Elevated Markers Research Articles

Generation of BT-Amide, a Bone-Targeted Pyk2 Inhibitor, Effective via Oral Administration, for the Prevention of Glucocorticoid-Induced Bone Loss.

Glucocorticoid-induced osteoporosis (GIOP) is the leading cause of iatrogenic osteoporosis due to the widespread clinical use of glucocorticoids (GC) as immunosuppressants. Previous research identified the proline-rich tyrosine kinase 2, Pyk2, as a critical mediator of GC-induced bone loss, and that blocking Pyk2 could protect the skeleton from adverse GC actions. However, systemic administration of current Pyk2 inhibitors causes harmful side effects, such as skin lesions. To address this, we developed bone-targeted (BT) Pyk2 inhibitors by conjugating them with bisphosphonates (BP), ensuring adherence to the bone matrix and reducing impact on noncalcified tissues. We synthesized BT-Amide by linking a derivative of TAE-226, a Pyk2 inhibitor, with alendronic acid. Oral administration (gavage) of BT-Amide prevented GC-induced bone loss in mice without causing skin lesions, or elevation of any organ toxicity markers. These findings introduce BT-Amide as the first orally effective bone-targeted Pyk2 inhibitor for preventing GC-induced bone loss while minimizing off-target effects.

Djenkolism: Acute Kidney Injury Unresponsive to Conservative Therapy - A Case Report

Djenkol beans (Archidendron jiringa), a popular food in Southeast Asia, can cause djenkolism—a condition leading to acute kidney injury due to the presence of djenkol acid. This case report details a 26-year-old male who presented with three days of anuria following the consumption of half a kilogram of djenkol beans. Upon admission, he exhibited severe abdominal pain, costovertebral tenderness, and elevated renal markers, leading to a diagnosis of obstructive uropathy caused by djenkolic acid crystals. Initial conservative treatment was ineffective, prompting the need for emergency ureteroscopy and placement of bilateral JJ stents to relieve the obstruction. Post-procedure, the patient experienced significant improvement, with a marked increase in urine output; post-obstructive diuresis in the first 24 hours, and resolution of abdominal pain, alongside improved renal function. This case underscores the importance of recognizing djenkolism as a potential cause of acute kidney injury, and advocating for timely diagnosis and intervention to mitigate kidney damage. Public awareness regarding the risks associated with djenkol consumption is also essential. Keywords: Djenkolism, Obstructive Uropathy, Post-Obstructive Diuresis, Acute Kidney Injury

Suspected hepatic hydrothorax secondary to cirrhosis in a dog

AbstractAn 8‐year‐old, entire, female labrador retriever presented with a 2‐week history of abdominal distension. Biochemistry identified hepatic dysfunction (elevated hepatobiliary markers, hypocholesterolaemia). Abdominal ultrasonography documented an irregular liver and a large volume of anechoic peritoneal effusion, which laboratory analysis confirmed as a protein‐poor transudate. Thoracic computed tomography identified a moderate volume of pleural effusion with a similar composition to the peritoneal fluid. Hepatic histopathology was consistent with cirrhosis secondary to chronic hepatitis and, in the absence of another cause for the pleural effusion, hydrothorax secondary to the hepatic disease was suspected. The patient was started on ciclosporin for treatment of the underlying liver disease, but developed signs consistent with disseminated intravascular coagulopathy 24 hours later and was humanely euthanased. As reported in humans, hydrothorax may therefore occur secondary to cirrhosis in dogs and should be considered as a differential diagnosis for pleural effusion in patients with advanced hepatic disease and concurrent peritoneal effusion.

