Elevated Marker Levels Research Articles

Actualización sobre la fisiopatología inflamatoria de la enfermedad mental

A chronic low-grade inflammation, both systemic and in the brain has been described in preclinical models of interest in psychosis and schizophrenia, most of which are based on the application of stress and immune challenges during periods of particular vulnerability in brain development. These data have been also described in humans, in plasma and in circulating peripheral blood cells as well as in brain tissue and cerebrospinal fluid. This inflammation consists not only of an increase in the activity of intracellular mechanisms and inflammatory and oxidative intercellular signals, but also in a failure in controlling mechanisms. The role of cytokines, innate immunity receptors, and inducible enzyme activation appear to be important. However, so far none of these factors have been identified as a specific and reliable trait or state biomarker of the disease. This review presents preclinical and clinical data on the inflammatory pathophysiology of schizophrenia on which the use of anti-inflammatory drugs, antioxidants, and regulators of the immune response added to standard antipsychotic treatment is based. The most recent meta-analyses indicate that the addition of aspirin, N-acetylcysteine, minocycline, and fatty acids to antipsychotic treatment improves the disease. The possibility of identifying patients with elevated levels of inflammatory markers is underlined as an interesting aspect to consider when introducing adjunctive drugs to antipsychotic treatment.

Injectable smart-blended hydrogel cross-linked with Vanillin to accelerate differentiation of intervertebral disc-derived stem cells (IVDSCs) for promoting degenerative nucleolus pulposus in a rat model.

The nucleus pulposus (NP) degradation is a primary factor in intervertebral disk degeneration (IVD) and a major contributor to low back pain. Intervertebral disk-derived stem cell (IVDSC) therapy presents a promising solution, yet identifying suitable cell carriers for NP transplantation remains challenging. The present study investigates this issue by developing smart injectable hydrogels incorporating vanillin (V) and hyaluronic acid (HA) encapsulated with IVDSCs to facilitate IVD regeneration. The hydrogel was cross linked by carbodiimide-succinimide (EDC-NHS) method. Enhanced mechanical properties were achieved by integrating collagen and HA into the hydrogel. The rheological analysis revealed the pre-gel viscoelastic and shear-thinning characteristics. In vitro, cell viability was maintained up to 500µg/mL, with a high proliferation rate observed over 14days. The hydrogels supported multilineage differentiation, as confirmed by osteogenic and adipogenic induction. Anti-inflammatory effects were demonstrated by reduced cytokine release (TNF-α, IL-6, IL-1β) after 24h of treatment. Gene expression studies indicated elevated levels of chondrocyte markers (Acan, Sox9, Col2). In vivo, hydrogel injection into the NP was monitored via X-ray imaging, showing a significant increase in disk height index (DHI%) after 8weeks, alongside improved histologic scores. Biomechanical testing revealed that the hydrogel effectively mimicked NP properties, enhancing compressive stiffness and reducing neutral zone stiffness post-denucleation. The results suggest that the synthesized VCHA-NP hydrogel can be used as an alternative to NPs, offering a promising path for IVD regeneration.

Impact of singular versus combinatorial environmental stress on RONS generation in Drosophila melanogaster larvae.

We investigated environmentally correlated abiotic stressor desiccation (D), heat (H), and starvation (S) in the generation of reactive oxygen and nitrogen species (RONS) using Drosophila melanogaster larvae as an experimental model, subjected to either individual stressors or exposed to a combinatorial form of stressors (D + H, H + S, and D + S). The study was also extended to find synergistic endpoints where the impacts of all three stressors (D + H + S) were exerted simultaneously. We estimated the lethal time (LT20) at specific doses using regression and probit analyses based on the larval survival. LT20 values were used as the base-level parameter for further oxidative stress experimental analysis work. First, all stressors led to the activation of a typical common oxidative stress-mediated response irrespective of the mode of exposure. As envisaged, D. melanogaster larvae exhibited a homeostatic stress tolerance mechanism, triggering an antioxidant defense mechanism, indicated by an elevated level of total antioxidant capacity and enhanced activities of superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase. In all types of stress-exposed regimes, we found a negative impact of stressors on the activity of mitochondrial enzyme aconitase. Elevated levels of other oxidative stress markers, viz., lipid peroxidation, protein carbonyl content, and advanced oxidative protein products, were obvious although the increment was treatment-specific. Desiccation stress proved to be the most dominant stressor compared to heat and starvation. Among the combination of stressors, rather than a single stressor, D + H impacted more than other binary stress exposures. Focusing on the impact of singular versus combinatorial stress exposure on RONS generation, we observed an increase in the RONS level in both singular and combinatorial forms of stress exposure although the magnitude of the increment varied with the nature of stressors and their combinations. The present study indicated an "additive" effect when all three stressors (D + H + S) operate simultaneously, rather than a "synergistic" effect.

