COVID-19-neutralizing antibodies predict disease severity and survival.

Coronavirus disease 2019 (COVID-19) exhibits variable symptom severity ranging from asymptomatic to life-threatening, yet the relationship between severity and the humoral immune response is poorly understood. We examined antibody responses in 113 COVID-19 patients and found that severe cases resulting in intubation or death exhibited increased inflammatory markers, lymphopenia, pro-inflammatory cytokines, and high anti-receptor binding domain (RBD) antibody levels. Although anti-RBD immunoglobulin G (IgG) levels generally correlated with neutralization titer, quantitation of neutralization potency revealed that high potency was a predictor of survival. In addition to neutralization of wild-type SARS-CoV-2, patient sera were also able to neutralize the recently emerged SARS-CoV-2 mutant D614G, suggesting cross-protection from reinfection by either strain. However, SARS-CoV-2 sera generally lacked cross-neutralization to a highly homologous pre-emergent bat coronavirus, WIV1-CoV, which has not yet crossed the species barrier. These results highlight the importance of neutralizing humoral immunity on disease progression and the need to develop broadly protective interventions to prevent future coronavirus pandemics.

Prenatal interleukin 6 elevation increases glutamatergic synapse density and disrupts hippocampal connectivity in offspring.

Early prenatal inflammatory conditions are thought to be a risk factor for different neurodevelopmental disorders. Maternal interleukin-6 (IL-6) elevation during pregnancy causes abnormal behavior in offspring, but whether these defects result from altered synaptic developmental trajectories remains unclear. Here we showed that transient IL-6 elevation via injection into pregnant mice or developing embryos enhanced glutamatergic synapses and led to overall brain hyperconnectivity in offspring into adulthood. IL-6 activated synaptogenesis gene programs in glutamatergic neurons and required the transcription factor STAT3 and expression of the RGS4 gene. The STAT3-RGS4 pathway was also activated in neonatal brains during poly(I:C)-induced maternal immune activation, which mimics viral infection during pregnancy. These findings indicate that IL-6 elevation at early developmental stages is sufficient to exert a long-lasting effect on glutamatergic synaptogenesis and brain connectivity, providing a mechanistic framework for the association between prenatal inflammatory events and brain neurodevelopmental disorders.

Anti- and pro-inflammatory milieu differentially regulate differentiation and immune functions of oligodendrocyte progenitor cells.

Oligodendrocyte progenitor cells (OPCs) were regarded for years solely for their regenerative role; however, their immune-modulatory roles have gained much attention recently, particularly in the context of multiple sclerosis (MS). Despite extensive studies on OPCs, there are limited data elucidating the interactions between their intrinsic regenerative and immune functions, as well as their relationship with the inflamed central nervous system (CNS) environment, a key factor in MS pathology. We examined the effects of pro-inflammatory cytokines, represented by interferon (IFN)-γ and tumour necrosis factor (TNF)-α, as well as anti-inflammatory cytokines, represented by interleukin (IL)-4 and IL-10, on OPC differentiation and immune characteristics. Using primary cultures, enzyme-linked immunosorbent assay and immunofluorescence stainings, we assessed differentiation capacity, phagocytic activity, major histocompatibility complex (MHC)-II expression, and cytokine secretion. We observed that the anti-inflammatory milieu (IL4 and IL10) reduced both OPC differentiation and immune functions. Conversely, exposure to TNF-α led to intact differentiation, increased phagocytic activity, high levels of MHC-II expression, and cytokines secretion. Those effects were attributed to signalling via TNF-receptor-2 and counteracted the detrimental effects of IFN-γ on OPC differentiation. Our findings suggest that a pro-regenerative, permissive inflammatory environment is needed for OPCs to execute both regenerative and immune-modulatory functions.

Cytokines enhance human Vγ9Vδ2 T-cell TCR-dependent and TCR-independent effector functions.

Vγ9Vδ2 T cells can recognize various molecules associated with cellular stress or transformation, providing a unique avenue for the treatment of cancers or infectious diseases. Nonetheless, Vγ9Vδ2 T-cell-based immunotherapies frequently achieve suboptimal efficacies in vivo. Enhancing the cytotoxic effector function of Vγ9Vδ2 T cells is one potential avenue through which the immunotherapeutic potential of this subset may be improved. We compared the use of four pro-inflammatory cytokines on the effector phenotype and functions of in vitro expanded Vγ9Vδ2 T cells, and demonstrated TCR-independent cytotoxicity mediated through CD26, CD16, and NKG2D, which could be further enhanced by IL-23, IL-18, and IL-15 stimulation throughout expansion. This work defines promising culture conditions that could improve Vγ9Vδ2 T-cell-based immunotherapies and furthers our understanding of how this subset might recognize and target transformed or infected cells.