Abstract 4145876: Prognostic significance of somatic mutations in myeloid cells of men with chronic heart failure – interaction between loss of Y chromosome and clonal hematopoiesis

Introduction: Age-associated clonal hematopoiesis of indeterminate potential (CHIP) has been associated with increased incidence and worse prognosis of chronic heart failure. CHIP is driven by somatic mutations in hematopoietic stem and progenitor cells (HSPC). Mosaic loss of the Y chromosome (LOY), the most common somatic mutation in blood cells of men, also correlates with clonal expansion of myeloid cells, increases with age and was experimentally shown to lead to diffuse cardiac fibrosis and subsequent heart failure in mice. However, the prognostic significance of LOY as well as its potential interaction with CHIP in patients with chronic heart failure is unknown. Aims/Methods: We investigated the prevalence and prognostic significance of the extent of LOY and the two most common CHIP-driver mutations DNMT3A and TET2 in 705 male patients with established chronic heart failure across the entire spectrum of left ventricular ejection fraction. Results: Both, LOY and DNMT3A/TET2 mutations, increased with age, and LOY co-occurred with DNMT3A/TET2 mutations in 27.1% of men at age > 70 years. LOY was an independent predictor of death during 3-years of follow-up across the entire spectrum of left ventricular ejection fraction. The co-occurrence of harboring LOY and DNMT3A/TET2 mutations significantly contributed to the observed increased mortality observed in carriers of DNMT3A/TET2 mutations. The detrimental effect of LOY on prognosis was confirmed in a validation cohort of patients with ischemic heart disease.scRNA sequencing of peripheral blood cells in patients with chronic ischemic heart failure showed increased profibrotic signaling in LOY monocytes with elevated markers of monocyte mediated inflammation and profibrotic cardiac remodeling (S100A8, TLR2, CLEC4D) and reduced expression of TGF-b inhibiting genes (SMAD7, TGIF2). The proinflammatory phenotype of LOY monocytes was further amplified in LOY monocytes of patients simultaneously harboring DNMT3A mutations, who displayed heightened expression of alarmins (S100A8, HMGB2) and interferon signaling related genes (IFNGR1, TRIM56, CD84) compared to patients without CHIP mutations. Conclusion: The age-associated acquisition of somatic mutations in blood cells of men with chronic heart failure is associated with increased mortality, with loss of Y chromosome emerging as an independent predictor of all-cause death across the entire spectrum of left ventricular function.

Accumulation of polyunsaturated lipids fuels ferroptosis to promote liver failure after extended hepatectomy in mice

Background Post-hepatectomy liver failure (PHLF) is a fatal complication of hepatectomy. However, the mechanism of hepatocyte injury in PHLF remains elusive. Methods PHLF was induced by extended 86% hepatectomy (eHx) in mice. Lipidomics was performed to investigate the eHx-induced lipid alteration in the residual liver. Ferroptosis was assessed to screen the hepatocyte injury induced by eHx. The therapeutic effects of ferrostatin-1 (Fer-1) on PHLF were evaluated. Results PHLF was induced by eHx with elevation in markers of hepatocyte injury and mortality in mice within 48 h after surgery. eHx-induced hepatocyte injury was manifested by hepatocyte enlargement and hepatocyte death with glycogen depletion and lipid accumulation. Lipidomics revealed that eHx induced the accumulation of ferroptosis-favored polyunsaturated lipids. Ferroptosis was found to mediate the eHx-induced hepatocyte death in the residual liver during the development of PHLF. Fer-1 could attenuate the eHx-induced ferroptotic hepatocyte death and PHLF in mice. Conclusions Ferroptosis partly mediates the eHx-induced hepatocyte injury during the development of PHLF. Accumulation of polyunsaturated lipids in hepatocytes may promote eHx-induced ferroptosis, and targeting lipid peroxidation is a potential therapeutic strategy for PHLF.

PROTECTIVE EFFECT OF COMBINATION OF ETHANOLIC EXTRACTS OF XIMENIA AMERICANA AND TERMINALIA MACROPTERA AGAINST ALCOHOL-INDUCED HEPATOTOXICITY IN RATS