Ameliorative effect of α-tocopherol and curcumin against the deleterious effects of hydrogenated (thermally oxidized) rice bran oil in rats

Rice bran oil (RBO) is known for its health benefits due to its high content of natural antioxidants like tocotrienols, tocopherols, and oryzanols, which combat oxidative stress and inflammation. However, repeated heating of RBO above 110°C leads to degradation, forming harmful oxidative components and reducing its antioxidant content. This study aimed to investigate the effects of long-term consumption of thermally oxidized RBO on rats and the potential protective effects of curcumin and α-tocopherol supplementation. RBO was subjected to oxidative degradation through repeated frying cycles at temperatures ranging from 100°C to 180°C for 45 days. Physicochemical and phytochemical parameters of the oxidized RBO were analyzed. In vivo experiments evaluated serum biochemical, hematological, and histopathological parameters, along with oxidative and inflammatory responses in rats fed with oxidized RBO for 45 days. Results showed that thermal oxidation at 180°C significantly altered the chemical composition of RBO, increasing oxidative markers and reducing nutritional components. Consumption of oxidized RBO led to decreased body weight gain, elevated levels of various biochemical markers indicating liver and kidney dysfunction, hyperlipidemia, and increased oxidative and inflammatory damage in rats. However, supplementation with curcumin and α-tocopherol effectively mitigated these harmful effects. In conclusion, long-term consumption of thermally oxidized RBO negatively affects health parameters in rats, but fortification with curcumin and α-tocopherol helps alleviate these adverse effects

Endoplasmic reticulum stress promotes oxidative stress, inflammation, and apoptosis: A novel mechanism of citrinin-induced renal injury and dysfunction

Citrinin (CTN) has been reported to induce renal failure and structural damage, but its nephrotoxic effects and mechanisms are not fully understood. Therefore, we established a model by orally administering CTN (0, 1.25, 5, or 20 mg/kg) to mice for 21 consecutive days. Histological and biochemical analyses revealed that CTN caused structural damage to renal tubules, increased inflammatory cell infiltration, and elevated levels of serum markers of renal function (creatinine, urea, and uric acid). Moreover, mRNA transcript levels of the inflammatory factors TNF-α, IL-1β, and IL-6 were increased, indicating the occurrence of an inflammatory response. Furthermore, exposure to CTN induced renal oxidative stress by decreasing antioxidant GSH levels, antioxidant enzyme (SOD, CAT) activities, and increasing oxidative products (ROS, MDA). In addition, CTN increased the expression of proteins associated with endoplasmic reticulum (ER)stress and apoptotic pathways. ER stress has been shown to be involved in regulating various models of kidney disease, but its role in CTN-induced renal injury has not been reported. We found that pretreatment with the ER stress inhibitor 4-PBA (240 mg/kg, ip) alleviated CTN-induced oxidative stress, NF-κB pathway mediated inflammatory response, and apoptosis. Interestingly, 4-PBA also partially alleviated renal structural damage and dysfunction. Thus, ER stress may be a novel target for the prevention and treatment of CTN-induced renal injury.

Evaluation of the antioxidant and anti-gastric cancer properties of Pistacia atlantica aqueous extract green-mediated silver nanoparticles

