression.

Perspective on using non-human primates in Exposome research

The physiological and pathological changes in the human body caused by environmental pressures are collectively referred to as the Exposome. Human society is facing escalating environmental pollution, leading to a rising prevalence of associated diseases, including respiratory diseases, cardiovascular diseases, neurological disorders, reproductive development disorders, among others. Vulnerable populations to the pathogenic effects of environmental pollution include those in the prenatal, infancy, and elderly stages of life. Conducting Exposome mechanistic research and proposing effective health interventions are urgent in addressing the current severe environmental pollution. In this review, we address the core issues and bottlenecks faced by current Exposome research, specifically focusing on the most toxic ultrafine nanoparticles. We summarize multiple research models being used in Exposome research. Especially, we discuss the limitations of rodent animal models in mimicking human physiopathological phenotypes, and prospect advantages and necessity of non-human primates in Exposome research based on their evolutionary relatedness, anatomical and physiological similarities to human. Finally, we declare the initiation of NHPE (Non-Human Primate Exposome) project for conducting Exposome research using non-human primates and provide insights into its feasibility and key areas of focus. SynopsisNon-human primate models hold unique advantages in human Exposome research.

Establishment and analysis of an animal model for nutcracker syndrome.

This study investigated the effects of renal vein congestion of varying durations on kidney damage by establishing an animal model of Nutcracker Syndrome (NCS). In addition, we assessed whether renal damage improved after relieving the congestion. We established a rat model of NCS and relieved renal congestion through secondary surgery, with renal vein reperfusion confirmed by animal ultrasound. Histopathological changes in congested kidneys were evaluated at 3, 6, and 9days using HE and Masson staining, and the expression of renal injury factors was determined using q-PCR. Renal tissue pathology changes were evident with prolonged obstruction time. Compared to the sham-operated group, no apparent fibrosis was observed in the kidneys at 3days post-congestion, whereas fibrosis was most severe at 9days post-congestion, with no significant improvement observed even after blood flow restoration. Six days post-congestion relief, some alleviation of renal fibrosis occurred. q-PCR results indicated a significant reduction in the expression of fibrosis markers after 3 or 6days of renal vein ligation release. Following blood flow restoration on the 9th day post-congestion, no significant changes in fibrosis markers were noted. Prolonged renal vein congestion in a rat model of NCS resulted in severe kidney damage and significant fibrosis after 9days. While relieving congestion within 6days led to some improvement, no reduction in fibrosis occurred after 9days, underscoring the importance of congestion duration in renal pathology.

Tau Immunotherapies for Alzheimer's Disease and Related Tauopathies: Status of Trials and Insights from Preclinical Studies.

The tau protein undergoes pathological changes in Alzheimer's disease and other tauopathies that eventually lead to functional impairments. Over the years, several therapeutic approaches have been examined to slow or halt the progression of tau pathology but have yet to lead to an approved disease-modifying treatment. Of the drugs in clinical trials that directly target tau, immunotherapies are the largest category and mostly consist of antibodies in different stages of development. There is a reasonable optimism that at least some of these compounds will have a clinically meaningful efficacy. This view is based on the significant although modest efficacy of some antibodies targeting amyloid-β in Alzheimer's disease and the fact that tau pathology correlates much better with the degree of dementia than amyloid-β lesions. In Alzheimer's disease, clearing pathological tau may therefore improve function later in the disease process than when removing amyloid-β. This review provides a brief update on the active and passive clinical tau immunization trials with insight from preclinical studies. Various epitopes are being targeted and some of the antibodies are said to target extracellular tau but because almost all of pathological tau is found intracellularly, the most efficacious antibodies should be able to enter the cell.

Tipping Point: Pathogenic Stress and the Biopolitics of Euthanasia

Hopelessness and demoralization following a terminal diagnosis can affect the capacity for self-governance. Such dispositions can increase the allostatic load—the cumulative burden of stress and anxiety—resulting in a neurophysiologic decline that can impair autonomy and influence the desire to end one's life deliberately. An allostatic overload is characterized by the inability to autoregulate stress and is associated with pathological changes to the hypothalamic–pituitary–adrenal axis and hippocampus. These changes raise concerns about the reliability of concepts of autonomy in extremis, potentially undermining arguments that are used to justify voluntary euthanasia and medically assisted death. Studies have associated depression and hopelessness with suicidal ideation in the general population. However, fewer studies have examined how patients without a history of depression or suicidal ideation may suddenly contemplate the act when facing a terminal prognosis. This paper will argue that an allostatic overload can help explain how the spectrum of physical and psychological comorbidities associated with the onset of a terminal illness can influence a decision to hasten death. Data show that patients with a terminal disease wishing to hasten death typically exhibit lower rates of clinical depression, higher rates of demoralization, and a greater likelihood of rational suicide. These differences indicate that suicidal ideation in the terminal disease patient population is different. Changes in autonomous decision-making secondary to pathological alterations in the brain may offer an explanation. Such changes have been shown to dysregulate executive control functions, specifically intentionality and voluntariness. Clinical evidence also indicates that spirituality and hopefulness can help manage the allostatic load during the palliative stages of a disease so that patients can better process end-of-life decisions. Based on these data, this paper will further argue that jurisdictions offering euthanasia are morally compelled to make mental and spiritual counseling available to patients seeking this course of action.