Objective: The aim of this study was to evaluate the hepatoprotective effect of the combination. Methods: Serum liver markers, tissue antioxidant activity, and histological changes in the livers of rats from the blank, negative (distilled water), positive (silymarin 100 mg/kg bw), and test (combination 500 mg/kg bw) groups were measured after 7 days of pretreatment and induction of hepatotoxicity by 10 g/kg bw alcohol every 12 h for 48 h. Results: Rats in the negative control group showed a highly significant (p<0.001) increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (BT) levels by 281.13%, 221.7%, and 93.44%, respectively, compared to rats in the blank group. Pretreatment with the combination resulted in a highly significant (p<0.001) decrease in AST, ALT, and BT levels of 69.19%, 62.24%, and 41.52%, respectively. The study of tissue oxidative stress parameters revealed a very significant (p<0.01) increase in superoxide dismutase (123.08%), glutathione (131.66%), and catalase (49.01%) activities and a significant (p<0.05) decrease in malondialdehyde concentration (59.72%) in the group pretreated with the combination compared with the negative control group. Steatosis and necrosis estimated at 50% were observed in rats in the negative control group. In contrast, necrosis observed in the group pre-treated with the combination was <10%. Conclusion: These data suggest that the combination is effective in preventing the elevation of biochemical markers and the imbalance of enzymatic and non-enzymatic antioxidant systems caused by alcohol.

Hormone Replacement Therapy Relieves Periodontitis by Inhibiting Alveolar Bone Loss and Inflammation.

Hormone replacement therapy (HRT) is a commonly used strategy for treating menopausal symptoms, while its relation with periodontitis remains unclear. This study aimed to explore the potential effects of HRT on periodontitis, mainly in aspects of bone loss and inflammation. The alveolar bone height (ABH), alveolar bone thickness (ABT), and bone mineral density (BMD) were measured in menopausal women with periodontitis who had received HRT or had not received HRT by cone beam computed tomography. Based on a rat model of periodontitis, the alveolar bone loss was evaluated by micro-computed tomography and bone-related biochemical markers. The expression/levels of inflammatory markers were measured to reflect periodontal inflammation. Although the differences were not all significant in each premolars/molars, the mesial/distal ABH and buccal/lingual ABT were lower, and the mesial/distal BMD was higher in patients in the HRT group than those in the control group. In a rat model of periodontitis, the alveolar bone loss was relieved by HRT. Additionally, HRT significantly weakened the elevation of inflammatory markers, including TNF-α, IL-1β, and IL-6 in periodontitis rats. HRT contributes to the remission of periodontitis by inhibiting alveolar bone loss and inflammation.

Hepatoprotective effects of ethanolic extract of Corallocarpus epigaeus roots on nitrobenzene-induced liver injury in Wistar rats

ABSTRACT This study examined the potential of Corallocarpus epigaeus ethanolic root extract to combat free radicals using DPPH, FRAP, hydroxyl radical, hydrogen peroxide, and nitric oxide scavenging assays. Rats were initially exposed to a single oral dose of nitrobenzene (50 mg kg−1 body weight), followed by a 15-d oral regimen of the ethanolic root extract of C. epigaeus at 200 mg kg−1 body weight. The assessment of serum liver marker enzymes (AST, ALT, and ALP), lipid peroxidation levels, antioxidant enzyme activities, and histopathological examinations of liver tissues were carried out. The C. epigaeus ethanolic root extract demonstrated antioxidant properties and contained flavonoids, tannins, carotenoids, lycopene, and phenolic compounds. In Nitrobenzene-induced rats, elevated serum markers and increased liver lipid peroxidation were observed that were normalized by the extract. It also increased antioxidant enzyme activities, including superoxide dismutase, catalase, and glutathione peroxidase. Histopathological analysis confirmed the hepatoprotective effects of the extract.

Association between depression and anxiety and inability to achieve remission in rheumatoid arthritis and psoriatic arthritis.