In the presence work, silver nanoparticles were synthesized by a facile green procedure using Pistacia atlantica bark extract as natural reducing and pectin as stabilizing reagent. The physicochemical characteristics of the synthesized Pectin/Ag NPs are further confirmed by several characterization methods such as FT-IR, XRD, FESEM-EDX and TEM analyses. The Fourier transform infrared spectrometer was utilized to investigate the functional groups present in pectin capped silver nanoparticles that were responsible for the capping and remarkably dispersed nanoparticles with no aggregation. The latest research concentrated on the cellular and molecular components. The MTT test was done to assess the effectiveness of the Pectin/Ag NPs nanocomposite on inhibiting human gastric cancer cells and its cytotoxic effects on the treated cells. The evaluation was conducted on healthy (HUVEC) and stomach cancer cells, specifically NCI-N87 and MKN45. The nanocomposite exhibited IC50 values of 75 µg/mL against MKN45 and 152 µg/mL against NCI-N87. A decrease in the viability of gastric cancer cells was noted in the nanocomposite presence, which was dependent on the dosage. Additionally, the nanocomposite triggered a 70–90 % increase in cell apoptosis, resulting in elevated levels of pro-apoptotic markers (Bax and cleaved caspase-8) and reduced levels of the anti-apoptotic marker, Bcl-2. The Pectin/Ag NPs exhibited suppressive properties on colony formation. Our findings suggest that the Pectin/Ag NPs have the ability to enhance p53 expression while reducing the STAT3 expression in the cells that were treated. The findings suggest that STAT3 and p53 are essential factors in the biological responses triggered by the extract in human gastric carcinoma cells. The results suggest that the nanocomposite has the potential to serve as an effective treatment for human gastric cancer cells.

Successful treatment of Enterococcus gallinarum infection in a neonate with vancomycin: a case report

BackgroundEnterococcus gallinarum (EG) is typically found in the gastrointestinal tracts of birds and mammals. Although its strains are rarely isolated from clinical specimens, EG can lead to septicemia in immunocompromised individuals. EG infections are uncommon in household settings, but their incidence has been rising due to increased antibiotic usage and invasive treatments, particularly in Neonatal Intensive Care Units (NICUs). EG inherently exhibits resistance to vancomycin but is highly sensitive to linezolid. Despite showing in vitro resistance, vancomycin has shown clinical efficacy in treating EG meningitis.Case presentationA neonate born at 30 + 2 weeks gestation was admitted to the Neonatal Intensive Care Unit (NICU) after EG was detected in blood and cerebrospinal fluid cultures. Susceptibility testing indicated that the bacterial strain was resistant to vancomycin and sensitive to linezolid. Initially, vancomycin was selected for treatment. However, due to persistent EG cultures in the blood and cerebrospinal fluid, the treatment was adjusted to linezolid. This led to a rapid decrease in platelet (PLT) count, suspected to be an adverse reaction. Concurrently, the patient experienced recurrent fever and elevated inflammatory marker levels, prompting the discontinuation of linezolid and a return to vancomycin. Subsequent administration of vancomycin stabilized the patient’s condition, as evidenced by improved C-reactive protein (CRP), procalcitonin (PCT), and cerebrospinal fluid parameters, ultimately leading to discharge after an eight-week treatment period.ConclusionThis retrospective analysis highlights the efficacy of vancomycin in treating EG infections, suggesting that specific genetic phenotypes may influence treatment sensitivity. Monitoring vancomycin blood levels is crucial for determining treatment effectiveness.

Insomnia and circadian rhythms dysregulation in people who have attempted suicide: correlations with markers of inflammation and suicidal lethality

Introduction Suicide is a widespread problem, with risk factors still a challenge. The aim was to assess correlations among insomnia, circadian rhythm, and inflammatory markers in individuals who attempted suicide. Materials and Methods Consecutive patients hospitalised following an attempted suicide, were assessed. Psychiatric diagnosis (DSM-5-TR Criteria), lethality of the suicide attempt (Suicide Intent Scale-SIS), and inflammatory parameters NLR (neutrophil-lymphocyte ratio) PLR (platelet-lymphocyte ratio), and SII (systemic inflammation index/neutrophil-to-platelet ratio on lymphocytes), were computed. Depressive and manic symptoms (Beck Depression Inventory-BDI-II, Young Mania Rating Scale- YMRS), circadian rhythms disturbances (Biological Rhythms Interview of Assessment in Neuropsychiatry-BRIAN), insomnia symptoms (Insomnia Severity Index-ISI) were assessed together with socio-demographic, clinical and pharmacological data. Results The final sample included 52 individuals. Patients who experienced insomnia during the preceding two weeks utilised high lethality methods, reported heightened dysregulation of chronobiological rhythms, heightened severity of depression, and elevated levels of inflammatory markers. High lethality was best predicted by insomnia symptoms (OR = 20.1, CI-95% 4.66-87.25, p = 0.001), by disturbances of circadian rhythms (OR = 6.97, CI-95% 1.82-26.66, p = 0.005), and by NLR indices (OR 4.00, CI-95% 1.14-13.99, p = 0.030). Conclusions Sleep disturbances may be a risk factor for suicidal lethality, along with markers of inflammation. It is plausible that insomnia and circadian sleep dysregulation may contribute to inflammation, thereby promoting suicidal risk.

