Search Results (3,955)

Ischemic stroke is a primary cause of cerebrovascular diseases and continues to be one of the leading causes of death and disability among patients worldwide. Pathological processes caused by vascular damage due to stroke occur in a time-dependent manner and are classified into three categories: acute, subacute, and chronic. Current treatments for ischemic stroke are limited to effectiveness in the early stages. In this study, we investigated the therapeutic effect of an oriental medicine, Gosha-jinki-gan (TJ107), on improving chronic ischemic stroke using the mouse model with middle cerebral artery occlusion (MCAO). The changes in the intracerebral inflammatory response (macrophages (F4/80), TLR2•4, IL-23, IL-17, TNF-α, and IL-1β) were examined using real-time RT-PCR. The MCAO mice showed the increased expression of glial fibrillary acidic protein (GFAP) and of F4/80, TLR2, TLR4, IL-1β, TNF-α, and IL-17 in the brain tissue from the MCAO region. This suggests that they contribute to the expansion of the ischemic stroke infarct area and to the worsening of the neurological symptoms of the MCAO mice in the chronic phase. On the other hand, the administration of TJ107 was proven to reduce the infarct area, with decreased GFAP expression, suppressed macrophage infiltration in the brain, and reduced TNF-α, IL-1β, and IL-17 production compared with the MCAO mice. This study first demonstrated Gosha-jinki-gan’s therapeutic effects on the chronic ischemic stroke. Full article

Background: Bipolar disorder (BD) is a chronic and disabling psychiatric condition characterized by recurring episodes of mania, hypomania, and depression. Despite the availability of mood stabilizers, antipsychotics, and antidepressants, long-term management remains challenging due to incomplete symptom control, adverse effects, and high relapse rates. Methods: This paper is a narrative review aimed at synthesizing emerging trends and future directions in the pharmacological treatment of BD. Results: Future pharmacotherapy for BD is likely to shift toward precision medicine, leveraging advances in genetics, biomarkers, and neuroimaging to guide personalized treatment strategies. Novel drug development will also target previously underexplored mechanisms, such as inflammation, mitochondrial dysfunction, circadian rhythm disturbances, and glutamatergic dysregulation. Physiological endophenotypes, such as immune-metabolic profiles, circadian rhythms, and stress reactivity, are emerging as promising translational tools for tailoring treatment and reducing associated somatic comorbidity and mortality. Recognition of the heterogeneous longitudinal trajectories of BD, including chronic mixed states, long depressive episodes, or intermittent manic phases, has underscored the value of clinical staging models to inform both pharmacological strategies and biomarker research. Disrupted circadian rhythms and associated chronotypes further support the development of individualized chronotherapeutic interventions. Emerging chronotherapeutic approaches based on individual biological rhythms, along with innovative monitoring strategies such as saliva-based lithium sensors, are reshaping the future landscape. Anti-inflammatory agents, neurosteroids, and compounds modulating oxidative stress are emerging as promising candidates. Additionally, medications targeting specific biological pathways implicated in bipolar pathophysiology, such as N-methyl-D-aspartate (NMDA) receptor modulators, phosphodiesterase inhibitors, and neuropeptides, are under investigation. Conclusions: Advances in pharmacogenomics will enable clinicians to predict individual responses and tolerability, minimizing trial-and-error prescribing. The future landscape may also incorporate digital therapeutics, combining pharmacotherapy with remote monitoring and data-driven adjustments. Ultimately, integrating innovative drug therapies with personalized approaches has the potential to enhance efficacy, reduce adverse effects, and improve long-term outcomes for individuals with bipolar disorder, ushering in a new era of precision psychiatry. Full article