To investigate the association between depression and anxiety and the inability to achieve remission in rheumatoid arthritis(RA) and psoriatic arthritis(PsA) patients. In addition, the association between depressive and anxiety symptoms and disease activity components were explored. 400 RA and 367 PsA patients from the tREACH and DEPAR were included, respectively. Patients had a possible depression or anxiety disorder if they scored >7 on the Hospital Anxiety and Depression Scale(HADS). Remission was defined as DAS44<1.6 in RA and DAPSA≤4 in PsA. Mixed models were used to assess the association between depression/anxiety, at any timepoint during 2 years, and remission during 2 years, and to explore which disease activity components are most influenced by depression/anxiety. At baseline, 20% of RA patients had a possible depression and 30% a possible anxiety disorder. In PsA this was 18% and 23%. After adjustment for concurrent anxiety symptoms depression was associated with a lower odds of achieving remission during 2 years of follow-up (OR 0.45(95%CI 0.25-0.80) for RA and OR 0.24(95%CI 0.08-0.71) for PsA). Anxiety was not associated with remission after adjustment for concurrent depression symptoms.The presence of depression/anxiety was associated with higher tender joint count, worse general health, more pain and slightly elevated inflammation markers, but not with more swollen joints in both RA and PsA. The presence of depressive symptoms in RA and PsA patients at baseline or during follow-up was associated with a lower likelihood of achieving remission. Healthcare professionals should, therefore, be aware of symptoms of depression.

NLRP3 inflammasome activation contributes to acute liver injury caused by CVA6 infection in mice

BackgroundCoxsackievirus (CV) A6 has emerged as an important causative agent in global outbreaks of hand, foot, and mouth disease (HFMD), which typically presents as a mild illness with a large generalized rash, herpes. However, some patients can develop encephalitis, pneumonia, myocarditis and liver injury. Our previous study took the view that CVA6 could replicate in mouse liver, leading to acute liver injury; however, the precise underlying mechanism remains elusive.Methods10-day-old wild-type (WT, C57BL/6J) and NLRP3 knock-out (KO) mice were intraperitoneal (i.p.) inoculated with a lethal dose of the CVA6 strain. The muscle homogenate supernatant from normal mice was used to inoculate mock-infected mice. At 5 days post infection (dpi), the mouse liver was taken out for histopathological analyses and molecular biology experiments.ResultsOur in vivo experiments demonstrated that CVA6 caused severe liver injury in mice, as evidenced by pathological changes in liver slices, elevated liver injury markers (e.g., AST, ALT, LDH) and pro-inflammatory cytokines (e.g., IL-6, MCP-1, TNF-α, IL-1β). Further results revealed the activation of NLRP3 inflammasome characterized by the increase in the expression of NLRP3, Cleaved-Casp-1 (p20), mature IL-1β and IL-18. Importantly, upon CVA6 infection, NLRP3 KO mice exhibited attenuated pathological damage and reduced levels of pro-inflammatory cytokines production (e.g., TNF-α and IL-1β) compared with WT mice. Finally, increased levels of blood ALT, AST, LDH were strongly correlated with the severity of CVA6 patients.ConclusionCollectively, our findings suggest that the activation of NLRP3 inflammasome is involved in CVA6 infection-induced acute liver injury, providing novel insights into CVA6 infection associated adverse clinical outcomes.

Improvement in Kidney damage resulting from stanozolol intramuscular injections in rats by Natural Cocoa Powder (NCP) Administration.