Alpha-Pinene Decreases the Elevated Levels of Astrogliosis, Pyroptosis, and Autophagy Markers in the Hippocampus Triggered by Kainate in a Rat Model of Temporal Lobe Epilepsy.

The development and progression of temporal lobe epilepsy (TLE) are heavily influenced by inflammation, excessive activation of glial cells, and neuronal cell death. This study aimed to investigate the effects of treatment with alpha-pinene (APN) on pro-and anti-inflammatory cytokine levels, astrogliosis, pyroptosis, and autophagy markers in the hippocampus in a rat model of TLE induced by kainic acid (KA). Male Wistar rats were employed, and TLE was induced by intracerebroventricular injection of KA. APN (50mg/kg) was intraperitoneally administered for 19days, including two weeks before and five days after the administration of KA. After full recovery from anesthesia and KA injection, the seizure-related behavioral expressions were evaluated. On day 19, the hippocampal levels of IL-1β, TNF-α, progranulin, IL-10, ERK1/2, phospho-ERK1/2, NF-κB, GFAP, S100-B, NLRP1, NLRP3, caspase-1, and becline-1 were examined. The results revealed that treatment with APN significantly diminished the heightened levels of IL-1β, TNF-α, progranulin, ERK1/2, and NF-κB and reversed the reduced levels of the anti-inflammatory cytokine, IL-10, in the hippocampus caused by KA. Furthermore, administration of APN significantly reduced the levels of astrogliosis, pyroptosis, and autophagy markers in the hippocampus that were elevated by KA. It can be concluded that treatment with APN for 19days alleviated neuroinflammation by inhibiting ERK1/2 and NF-κB signaling pathways and prevented increases in astrogliosis, pyroptosis, and autophagy markers in the hippocampus in a rat model of TLE.

Contribution of initial lymphatics to oral wound healing after tooth extraction.

Lymphatics are involved in the resolution of inflammation and wound healing, but their role in the oral wound healing process after tooth extraction has never been investigated. We therefore sought to evaluate the healing process following the extraction of maxillary molars in two transgenic mouse models: K14-VEGFR3-Ig mice, which lack initial mucosal lymphatic vessels, and K14-VEGFC mice, which have hyperplastic mucosal lymphatics. Maxillary molars were extracted from both transgenic mouse types and their corresponding wild-type (WT) controls. Mucosal and alveolar bone healing were evaluated. A delayed epithelialization and bone regeneration were observed in K14-VEGFR3-Ig mice compared with their WT littermates. The hampered wound closure was accompanied by decreased levels of epidermal growth factor (EGF) and persistent inflammation, characterized by infiltrates of immune cells and elevated levels of pro-inflammatory markers in the wounds. Hyperplastic mucosal lymphatics did not enhance the healing process after tooth extraction in K14-VEGFC mice. The findings indicate that initial mucosal lymphatics play a major role in the initial phase of the oral wound healing process.

Comparative Characteristics of Inflammatory Markers in Alzheimer’s Disease in Males and Females

Background: the role of the sex factor in the differences between the manifestations of normality and pathology is not limited to the phenomenon of sexual dimorphism. It is known that the prevalence of certain diseases in males and females is different, in particular, there is a multiple increase in the incidence of dementia in females compared to males in Alzheimer’s disease (AD). Taking into account the role of neuroinflammation in the pathogenesis of neurodegenerative diseases, there is reason to assume gender differences in inflammation indicators at different stages of dementia in AD. The aim of the study was to conduct comparative analysis of indicators of the inflammatory system in the blood plasma of males and females at different stages of Alzheimer’s disease. Patients, control group and methods: a total of 210 patients with AD (101 males and 109 females) aged 49 to 94 years (average age 72.3 ± 8.2) with varying degrees of dementia severity, i.e. mild, moderate, severe, were examined. In peripheral blood plasma, the enzymatic activity of leukocyte elastase (LE) and the functional activity of α1-proteinase inhibitor (α1-PI) were determined by the spectrophotometric method, and the level of C-reactive protein (CRP) and IL-6 were determined by the enzyme-linked immunosorbent method (ELISA). The control group consisted of 52 healthy people, who did not differ from the patients in age and gender. Results and discussion: in the blood of patients with varying severity of dementia in AD, a statistically significant increase in α1-PI activity was observed compared to controls (p < 0.0001), regardless of gender. For all subgroups of patients with AD, the indicators of LE enzymatic activity were within the control range or beyond its lower limit. Low LE activity was observed in males compared to females both in the general group and in moderate dementia (p = 0.005105, p = 0.028672, respectively). In severe dementia, a significant decrease in LE activity compared to the controls did not depend on gender. Low LE activity in the blood of patients with AD, along with elevated levels of other inflammatory markers, may reflect a critical violation of the permeability of the blood-brain barrier and/or functional exhaustion of neutrophils due to a long-term inflammatory process. In males, compared with females, an increase in the level of the pro-inflammatory cytokine IL-6 was detected in the general group and in moderate dementia (p = 0.021238, p = 0.027894, respectively). A highly significant increase in CRP levels was only detected in males in subgroups with different severity of dementia. CRP levels in males were significantly higher than in females at the stage of moderate and severe dementia (p = 0.000906, p = 0.000049, respectively). Conclusion: distinctive features of inflammatory markers spectrum were identified, depending on gender and severity of dementia in AD. These results can be used to develop sex-specific preventive or therapeutic strategies for patients with mild cognitive impairment to determine risk and resistance to developing dementia.