Diabetic retinopathy (DR) is a progressive, multifactorial complication of diabetes and one of the major global causes of visual impairment. Its pathogenesis involves chronic hyperglycaemia-induced oxidative stress, inflammation, mitochondrial dysfunction, neurodegeneration, and pathological angiogenesis, as well as emerging systemic contributors such as gut microbiota dysregulation. While current treatments, including anti-vascular endothelial growth factor (anti-VEGF) agents, corticosteroids, and laser photocoagulation, have shown clinical efficacy, they are largely limited to advanced stages of DR, require repeated invasive procedures, and do not adequately address early neurovascular and metabolic abnormalities. Resveratrol (RSV), a naturally occurring polyphenol, has emerged as a promising candidate due to its potent antioxidant, anti-inflammatory, neuroprotective, and anti-angiogenic properties. This review provides a comprehensive analysis of the molecular mechanisms by which RSV exerts protective effects in DR, including modulation of oxidative stress pathways, suppression of inflammatory cytokines, enhancement of mitochondrial function, promotion of autophagy, and inhibition of pathological neovascularisation. Despite its promising pharmacological profile, the clinical application of RSV is limited by poor aqueous solubility, rapid systemic metabolism, and low ocular bioavailability. Various routes of administration, including intravitreal injection, topical instillation, and oral and sublingual delivery, have been investigated to enhance its therapeutic potential. Recent advances in drug delivery systems, including nanoformulations, liposomal carriers, and sustained-release intravitreal implants, offer potential strategies to address these challenges. This review also explores RSV’s role in combination therapies, its potential as a disease-modifying agent in early-stage DR, and the relevance of personalised medicine approaches guided by metabolic and genetic factors. Overall, the review highlights the therapeutic potential and the key translational challenges in positioning RSV as a multi-targeted treatment strategy for DR. Full article

Background: Traumatic brain injury (TBI) remains a significant contributor to global mortality and long-term neurological disability. Accurate prognostic biomarkers are crucial for enhancing prognostic accuracy and guiding personalized clinical management. Objective: This review assesses the prognostic value of arterial spin labeling (ASL), a non-invasive MRI technique, in adult and pediatric TBI, with a focus on quantitative cerebral blood flow (CBF) and arterial transit time (ATT) measures. A comprehensive literature search was conducted across PubMed, Embase, Scopus, and IEEE databases, including observational studies and clinical trials that applied ASL techniques (pCASL, PASL, VSASL, multi-PLD) in TBI patients with functional or cognitive outcomes, with outcome assessments conducted at least 3 months post-injury. Results: ASL-derived CBF and ATT parameters demonstrate potential as prognostic indicators across both acute and chronic stages of TBI. Hypoperfusion patterns correlate with worse neurocognitive outcomes, while region-specific perfusion alterations are associated with affective symptoms. Multi-delay and velocity-selective ASL sequences enhance diagnostic sensitivity in TBI with heterogeneous perfusion dynamics. Compared to conventional perfusion imaging, ASL provides absolute quantification without contrast agents, making it suitable for repeated monitoring in vulnerable populations. ASL emerges as a promising prognostic biomarker for clinical use in TBI. Conclusion: Integrating ASL into multiparametric models may improve risk stratification and guide individualized therapeutic strategies. Full article

Post-traumatic stress disorder (PTSD) is a chronic mental health condition resulting from exposure to traumatic events. It is associated with long-term neurobiological changes and disturbances in emotional regulation. Understanding the sociodemographic profiles, biomarkers, and emotional control in patients with PTSD helps to better comprehend the impact of the disorder on the body and its clinical course. An analysis of biomarkers such as Interleukin-18 (IL-18), Inositol-Requiring Enzyme 1 (IRE1), Phosphorylated Extracellular Signal-Regulated Kinase (pERK), and Activating Transcription Factor–6 (ATF-6) in PTSD patients with varying durations of illness (≤5 years and >5 years) and a control group without PTSD revealed significant differences. Patients with recently diagnosed PTSD (≤5 years) showed markedly elevated levels of inflammatory and cellular stress markers, indicating an intense neuroinflammatory response during the acute phase of the disorder. In the chronic PTSD group (>5 years), the levels of these biomarkers were lower than in the recently diagnosed group, but still significantly higher than in the control group. An opposite trend was observed regarding the suppression of negative emotions, as measured by the Courtauld Emotional Control Scale (CECS): individuals with chronic PTSD exhibited a significantly greater suppression of anger, depression, and anxiety than those with recent PTSD or healthy controls. Correlations between biomarkers were strongest in individuals with chronic PTSD, suggesting a persistent neuroinflammatory dysfunction. However, the relationships between biomarkers and emotional suppression varied depending on the stage of PTSD. These findings highlight the critical role of PTSD duration in shaping the neurobiological and emotional mechanisms of the disorder, which may have important implications for therapeutic strategies and patient monitoring. Full article