BackgroundStanozolol, an anabolic steroid, has been shown to induce kidney damage through mechanisms involving oxidative stress and inflammation. Natural Cocoa Powder (NCP), known for its high antioxidant content, may offer protective effects against such damage. AimThis study aimed to evaluate the potential of Natural Cocoa Powder (NCP) in ameliorating kidney damage caused by stanozolol intramuscular injections in rats. MethodsThirty rats were randomly assigned into five groups (G1–G5) and fed with standard rat chow. G1 and G3 received 2 mg/kg stanozolol intramuscularly twice weekly, G2 and G4 received 5 mg/kg stanozolol twice weekly, while G5 served as the control with no stanozolol. G1, G2, and G5 had 24-hour access to water, while G3 and G4 had water replaced with 2% NCP from 6 am to 6 pm daily. After 8 weeks, kidneys were perfusion-fixed and analyzed histomorphometrically for proximal/distal tubules, Bowman's space, glomerular tuft, and renal corpuscle composition.Before and after treatments, renal function was measured by serum creatinine and blood urea nitrogen, whilst systemic inflammation was monitored by erythrocyte sedimentation rate and serum C-reactive protein tests. Results & DiscussionStanozolol administration significantly increased kidney damage in a dose-dependent manner, with marked rises in the volume densities of the proximal convoluted tubule (PCT), distal convoluted tubule (DCT), glomerular tuft, and renal corpuscle. At higher doses, PCT and DCT volume densities increased by 143% and 223%, respectively, compared to controls. Natural cocoa powder (NCP) mitigated these effects, reducing PCT, DCT, and glomerular tuft volume densities by 92%, 77%, and 86%, respectively. Stanozolol also elevated serum markers of kidney dysfunction and inflammation, such as blood urea nitrogen (BUN), serum creatinine (SCr), and C-reactive protein (CRP). While NCP significantly lowered BUN and SCr levels, it did not fully normalize CRP, which remained elevated in stanozolol-treated rats. ConclusionIncreased volume density of kidney components indicated hypertrophy, which was associated with elevated serum creatinine, blood urea nitrogen (BUN), and C-reactive protein (CRP) levels, reflecting impaired renal function and heightened systemic inflammation. The reduction in these markers with NCP ingestion suggests its potential to mitigate stanozolol-induced renal damage. It is proposed that the antioxidant properties of NCP may have reduced inflammation by counteracting oxidative stress, thereby contributing to the observed improvement in kidney function and structure.

Chemopreventive potential of goniothalamin in diethylnitrosamine-induced hepatocellular carcinoma through the suppression of P13K/AKT signalling pathway.

Liver cancer is the most lethal form of cancer and carries a high risk of death around the world. Goniothalamin (GTN) is a styryl-lactone that possesses antiproliferative and apoptotic activity. The molecular action of GTN is not yet fully evaluated. Thus, our research has been intended to assess the chemopreventive and apoptotic activities of diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in rats. Rats were separated into 4 groups: control, DEN only, DEN + GTN (30 mg/kg bw), and GTN (30 mg/kg bw) alone. We evaluated body weight, liver weight, tumor incidence, hepatic toxic markers, antioxidants, inflammatory cytokines, histopathology, immunohistochemistry, and Western blot studies. DEN lessened body weight, antioxidants, and apoptosis, whereas it elevated tumor incidence, toxic markers, cytokines, and Bcl-2 expression. GTN treatment maintains body weight, liver weight, and antioxidant levels, and it also prevents tumor incidence, oxidative stress, toxic markers, pro-inflammatory cytokines, and histological changes. It triggers apoptosis by constraining Bcl-2 and elevating caspase-3 levels. GTN also attenuated the P13K/ AKT signaling which enhanced apoptosis. These findings revealed that GTN subdues the P13K/AKT pathway and has auspicious chemopreventive and apoptotic actions in DEN-induced HCC. Therefore, GTN would be suggested as a new medicine in natural remedies for liver cancer.

Analysis of Serum and Synovial Inflammatory Markers in Periprosthetic Joint Infections: A Narrative Review.

Periprosthetic joint infection (PJI) is considered a rare but devastating complication after total joint arthroplasty (TJA). The problem lies in the fact that there is a paucity of "gold standard" diagnostic tests that make the diagnosis of PJI extremely challenging. Recently, there have been increasing evidence-based guidelines that have been introduced to standardise the approach to a patient with a suspected PJI. Diagnosing a case of PJI traditionally involves initial screening for elevated serum inflammation markers C-reactive protein (CRP) (mg/dL) and erythrocyte sedimentation rate (ESR), and aspiration remains the sole confirmatory investigation. However, several factors would affect the values of the aforementioned markers, such as gender, age, and the presence of inflammatory circumstances. Serum D-dimer that detects fibrinolytic activities during infection has high sensitivity, but the specificity was not persuasive as it would elevate during other conditions, such as venous thromboembolism. Therefore, there is also a need for a simultaneous and secondary marker. There are also several synovial biomarkers, including ESR, CRP, alpha-defensin, and synovial fluid leukocyte count and differential for the detection of PJI. In this narrative review, we want to sum up the serum and inflammatory markers that have been introduced so far for detecting PJI.