Multi-Omics Classification of Intrahepatic Cholangiocarcinoma: A Systematic Review and Meta-Analysis.

Intrahepatic cholangiocarcinoma (ICC) is a heterogeneous disease characterized by a dismal prognosis. Various attempts have been made to classify ICC subtypes with varying prognoses, but a consensus has yet to be reached. This systematic review aims to gather relevant data on the multi-omics-based ICC classification. The PubMed, Embase, and Cochrane databases were searched for terms related to ICC and multi-omics analysis. Studies that identified multi-omics-derived ICC subtypes and investigated clinicopathological predictors of long-term outcomes were included. Nine studies, which included 910 patients, were considered eligible. Mean 3- and 5-year overall survival were 25.7% and 19.6%, respectively, for the multi-omics subtypes related to poor prognosis, while they were 70.2% and 63.3%, respectively, for the subtypes linked to a better prognosis. Several negative prognostic factors were identified, such as genes' expression profile promoting inflammation, mutations in the KRAS gene, advanced tumor stage, and elevated levels of oncological markers. The subtype with worse clinicopathological characteristics was associated with worse survival (Ref.: good prognosis subtype; pooled hazard ratio 2.06, 95%CI 1.67-2.53). Several attempts have been made to classify molecular ICC subtypes, but they have yielded heterogeneous results and need a clear clinical definition. More efforts are required to build a comprehensive classification system that includes both molecular and clinical characteristics before implementation in clinical practice to facilitate decision-making and select patients who may benefit the most from comprehensive molecular profiling in the disease's earlier stages.

The association between genetically predicted systemic inflammatory regulators and endometriosis: A bidirectional Mendelian randomization study.

Elevated levels of various cellular inflammatory markers have been observed in patients with endometriosis (EMs). However, a causal relationship between these markers and EMS has not been firmly established. This study aimed to assess the causality between cellular inflammatory markers and the onset of EMS using a bidirectional Mendelian randomization approach. Genetic associations for EMs were derived from the largest and most recent genome-wide association study (GWAS) involving 1937 EMS cases and 245,603 controls of European ancestry. Single nucleotide polymorphisms associated with 41 cellular cytokines and other systemic inflammatory regulators were identified from 8293 Finnish participants. Estimates were obtained using inverse-variance weighted, with sensitivity analyses conducted using MR-Egger, weighted median, and MR-PRESSO. Among the 41 systemic inflammatory regulators included in the analysis, none were associated with the risk of EMs. Elevated levels of IL-6 were associated with an increased risk of EMs (OR = 1.351, 95%CI = 1.015-1.797). Conversely, genetically predicted elevated levels of platelet-derived growth factor (PDGF-BB) were associated with a reduced risk of EMs (OR = 0.856, 95%CI = 0.742-0.987). Genetically predicted elevations in IL-6 may contribute to an increased risk of EMs, while elevated PDGF-BB levels appear protective, suggesting potential therapeutic targets for EMs. Other systemic inflammatory regulators seem unrelated to EMs risk, potentially representing downstream effects or consequences of shared factors between inflammation and EMs.