Oxidative stress and inflammation cause auditory system damage via glial cell activation and dysregulated expression of gap junction proteins in an experimental model of styrene-induced oto/neurotoxicity.

BACKGROUND: Redox imbalance and inflammation have been proposed as the principal mechanisms of damage in the auditory system, resulting in functional alterations and hearing loss. Microglia and astrocytes play a crucial role in mediating oxidative/inflammatory injury in the central nervous system; however, the role of glial cells in the auditory damage is still elusive. OBJECTIVES: Here we investigated glial-mediated responses to toxic injury in peripheral and central structures of the auditory pathway, i.e., the cochlea and the auditory cortex (ACx), in rats exposed to styrene, a volatile compound with well-known oto/neurotoxic properties. METHODS: Male adult Wistar rats were treated with styrene (400 mg/kg daily for 3 weeks, 5/days a week). Electrophysiological, morphological, immunofluorescence and molecular analyses were performed in both the cochlea and the ACx to evaluate the mechanisms underlying styrene-induced oto/neurotoxicity in the auditory system. RESULTS: We showed that the oto/neurotoxic insult induced by styrene increases oxidative stress in both cochlea and ACx. This was associated with macrophages and glial cell activation, increased expression of inflammatory markers (i.e., pro-inflammatory cytokines and chemokine receptors) and alterations in connexin (Cxs) and pannexin (Panx) expression, likely responsible for dysregulation of the microglia/astrocyte network. Specifically, we found downregulation of Cx26 and Cx30 in the cochlea, and high level of Cx43 and Panx1 in the ACx. CONCLUSIONS: Collectively, our results provide novel evidence on the role of immune and glial cell activation in the oxidative/inflammatory damage induced by styrene in the auditory system at both peripheral and central levels, also involving alterations of gap junction networks. Our data suggest that targeting glial cells and connexin/pannexin expression might be useful to attenuate oxidative/inflammatory damage in the auditory system.

Oral colon-targeted pH-responsive polymeric nanoparticles loading naringin for enhanced ulcerative colitis therapy.

An oral colon-targeted drug delivery system holds great potential in preventing systemic toxicity and preserving the therapeutic benefits of ulcerative colitis (UC) treatment. In this study, we developed a negatively charged PLGA-PEG nanoparticle system for encapsulating naringin (Nar). Additionally, chitosan and mannose were coated on the surface of these nanoparticles to enhance their mucosal adsorption and macrophage targeting abilities. The resulting nanoparticles, termed MC@Nar-NPs, exhibited excellent resistance against decomposition in the strong acidic gastrointestinal environment and specifically accumulated at inflammatory sites. Upon payload release, MC@Nar-NPs demonstrated remarkable efficacy in alleviating colon inflammation as evidenced by reduced levels of pro-inflammatory cytokines in both blood and colon tissues, as well as the scavenging of reactive oxygen species (ROS) in the colon. This oral nanoparticle delivery system represents a novel approach to treating UC by utilizing Chinese herbal ingredient-based oral delivery and provides a theoretical foundation for local and precise intervention in specific UC treatment.

Synthesis, characterization, and anti-inflammatory activity of tetrahydropiperine, piperic acid, and tetrahydropiperic acid via down regulation of NF-κB pathway.

The present study describes the synthesis, characterization, and evaluation of tetrahydropiperine (THP), piperic acid (PA), and tetrahydropiperic acid (THPA) as anti-inflammatory agents. THPA demonstrated potent anti-inflammatory activity among all the compounds. The anti-inflammatory potential was investigated in both in-vitro and in-vivo experimental models. Our findings demonstrated that THPA effectively suppressed the production of pro-inflammatory mediators, including nitric oxide and pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) in both in vitro and in vivo. Additionally, THPA attenuated the expression of i-NOS and COX-2 in RAW 264.7 macrophages. The oral administration of THPA significantly reduced carrageenan induced paw edema thickness and alleviated liver, lung, and kidney injury induced by LPS. THPA also reduced the infiltration of inflammatory cells, prevented the occurrence of significant lesions, and mitigated tissue damage. Moreover, THPA significantly improved the survival rate of mice challenged with LPS. Our western blot studies also found that LPS induced NF-κB activation was downregulated by treatment with THPA in an in vivo system. These results collectively illustrated the potential of THPA as a therapeutic agent for treating inflammatory diseases.