Overexpression of SULT1E1 alleviates salt-processed Psoraleae Fructus-induced cholestatic liver damage

ObjectiveSalt-processed Psoraleae fructus (SPF) is widely used as a phytoestrogen-like agent in the treatment of osteoporosis. However, due to improper clinical use or misuse, resulting in liver damage. In this study, network pharmacology was employed to analyze the mechanism of cholestatic liver damage. An adeno-associated virus overexpressing SULT1E1 (rAAV8-SULT1E1) was constructed and the hepatotoxicity of SPF, psoralen, and isopsoralen was determined. MethodsBy utilizing three databases inclding TCMSP, TCMID, and BATMAN- TCM, the targets of the three databases were summarized, and a total of 45 psoralen compounds were included. Network pharmacology analysis was then performed. The adenoviral vectors were injected into the tail vein of C57BL6 mice to elucidate the role of SULT1E1 in SPF-induced cholestasis-mediated hepatotoxicity in vivo. SPF (10 g/kg), psoralen, and isopsoralen (50 mg/kg each) were intragastrically administered to mice for 30 d. B-ultrasound and samples were collected and examined for follow-up experiments. ResultsA total of 854 targets were predicted for 45 active components, with 151 cholestasis-mediated hepatotoxicity-related disease targets obtained for SPF. A total of 126 pathways were enriched based on KEGG pathway analysis, with the “estrogen signaling pathway” identified as one of the top 20 pathways. In terms of pathological hepatic changes, treated mice had visually swollen hepatocytes, dilated bile ducts, and elevated serum biochemical markers, which were more prominent in mice treated with isopsoralen than in those treated with other compounds. Notably, the overexpression of SULT1E1 could reverse liver damage in each treatment group. B-ultrasound was used to observe the size of the gallbladder in vivo. The size of the gallbladder was found to significantly increase on day 30 after treatment in the SPF-, psoralen-, and isopsoralen-treated groups, especially the SPF group. Compared with the expression levels in the negative control group (rAAV8-empty+con), the expression levels of FXR, Mrp2, Bsep, SULT1E1, SULT2A1, Ntcp, and Nrf2 decreased, whereas those of CYP7a1 and IL-6 increased in the SPF-, psoralen-, and isopsoralen-treated groups. ConclusionThe overexpression of SULT1E1 could alleviate the decreased or increased expression of indicators, indicating that SULT1E1 is an important target gene for SPF-induced liver damage. The severity of liver damage was significantly lower in the rAAV8-SULT1E1 groups than in the rAAV8-empty groups.

Short-chain chlorinated paraffins induce liver injury in mice through mitochondrial disorders and disruption of cholesterol-bile acid pathway.

Short-chain chlorinated paraffins (SCCPs) are pervasive organic pollutants recognized for their persistence and bio-toxicity. This study investigated the hepatotoxic mechanisms of SCCPs at environmentally relevant concentration (0.7 μg/kg). The results showed that SCCPs exposure in mice resulted in dysregulated blood and liver lipids, marked by elevated cholesterol levels. Additionally, liver function was compromised, as indicated by increased levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Histopathological examination of liver tissue post-SCCPs exposure revealed hepatocyte enlargement, vacuolar degeneration, and mild ballooning degeneration. Mechanistically, SCCPs induced mitochondrial abnormalities, evidenced by heightened Hoechst 33258 fluorescence, and augmented reactive oxygen species and malondialdehyde levels in liver tissue. This was accompanied by a reduction in total antioxidant capacity, culminating in elevated apoptosis markers, including cytochrome C and caspase-3. Moreover, SCCPs perturbed hepatocellular energy metabolism, characterized by increased glycolysis, lactic acid, and fatty acid oxidation, alongside a disruption in the tricarboxylic acid cycle and a decline in mitochondrial energy metabolic function. Furthermore, SCCPs exposure downregulated the expression of genes involved in bile acid synthesis (cyp27a1, fxr, and shp), thereby precipitating the cholesterol-bile acid metabolism disorders and cholesterol accumulation. Collectively, these findings underscore that SCCPs, even at environmentally relevant levels, can induce lipid dysregulation, mitochondrial disorders and cholesterol deposition in the hepatocytes, contributing to liver damage. The study's insights contribute to a comprehension of SCCPs-induced hepatotoxicity and may inform potential preventative and treatment targets for hepatic damage associated with SCCPs exposure.