Antibiotic Resistance and Inflammatory Response in Urology Infections Caused by E. coli: A Molecular and Clinical Investigation

Background: Urinary tract infections (UTIs) are a common condition resulting from bacterial invasion of the urinary system, which includes the kidneys, ureters, bladder, and urethra. These infections are particularly prevalent among females due to anatomical differences and hormonal factors. UTIs can range from uncomplicated cases, where there are no structural abnormalities, to more severe infections that may ascend to the kidneys, causing pyelonephritis. Methods: This study aimed to isolate and diagnose Escherichia coli (E. coli) bacteria in patients with UTIs, identify specific virulence genes, and assess the bacteria's resistance to various antibiotics. A total of 100 clinical samples were collected from patients with UTIs at the General Hospital of Homadiyah and Ahmed Maher from October 2021 to December 2022. Bacterial identification was performed using biochemical tests and polymerase chain reaction (PCR) techniques, while antibiotic sensitivity was assessed using the Kirby-Bauer disk diffusion method. Additionally, inflammatory markers (TNF-α, IL-6, and IL-8) were measured using ELISA. Results: E. coli was isolated in 56% of the samples, with the highest prevalence in patients aged 31-40 years. The antibiotic sensitivity test revealed varying levels of resistance, with the highest sensitivity observed to third-generation cephalosporins, particularly ceftriaxone (32.2% resistance). PCR analysis identified the presence of several virulence genes, including the Hly gene in 96.6% of isolates and the iha gene in 10% of isolates. Elevated levels of inflammatory markers were observed in patients with UTIs, indicating a strong immune response to bacterial infection. Conclusion: E. coli is a significant pathogen in UTIs, exhibiting considerable antibiotic resistance, particularly to first-generation cephalosporins. The presence of specific virulence genes correlates with the severity of infection. These findings underscore the need for targeted antibiotic therapy and the development of strategies to manage antibiotic resistance in UTIs.

Antineutrophil cytoplasmic antibody is an independent risk factor in rheumatoid arthritis-associated interstitial lung disease

ObjectivesThis study aimed to investigate the clinical relevance of antineutrophil cytoplasmic antibody (ANCA) in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). MethodsDetailed clinical records of rheumatoid arthritis (RA) patients who underwent ANCA screening tests were collected. ANCA measurements were determined by indirect immunofluorescence assay (IIF) and enzyme-linked immunosorbent assay (ELISA). Clinical characteristics were compared between ANCA-positive and ANCA-negative groups, and multivariable logistic models were used to evaluate the independent association of ANCA with ILD in RA patients. ResultsThe prevalence of ANCA by IIF was significantly higher in RA-ILD patients compared to those with RA without ILD (31.7 % vs. 19.5 %, p < 0.001). RA-ILD patients positive for ANCA exhibited elevated levels of inflammatory markers and greater disease activity, and showed more severe impairment of lung function compared to ANCA-negative RA-ILD patients. Multivariable logistic regression analysis revealed an independent association of ANCA, especially pANCA, with RA-ILD. ANCA specificities for BPI, elastase, and cathepsin-G were found in 15.6 % of RA-ILD patients; the specificities for most others remain unknown. ConclusionsThe findings suggest a potential role for ANCA/pANCA in stratifying the risk of RA and provide supplementary information to the existing clinically available assays. This additional information may be valuable in identifying RA patients who require further investigations for RA-ILD, such as high-resolution computed tomography (HRCT). These results emphasize the potential clinical relevance of ANCA in the context of RA-ILD.

Diagnostic and Prognostic Potential of Biochemical and Hematological Markers in Tobacco Users with Oral Pre-Cancer Lesions

Oral Pre-Cancer Lesions (OPLs) including leukoplakia, erythroplakia, and submucous fibrosis denote biochemical and histopathologically altered changes in the oral mucosa marked by subcellular and structural anomalies evocating of potential for a malignant transformation, which is primarily caused by tobacco exposure. Early diagnosis is of paramount importance to halt the progression of premalignant lesions to high-grade dysplasia and even oral cancer. Objective: To find the diagnostic and prognostic potential of biochemical and haematological markers in Tobacco Users (TU) with OPL. Methods: PRISMA guidelines were followed to perform this systematic review. After retrieving 170 epidemiological studies published from 2013 to 2023, through multiple databases (PubMed, Google Scholar, Sci-hub, and Science Direct), 21 were included to determine the potential of biochemical and haematological markers in risk stratification and early detection of OPL. Results: According to the following systematic review, extracted data showed specific biochemical and haematological indicators that could serve as markers in risk stratification and early detection of OPL. The OPL group exhibited significantly higher levels of biochemical markers IL-6, IL-8, TNF-α, HCC-1, PF-4, FRR, TP, MDA, MMP-12, and Ceruloplasmin and hematological markers NLR, PLR, CRP, ESR, WBC, and low Hb as compared to the control group. Following risk stratification, a group with older age, tobacco association with OPL, and elevated levels of markers were categorised as a higher-risk group. Conclusions: The biochemical and haematological markers are potential promising markers in the early detection of OPL from malignant lesions with diagnostic and prognostic significance.