IgA nephropathy is the most common primary glomerulonephritis, with pathohistological changes described by the Oxford classification, while the Banff classification is used in transplant pathology. This study included 253 patients with IgA nephropathy in native kidneys, divided into the pediatric (n = 105) and adult (n = 148) groups. It aimed to examine clinical, and Oxford and Banff morphological parameters in relation to age, correlations of clinical data with pathohistological parameters, and predictors of the disease outcome. Pediatric patients more frequently presented with macroscopic hematuria, while adults showed higher urea and creatinine levels, and lower eGFR. Examining Oxford classification parameters, chronic glomerular and tubulointerstitial lesions were more common in adults. Banff parameters revealed more frequent chronically active glomerular, inflammatory, chronic tubulointerstitial, and vascular lesions in adults. All inflammatory, chronic tubulointerstitial, and vascular parameters correlated with serum urea levels, eGFR and CKD stage in adults, while less frequent in pediatric patients. Tubulointerstitial Oxford and Banff parameters were strong predictors of CKD and proteinuria progression in children, while such predictors were fewer in adults; segmental glomerulosclerosis predicted hematuria progression in adults. Banff parameters (cg, t, ti, i, i-IFTA, ptc, cv), not in Oxford classification, significantly predict outcomes and are recommended for incorporation into IgA nephropathy reports. Full article

Introduction: Renal malacoplakia is a rare chronic granulomatous disease, often associated with immunosuppression and persistent Gram-negative infections, particularly Escherichia coli. Case Presentation: We present a case involving a 31-year-old woman with hypertension, gestational diabetes, and prior uterine curettage after labor induction for preeclampsia at 23 weeks. She developed urinary sepsis post-procedure. Imaging revealed bilateral nephromegaly, while laboratory tests showed acute kidney injury (KDIGO stage III), anemia, and thrombocytopenia. Blood and urine cultures grew Escherichia coli. Renal biopsy confirmed malacoplakia, demonstrating PAS-positive Michaelis–Gutmann bodies and Von Hansemann cells. The patient responded to prolonged antibiotic therapy and supportive care. Discussion and Conclusion: This case highlights the importance of considering renal malacoplakia in patients with atypical urinary tract infections and nephromegaly, particularly in obstetric settings. Histopathological confirmation is essential, and timely treatment with intracellularly active antibiotics can lead to favorable outcomes. Early diagnosis is critical to prevent irreversible renal damage. Full article

Background/Objectives: Chronic kidney disease of unknown etiology (CKDu) disproportionately affects young male agricultural workers who are otherwise healthy. There is a scarcity of biomarkers for early detection of this type of kidney disease. We hypothesized that small extracellular vesicles (sEVs) released into urine may provide novel biomarkers. Methods: We obtained two urine samples at the start and the end of a workday in the fields from a limited set of workers with and without kidney impairment. Isolated sEVs were characterized for size, surface marker expression, and purity and, subsequently, their lipid composition was determined by mass spectrometry. Results: The number of particles per ml of urine normalized to osmolality and the size variance were larger in workers with possible CKDu than in control workers. Surface markers CD9, CD63, and CD81 are characteristic of sEVs and a second set of surface markers suggested the kidney as the origin. Differential expression of CD25 and CD45 suggested early inflammation in CKDu workers. Of the twenty-one lipids differentially expressed, several were bioactive, suggesting that they may have essential functions. Remarkably, fourteen of the lipids showed intermediate expression values in sEVs from healthy individuals with acute creatinine increases after a day of work. Conclusions: We identified twenty-one possible lipid biomarkers in sEVs isolated from urine that may be able to distinguish agricultural workers with early onset of CKDu. Differentially expressed surface proteins in these sEVs suggested early-stage inflammation. This pilot study was limited in the number of workers evaluated, but the approach should be further evaluated in a larger population. Full article