Vanillic acid ameliorates diethyl phthalate and bisphenol S-induced oxidative stress and neuroinflammation in the hippocampus of experimental rats.

Long-term adverse effects on human health are caused by exogenous compounds that alter the functions of biological systems, especially neuroendocrine disruptors like diethyl phthalate (DEP) and bisphenol S (BPS). Although vanillic acid (VA) has pertinent neuropharmacological characteristics, its effect against DEP + BPS-induced neurotoxicity has not been explored. This study proposed that VA may offer protection against the neurotoxicity caused by DEP + BPS. Thirty male Wistar rats were randomly distributed across five groups: a control group receiving DMSO, a group exposed to a mixture of BPS and DEP, two BPS + DEP-exposed groups treated with VA at doses of 25 mg/kg or 50 mg/kg, and a nonexposed group treated with 50 mg VA/kg. After 21 days, the hippocampal tissues were processed for biochemical analyses. Our results indicate that exposure to DEP + BPS upregulated neurosignaling mediators (NTPDase, ADA, MAO-A, and Ca2+), inhibited others (AChE and Ca2+/Mg2+-ATPase), decreased hippocampus antioxidants (GSH, GPx, CAT, and SOD), and elevated markers of oxidative stress/damage (NO, H2O2, MDA, and AOPP). AR, BAX, TNF-α, BAK1, and IL-1β expressions were upregulated, while IL-10 and BDNF expressions were downregulated. NF-κB and caspase-3/9 pathways were also upregulated. Co-treatment with vanillic acid remarkably precluded these neurotoxic outcomes by improving neurosignaling, augmenting antioxidant status, abrogating oxidative damage, inflammation (TNF-α, IL-1β), and apoptosis (BAX, BAK1, caspase-3/9). Vanillic acid also restored IL-10 and BDNF levels, thereby exhibiting neuroprotective effects, corroborated by histological examinations. We posit vanillic acid as a safe and effective therapeutic agent against neurotoxicity occasioned by exposure to neuroendocrine disruptors.

Patients with crush syndrome and kidney disease: lessons learned from the earthquake in Kahramanmaraş, Türkiye

This study investigated in-hospital outcomes and related factors in patients diagnosed with postearthquake crush syndrome after the earthquakes in Kahramanmaraş, Türkiye. One thousand twenty-four adult patients diagnosed with crush syndrome were analyzed. Data on demographic characteristics, clinical presentation, laboratory values, treatments, and outcomes were collected. A total of 9.8% of patients died during their hospital stay. Nonsurvivors were generally older, more likely to have preexisting chronic kidney disease, and faced more severe injuries and complications, including hypotension-shock, arrhythmias, elevated markers of renal dysfunction, and higher rates of acute kidney injury (AKI) and compartment syndrome. In addition, intensive care unit needs were higher. Multivariate analysis confirmed that age, injury severity, shock, high potassium, uric acid, and lactate levels on admission, development of AKI, compartment syndrome, and intensive care unit admission were significant predictors of mortality. Better disaster preparedness and improved health care infrastructure could be potential explanations for improved in-hospital mortality in the current era, as compared to previous earthquakes.