TBHQ mitigates fatty liver ischemia–reperfusion injury by activating Nrf2 to attenuate hepatocyte mitochondrial damage and macrophage STING activation

BackgroundLiver ischemia–reperfusion (IR) injury is an inevitable pathophysiological process in various liver surgeries. Previous studies have found that IR injury is exacerbated in fatty liver due to significant hepatocellular damage and macrophage inflammatory activation, though the underlying mechanisms are not fully understood. In this study, we aim to explore the role and mechanism of Nrf2 (Nuclear factor erythroid 2-related factor 2) signaling in regulating hepatocellular damage and macrophage immune response in fatty liver IR injury. MethodsThe study used high-fat diet-induced fatty liver mice to establish an IR model, alongside an in vitro co-culture system of primary hepatocytes and macrophages. This approach was used to examine mitochondrial dysfunction, oxidative stress, mitochondrial DNA (mtDNA) release, and activation of macrophage STING (Stimulator of interferon genes) signaling. We also conducted recovery verification using H-151 (a STING inhibitor) and tBHQ (an Nrf2 activator). ResultsCompared to the control group, mice on a high-fat diet demonstrated more severe liver IR injury, as evidenced by increased histological damage, elevated liver enzyme levels, and heightened inflammatory markers. The HFD group showed significant oxidative stress and mitochondrial dysfunction and damage post-IR, as indicated by elevated levels of ROS and lipid peroxidation markers, and decreased antioxidant enzyme activity. Elevated mtDNA release from hepatocytes post-IR activated macrophage STING signaling, worsening inflammation and liver damage. However, STING signaling inhibition with H-151 in vivo or employing STING knockout macrophages significantly reduced these injuries. In-depth mechanism studies have found that the transfer of Nrf2 protein into the nucleus of liver cells after IR in fatty liver is reduced. Pre-treatment with tBHQ ameliorated liver oxidative stress, mitochondrial damage and suppressed the macrophage STING signaling activation. ConclusionsOur study reveals a novel mechanism where the interaction between hepatocellular damage and macrophage inflammation intensifies liver IR injury in fatty liver. Enhancing Nrf2 activation to protect mitochondrial from oxidative stress damage and inhibiting macrophage STING signaling activation emerge as promising strategies for clinical intervention in fatty liver IR injury.

The Survival of Human Intervertebral Disc Nucleus Pulposus Cells under Oxidative Stress Relies on the Autophagy Triggered by Delphinidin.

Delphinidin (Delp), a natural antioxidant, has shown promise in treating age-related ailments such as osteoarthritis (OA). This study investigates the impact of delphinidin on intervertebral disc degeneration (IVDD) using human nucleus pulposus cells (hNPCs) subjected to hydrogen peroxide. Various molecular and cellular assays were employed to assess senescence, extracellular matrix (ECM) degradation markers, and the activation of AMPK and autophagy pathways. Initially, oxidative stress (OS)-induced hNPCs exhibited notably elevated levels of senescence markers like p53 and p21, which were mitigated by Delp treatment. Additionally, Delp attenuated IVDD characteristics including apoptosis and ECM degradation markers in OS-induced senescence (OSIS) hNPCs by downregulating MMP-13 and ADAMTS-5 while upregulating COL2A1 and aggrecans. Furthermore, Delp reversed the increased ROS production and reduced autophagy activation observed in OSIS hNPCs. Interestingly, the ability of Delp to regulate cellular senescence and ECM balance in OSIS hNPCs was hindered by autophagy inhibition using CQ. Remarkably, Delp upregulated SIRT1 and phosphorylated AMPK expression while downregulating mTOR phosphorylation in the presence of AICAR (AMPK activator), and this effect was reversed by Compound C, AMPK inhibitor. In summary, our findings suggest that Delp can safeguard hNPCs from oxidative stress by promoting autophagy through the SIRT1/AMPK/mTOR pathway.