Manifestation of polystyrene microplastic accumulation in brain with emphasis on morphometric and histopathological changes in limbic areas of Swiss albino mice

The widespread problem of microplastic (MP) contamination is becoming a major threat to the globe. Although most of the research to date has concentrated on the physiological impacts of MPs exposure, a relatively new field of study is beginning to examine its effects on the behaviour and limbic regions of the brain. In this study, exposure to polystyrene MPs (PS-MPs) for acute and sub-chronic durations negatively affected cognition and induced anxiety-like behaviour in mice. PS-MPs were detected in vital organs of mice, including the brain, which induced neurobehavioural and pathological changes in the limbic system. Furthermore, morphometric analysis revealed a significant decrease in the total cell count in the Dentate Gyrus (DG) and Cornu Ammonis (CA) regions of the hippocampus. Signs of neuronal injury and dystrophic changes were observed in the cortex, amygdala, and hypothalamus, potentially affecting anxiety and fear responses. Our study thus provides insight into the effect of PS-MPs on the neurobiology of the brain’s limbic system and related behavioural alterations.

Comparison and evaluation of DNA vaccines against Nocardia seriolae infection in largemouth bass (Micropterus salmoides)

Chronic granulomatous diseases caused by Nocardia seriolae have resulted in substantial economic losses for the aquaculture industry. DNA vaccines are considered a promising approach for controlling infectious diseases. To develop effective DNA vaccines against N. seriolae, we selected Ag85L, MmaA4, HspX, Rv3407, and HtpG as candidate antigens. Among these, pcDNA-Ag85L and pcDNA-MmaA4 were the most effective against N. seriolae infection in largemouth bass (Micropterus salmoides), achieving the highest relative percentage survival (RPS) rates of 78.6 % and 92.9 %, respectively. Tissue bacterial loads and histopathological tests revealed a significant reduction in bacterial abundance in the liver, spleen, head kidney, and trunk kidney of the immunised groups compared to that in the control group. Additionally, no distinct pathological changes were observed in the spleen or head kidney tissues. The expression levels of immune-related genes including IL-1β, IL-8, MHCI, MHCII, CD4, and CD8α were significantly upregulated in the pcDNA-Ag85L and pcDNA-MmaA4 immunised groups, thus indicating that the two DNA vaccines mediated immune protection by promoting both humoral and cellular immune responses. Overall, the pcDNA-Ag85L and pcDNA-MmaA4 DNA vaccines demonstrated strong potential for protecting largemouth bass against N. seriolae infection, offering an innovative solution for controlling granulomatous diseases in fish.

Noninvasive optical monitoring of cerebral hemodynamics in a preclinical model of neonatal intraventricular hemorrhage.

Intraventricular hemorrhage (IVH) is a common complication in premature infants and is associated with white matter injury and long-term neurodevelopmental disabilities. Standard diagnostic tools such as cranial ultrasound and MRI are widely used in both preclinical drug development and clinical practice to detect IVH. However, these methods only provide endpoint assessments of blood accumulation and lack real-time information about dynamic changes in ventricular blood flow. This limitation could potentially result in missed opportunities to advance drug candidates that may have protective effects against IVH. In this pilot study, we aimed to develop a noninvasive optical approach using diffuse correlation spectroscopy (DCS) to monitor real-time hemodynamic changes associated with hemorrhagic and sub-hemorrhagic events in a preclinical rabbit model of IVH. DCS measurements were conducted during the experimental induction of IVH, and results were compared with ultrasound and histological analysis to validate findings. Significant changes in hemodynamics were detected in all animals subjected to IVH-inducing procedures, including those that did not show clear positive results on ultrasound. The study revealed progressively elevated coefficients of variation in blood flow, particularly driven by increased oscillations within the 0.05-0.1 Hz frequency band. These hemodynamic changes were more pronounced in animals that developed IVH, as confirmed by ultrasound. Our findings suggest that real-time optical monitoring with DCS can provide critical insights into pathological blood flow changes, offering a more sensitive and informative tool for evaluating potential therapeutics in the context of IVH.

The Diagnostic Challenges of Late-onset Neuropsychiatric Symptoms and Early-onset Dementia: A Clinical and Neuropathological Case Study

The emergence of new-onset neuropsychiatric symptoms in middle age presents a diagnostic challenge, particularly when differentiating between a primary psychiatric disorder and an early neurodegenerative disease. The discrepancy between bedside clinical diagnosis and subsequent neuropathological findings in such cases further highlights the difficulty of accurately predicting pathology, especially when there are no evident focal lesions or changes in brain volume. Here we present the case of a 59-year-old woman with inconclusive neuroimaging who exhibited pronounced neuropsychiatric and behavioral symptoms initially suggestive of a mood disorder, then of behavioral variant frontotemporal dementia. However, upon autopsy, we identified coexisting Lewy body disease pathology and tau-related changes, including argyrophilic grain disease and primary age–related tauopathy. This case illustrates the challenges encountered when diagnosing late-onset neuropsychiatric symptoms, emphasizes the link between such symptoms and early-onset dementia and argyrophilic grain disease, and contributes to our understanding of the impact of mixed neuropathology in this population. Accurate diagnosis is essential for the development of molecular-specific therapies and, as well as for accurate prognosis and enrollment in clinical trials.