Enhanced platelet sensitization is accompanied by increased expression of the transporter MRP4 and elevated plasma S1P levels in mild COVID-19 convalescents

Viral infections can lead to platelet activation and hemostatic complications. However, the extent to which platelet reactivity remains altered after convalescence, contributing to long-term health impairments as observed after COVID-19 is not yet fully understood. Therefore, we conducted a cohort study (DRKS00025217) to determine platelet function in individuals convalesced from mild COVID-19. Assays were performed ex vivo with blood from convalescents at 2–15 weeks and 6–10 months after convalescence, focusing on platelet aggregation, activation markers, and thrombin formation. In addition, two other potentially relevant factors for platelet function were examined: the immunomodulatory mediator sphingosine-1-phosphate (S1P) and the platelet expression of the transporter MRP4 (ABCC4). Our findings indicate that robust platelet functions, including platelet aggregation determined by light transmission aggregometry, and thrombin formation, were not altered in convalescents compared to matched control individuals. However, an elevation in subtle platelet activation markers, such as P-selectin surface expression and activation of glycoprotein IIb/IIIa, was observed 2–15 weeks after convalescence. This was accompanied by an increased expression of MRP4 in platelets and significantly elevated levels of S1P in platelet-poor plasma. Our findings suggest increased platelet sensitization and a pro-inflammatory state even after convalescence from mild COVID-19, pointing toward MRP4 and S1P as associated factors.

A comprehensive meta-analysis of in vitro studies on polycystic ovary syndrome cell lines

Introduction: Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder affecting women of reproductive age. In vitro studies using PCOS cell lines have been instrumental in understanding the pathophysiology and identifying potential therapeutic targets. This meta-analysis aims to synthesize and evaluate the existing literature on PCOS cell line research. Methods: A systematic search of PubMed, Scopus, and Web of Science databases up to January 2024, using relevant keywords and medical subject headings. Inclusion criteria were original research articles in English, focusing on PCOS cell lines and reporting quantitative data. Data extraction included study design, cell line model, outcomes, and main findings. Results: A total of 48 studies met the inclusion criteria, involving human granulosa-derived (KGN, COV434), theca-derived (HsTE-1, HsTE-10), and ovarian surface epithelial (IOSE-80) cell lines. These studies focused on the evaluation of hormonal imbalances, insulin resistance, and inflammation. The meta-analysis revealed that PCOS cell lines exhibited increased androgen production, elevated insulin resistance markers, and pro-inflammatory cytokine expression compared to control cell lines. Conclusion: In vitro studies using PCOS cell lines have provided valuable insights into the molecular mechanisms underlying PCOS pathogenesis. These cell lines serve as valuable tools for understanding the complex interplay between hormonal dysregulation, insulin resistance, and inflammation.

Combining Chemotherapy Agents and Autophagy Modulators for Enhanced Breast Cancer Cell Death

Purpose: Autophagy, governed by genes with dual roles in cell death and survival, plays a crucial role in cancer persistence. Arsenic trioxide (ATO), carboplatin (CP), and cyclophosphamide (CY) are used to treat various cancers. ATO impedes cell proliferation and triggers apoptosis in cancer cells. CP, a platinum-based drug, damages cancer cell DNA, while CY acts as an alkylating agent, disrupting cell proliferation. This study investigates the combined effects of ATO, CP, and CY on inducing apoptosis and modulating autophagy in triple-negative breast cancer (TNBC) cell lines, BT-20 and MDA-MB-231. Methods: The cytotoxic effects of ATO, CP, and CY, alone and in combination, were evaluated using the MTT assay on BT-20 and MDA-MB-231 cells. Apoptosis and cell cycle progression were analyzed by annexin-V FITC/PI staining and flow cytometry. Gene expression of autophagy- and apoptosis-related markers, including Beclin 1, LC3, caspase 3, and BCL2, was quantified using RT-PCR. Data were analyzed using GraphPad Prism 4.0 with one-way ANOVA followed by Dunnett's test. Results: The The combination of ATO, CP, and CY significantly reduced cell viability and enhanced apoptosis, evidenced by increased caspase-3 activity and reduced BCL2 expression. Cell cycle arrest in the G1 phase was observed, alongside elevated autophagy markers Beclin 1 and LC3. Conclusion: The combination of ATO, CP, and CY induces synergistic effects in promoting apoptosis and autophagy in TNBC cell lines. These findings suggest that this combination therapy could be a promising approach to enhancing treatment efficacy in aggressive breast cancers, offering new insights into potential therapeutic strategies.