Effect of Lactiplantibacillus plantarum on the growth, hemato-biochemical, inflammation, apoptosis, oxidative stress markers, involved gens and histopathological alterations in growing rabbits challenged with aflatoxin B1

Aflatoxin B1 (AFB1) is a significant pollutant found in food and feed, posing a threat to public health. The objective of this study was to assess the effect of Lactiplantibacillus plantarum (LACP) against AFB1 in growing rabbits by investigating growth, serum metabolites, immunity, antioxidant capacity, and inflammatory response. A total of 60 growing male rabbits (721.5 ± 2.68g) were allocated to 4 experimental groups. The control group receiving only a basal diet, the AFB1 group (0.3 mg AFB1/kg diet), the LACP group (1 × 109 cfu/g /kg diet), and the combination group (1 × 109 cfu/g + 0.3 mg AFB1/kg diet; AFB1+ LACP) for 8 wk. The administration of AFB1 alone significantly decreased the final body weight, body gain, and feed intake, while significantly increasing the feed conversion ratio (P < 0.05). A significant decline in total proteins and globulins, along with elevated levels of hepatic enzymes (AST, ALP, ALT, and GGT) and renal function markers (creatinine and uric acid), were observed in the AFB1-contaminated group (P < 0.05). Immunoglobulins (IgG and IgM) were significantly decreased, alongside a significant elevation of triglycerides, direct bilirubin, and indirect bilirubin in growing rabbits fed diets with AFB1 (P < 0.05). Supplementing the AFB1 diet with LACP restored the growth reduction, improved liver (AST, ALP, ALT, and GGT) and kidney (creatinine and uric acid) functions, and enhanced immune markers in rabbit serum (P < 0.05). Antioxidant indices (SOD, GSH, and CAT) were significantly decreased in the AFB1 group (P < 0.05). However, the addition of LACP to the AFB1-contaminated diets improved antioxidant capacity and malondialdehyde (MDA) and protein carbonylation (PC) in hepatic tissues of rabbits (P < 0.05). Serum interlukin-4 (IL-4) and interferon gamma (IFN-γ) levels were significantly increased in the AFB1 group (P < 0.05), but the addition of LACP significantly reversed this elevation. AFB1 downregulated the expression of immune-inflammatory genes such Nrf2, IL-10, and BCL-2 genes, while up-regulating the caspase-3 (CASP3) gene (P < 0.05). Supplementing AFB1 diet with LACP significantly decreased the expression of immune-inflammatory genes (Nrf2, IL-10, and BCL-2) and reduced the expression of the apoptotic-related gene CASP3. This study highlights the potential of L. plantarum (1 × 109 cfu/g /kg diet) as a protective agent against AFB1 in growing rabbits by enhancing antioxidant and immune function and reducing apoptosis and inflammation pathways.

The impact of ischemic stroke on bone marrow microenvironment and extracellular vesicles: A study on inflammatory and molecular changes

An ischemic stroke (IS) is caused due to the lack of blood flow to cerebral tissue. Most of the studies have focused on how stroke affects the localized tissue, but it has been observed that a stroke can cause secondary complications in distant organs, such as Bone Marrow (BM). Our study focused on the effect of ischemic strokes on the bone marrow microenvironment. Bone marrow (BM) is a vital organ that maintains inflammatory homeostasis and aids in the repair of damaged tissue after injury/IS. We used the middle cerebral artery occlusion (MCAO) model of ischemic stroke on adult mice (6 months) and investigated the changes in the BM environment. BM cells were used for western blot and RT-PCR, and the BM supernatant was used for cytokine analysis and extracellular vesicle (EVs) isolation. We observed a significant increase in the total cell number within the BM and an increase in TNF-alpha and MCP-1, which are known for inducing a pro-inflammatory environment. Western blots analysis on the whole BM cell lysate demonstrated elevated levels of inflammatory factors (IL-6, TNF-alpha, and TLR-4) and senescence markers (p21 p16). EVs isolated from the BM supernatant showed no change in size or concentration; however, we found that the EVs carried increased miRNA-141-3p and miRNA-34a. Proteomic analysis on BM-derived EVs showed an alteration in the protein cargo of IS. We observed an increase in FgB, C3, Fn1, and Tra2b levels. The signaling pathway analysis showed mitochondrial function is most affected within the bone marrow. Our study demonstrated that IS induces changes in the BM environment and EVs secreted in the BM.