Chronic kidney disease (CKD) remains a global health burden, with limited therapeutic options that effectively target the underlying pathophysiology. Nuclear factor erythroid 2-related factor 2 (NRF2), a key regulator of oxidative stress and inflammation, has garnered significant attention as a potential therapeutic target in CKD. Despite encouraging preclinical results, no NRF2-targeted agents have achieved clinical approval for CKD treatment. This review synthesizes emerging evidence showing substantial heterogeneity in NRF2 activity across CKD subtypes, influenced by disease etiology, CKD stage, and rate of disease progression. We elucidate the key therapeutic implications across diverse CKD etiologies and highlight that the therapeutic efficacy of NRF2 activation depends on precise modulation tailored to disease context. Although NRF2 overactivation and the need for stage-dependent modulation are increasingly recognized, this review further delineates the consequences of indiscriminate NRF2 activation, demonstrating that its effects diverge across CKD etiologies and cellular contexts. These insights support a nuanced, context-specific approach to NRF2-targeted strategies and provide a framework to guide future drug development in CKD. Full article

Membranous nephropathy (MN) is the most prevalent cause of nephrotic syndrome (NS) in adults, and it can be primary (idiopathic) with an unknown cause or secondary due to a variety of conditions (lupus, infections, malignancies, medications, etc.). It progresses to chronic kidney disease (CKD) in up to 60% of patients, and 10 to 30% develop end-stage kidney disease (ESKD). This retrospective study examines the importance of specific factors, including baseline demographic and clinical data, kidney biopsy PH findings, and selected biochemical parameters, influencing MN outcomes after 10 years of follow-up. The cohort included 94 individuals in whom a diagnosis of MN was established by percutaneous biopsy of the left kidney’s lower pole at the University Clinical Center of Serbia (UCCS) between 2008 and 2013. According to the outcomes, patients were divided into three groups: the recovery (Rec) group, with complete remission, including normal serum creatinine (Scr) and proteinuria (Prt), the group with development of chronic kidney disease (CKD), and the group with development of end-stage kidney disease (ESKD). Nephropathologists graded pathohistological (PH) results from I to III based on the observed PH findings. During the follow-up period, 33 patients were in the Rec group, CKD developed in 53 patients, and ESKD developed in 8 patients. Baseline creatinine clearance levels (Ccr), Scr, and uric acid (urate) were found to be significantly associated with the outcomes (p < 0.001). The lowest values of baseline Scr and urate were observed in the Rec group. The presence of acute kidney injury (AKI) or CKD at the time of kidney biopsy was associated with the more frequent development of ESKD (p = 0.02). Lower Ccr was associated with a higher likelihood of progressing to CKD (B = −0.021, p = 0.014), whereas older age independently predicted progression to ESKD (B = 0.02, p = 0.032). Based on this study, it was concluded that the most important biochemical and clinical factors that are associated with the outcomes of this disease are the values of Scr, Ccr, and urate and the existence of CKD at the time of kidney biopsy. Unlike most previous studies, the presence of HTN had no statistical significance in the outcome of the disease. Full article

Background/Objectives: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver conditions globally. This study aimed to assess the long non-coding RNAs (lncRNAs) growth arrest-specific 5 (GAS5), miR-29a-3p, and neurogenic locus notch homolog protein 2 (NOTCH2) as biomarkers in patients with NAFLD and find out if they are related to any clinical factors. Subjects and Methods: Thirty-eight age-matched healthy persons and thirty-eight NAFLD patients were enrolled. Patients were split into the following three groups: non-alcoholic steatohepatitis (NASH) (n = 12), patients with NAFLD-related cirrhosis (n = 8), and patients with NAFLD-related simple steatosis (n = 18). Real-time PCR was utilized to examine the expression. Results: The lncRNA GAS5 and NOTCH2 were higher in NAFLD cases in comparison to controls. On the other hand, microRNA-29a-3p was underexpressed in NAFLD cases in comparison to controls. Regarding NAFLD diagnosis, lncRNA GAS5 was the best single marker with a sensitivity of 100% and a specificity of 94.7% at the cutoff values of ≥1.16-fold change. Regarding different stages of the disease, the highest level of lncRNA GAS5 was in cirrhosis. lncRNA GAS5 expression, among other studied parameters, is still a significant predictor of NAFLD (adjusted odds ratio of 162, C.I. = 5.7–4629) (p = 0.003). LncRNA GAS5 has a positive correlation with NOTCH2 and a negative correlation with miR-29a-3p. LncRNA GAS5, NOTCH2, and RNA-29a-3p were significantly different in NAFLD cases compared to controls. Conclusions: lncRNA GAS5 appears to be the most effective single marker for detecting NAFLD. LncRNA GAS5 expression is a significant independent predictor of NAFLD. LncRNA GAS5 can differentiate different NAFLD stages. Full article

Background: Patients diagnosed with melanoma are at increased risk of developing multiple primary melanomas (MPMs). Identifying clinical and genetic factors associated with MPM is critical for implementing personalized surveillance strategies. This study aims to describe the clinical, histopathological, and genetic characteristics of patients with MPM managed in a tertiary hospital and to contextualize findings within the current literature. Methods: We conducted a retrospective review of patients diagnosed with two or more primary melanomas between 2010 and 2023 at a tertiary dermatology unit. Demographic data, personal and family cancer history, phototype, melanoma characteristics, genetic testing, staging, treatments, and outcomes were collected. These data were compared with findings from the recent literature. Results: Thirteen patients (ten males, three females; median age: 59 years) were found to have a total of 33 melanomas. Most patients had Fitzpatrick phototype II and no immunosuppression. The number of melanomas per patient ranged from two to five. Synchronous lesions were observed in two patients. Common locations included the trunk and extremities. Histologically, 57% were in situ melanomas, and subsequent melanomas were generally thinner than the index lesion. Two patients showed progression to advanced disease. One patient was positive for MC1R mutation; the rest were negative or inconclusive. Additional phenotypic and environmental risk factors were extracted from patient records and are summarized as follows: Ten patients (76.9%) had Fitzpatrick skin phototype II, and three (23.1%) had phototype III. Chronic occupational sun exposure was reported in four patients (30.8%), while five (38.5%) recalled having suffered multiple sunburns during childhood or adolescence. Eight patients (61.5%) presented with a total nevus count exceeding 50, and five (38.5%) exhibited clinically atypical nevi. None of the patients reported use of tanning beds. Conclusions: Our findings are consistent with the existing literature indicating that patients with MPM often present with thinner subsequent melanomas and require long-term dermatologic follow-up. The inclusion of genetic testing and phenotypic risk factors enables stratified surveillance and supports the application of personalized medicine in melanoma management. Full article

Introduction: Chronic kidney disease (CKD) increases cardiovascular risk through mechanisms such as oxidative stress and the accumulation of advanced glycation end products (AGEs). Glycated albumin (GA) is associated with cardiovascular risk in CKD patients, but its relationship with AGEs and systemic inflammation remains unclear. This study investigated these associations in old patients with severe CKD, with and without diabetes. Methods: We conducted a cross-sectional analysis in 122 patients aged ≥ 65 years with CKD stages G3a–G5, including 67 diabetics and 55 non-diabetics. Patients with confounding comorbidities were excluded. We measured GA, AGEs, various AGEs receptors (RAGE) isoforms, and inflammatory cytokines (CRP, IL-6, TNFα, and MCP-1) using standardized assays. Statistical analyses included group comparisons, correlation coefficients, and multivariate regression. Results: Of 122 patients (mean age 77.7 ± 11.3 years), diabetics had higher GA percentages than non-diabetics (22.0 ± 7.1% vs. 17.5 ± 5.4%, p = 0.0001), while AGEs (2931 ± 763 vs. 3156 ± 809 AU; p = 0.118) and inflammatory markers (CRP 0.240[0.380] vs. 0.200[0.280] mg/dL; p = 0.142; IL-6 3.4[4.0] vs. 3.0[3.8] pg/mL; p = 0.238) were similar between groups. Overall, GA was inversely correlated with estimated glomerular filtration rate (eGFR) (ρ = −0.189, p = 0.037) and positively with glycated hemoglobin (HbA1c) (ρ = 0.525, p < 0.0001), but showed no significant correlation with AGEs, RAGE isoforms, or inflammatory cytokines. In multivariate analysis, only HbA1c remained independently associated with GA (β = 0.222, p = 0.005). Conclusions: In old patients with severe CKD, GA appears to be a more useful marker of glycemic control than glycation stress, the latter of which is the result of multiple factors, including impaired kidney function and systemic inflammation. Full article

Diabetic nephropathy affects approximately 30–40% of individuals with diabetes mellitus (DM) and is a major contributor to end-stage renal disease (ESRD). While angiotensin II receptor blockers (ARBs) have long served as a standard treatment, sodium-glucose cotransporter-2 inhibitors (SGLT2i) have recently gained attention for their renal and cardiovascular benefits. However, comparative real-world data on their long-term renal effectiveness remain limited. We conducted a retrospective, longitudinal study over a 2-year period to compare the impact of ARB monotherapy versus SGLT2i and angiotensin-converting enzyme inhibitor (ACEi) combination therapy on the progression of chronic kidney disease (CKD) in patients with DM. A total of 126 patients were included and grouped based on treatment regimen. Renal biomarkers were analyzed using t-tests and ANOVA (p < 0.01). Albuminuria was qualitatively classified via urinalysis as negative, level 1 (+1), level 2 (+2), or level 3 (+3). The ARB group demonstrated higher estimated glomerular filtration rate (eGFR) and lower serum creatinine (sCr) levels than the combination therapy group, with glycated hemoglobin (HbA1c), potassium (K⁺), and blood pressure remaining within normal limits in both cohorts. Albuminuria remained stable over time, with 60.8% of ARB users and 73.1% of combination therapy users exhibiting persistently or on-average negative results. Despite the expected additive benefits of SGLT2i/ACEi therapy, ARB monotherapy was associated with slightly more favorable renal function markers and a lower incidence of severe albuminuria. These findings suggest a need for further controlled studies to clarify the comparative long-term renal effects of these treatment regimens. Full article

The precipitation of cryoglobulins, serum immunoglobulins, below 37 °C defines the clinical cryoglobulinemic syndrome, a systemic vasculitis usually characterized by purpura, weakness, and arthralgia. In most cases, this condition is associated with chronic infection by the hepatitis C virus (HCV) and can evolve into B-cell dysregulation and malignancies. The current literature on non-HCV-associated cryoglobulinemia is very limited, and little is known about the immunological and serological profile of affected patients. The cryoglobulinemic syndrome not associated with HCV infection is often found concomitantly with other infections, autoimmune diseases, and B-cell lymphoproliferative disorders. The cryoprecipitation of fibrinogen has been described as a rare disorder, perhaps underestimated and not fully understood, causing thrombotic occlusion and ischemia in different rheumatic disorders. Cold temperature plays a pathogenetic role in autoimmune hemolytic anemias, in which the presence of cold agglutinins produced by B cells at the lymphoplasmacytic cell stage may promote agglutination of red blood cells in the coldest parts of the circulation, even at mild room temperatures, undergoing hemolysis. Laboratory methods for the detection and quantification of cryoproteins are downright critical, and their concurrent detection is pivotal for the diagnosis. In this review, we summarize the clinical involvement of cryoglobulins, cryofibrinogen, and cold agglutinins in non-HCV autoimmune diseases, underlining the crucial steps of the most employed analytic methods. Full article