Changes in cytokine and sequestosome-1 levels during twin pregnancy progression: Association with outcome.

BACKGROUND: Twin pregnancies are associated with complications and adverse outcomes. The number of twin pregnancies has increased in the last decades, due to the use of assisted reproductive techniques and delayed childbearing. Analysis of changes that occur during twin pregnancy progression and their association with outcome will lead to improved clinical interventions. OBJECTIVE: We evaluated if the plasma concentration of select cytokines and the level of sequestosome-1 (p62) in peripheral blood mononuclear cells (PBMCs) during each trimester of twin gestations was predictive of pregnancy outcome. STUDY DESIGN: This prospective, observational study was conducted at Careggi University Hospital, Florence, Italy. Plasma from 82 women with twin pregnancies was collected in each trimester for measurement of interleukin (IL)-1ß, IL-6, IL-10, IL-12 and tumor necrosis factor (TNF)-α. The intracellular PBMC concentration of p62, a protein involved in autophagy, kinase activity and cell differentiation, was also determined. RESULTS: IL-1ß (p < 0.001), IL-6 (p < 0.001), TNF-α (p < 0.001) and p62 (p < 0.05) increased from the 1st to the 2nd to the 3rd trimester. The TNF-α level was correlated with the IL-1ß concentration in the 1st and 3rd trimesters p < 0.01) and with the IL-6 concentration in each of the three trimesters (p < 0.01). The intracellular p62 level in PBMCs was negatively correlated with the concentration of IL-1ß in the 2nd trimester (p < 0.05) and negatively correlated with the IL-6 level in the 3rd trimester (p < 0.05). The TNF-α level was significantly higher in the 2nd (p < 0.05) and 3rd (p < 0.001) trimester in women with a spontaneous preterm delivery. The TNF-α concentrations in the 2nd (p < 0.05) and 3rd (p < 0.01) trimester, respectively, and 3rd trimester IL-6 (p < 0.01), were negatively associated with gestational age at delivery. The concentration of IL-6 was highest in the 2nd (p < 0.05) and 3rd (p < 0.05) trimesters in women who utilized assisted reproductive technologies. An elevated IL-1ß level in the 3rd trimester was associated with gestational diabetes mellitus (p < 0.05). CONCLUSION: Variations in cytokine levels between individual women during the three trimesters of twin gestations are predictive of spontaneous preterm delivery and the onset of gestational diabetes.

Protective effects of 17-ß-estradiol on liver injury: The role of TLR4 signaling pathway and inflammatory response.

Liver injury, a major global health issue, stems from various causes such as alcohol consumption, nonalcoholic steatohepatitis, obesity, diabetes, metabolic syndrome, hepatitis, and certain medications. The liver's unique susceptibility to ischemia and hypoxia, coupled with the critical role of the gut-liver axis in inflammation, underscores the need for effective therapeutic interventions. The study highlights E2's interaction with estrogen receptors (ERs) and its modulation of the Toll-like receptor 4 (TLR4) signaling pathway as key mechanisms in mitigating liver injury. Activation of TLR4 leads to the release of pro-inflammatory cytokines and chemokines, exacerbating liver inflammation and injury. E2 down-regulates TLR4 expression, reduces oxidative stress, and inhibits pro-inflammatory cytokines, thereby protecting the liver. Both classic (ERα and ERß) and non-classic [G protein-coupled estrogen receptor (GPER)] receptors are influenced by E2. ERα is particularly crucial for liver regeneration, preventing liver failure by promoting hepatocyte proliferation. Furthermore, E2 exerts anti-inflammatory, antioxidant, and anti-apoptotic effects by inhibiting cytokines such as IL-6, IL-1ß, TNF-α, and IL-17, and by reducing lipid peroxidation and free radical damage. The article calls for further clinical research to validate these findings and to develop estrogen-based treatments for liver injuries. Overall, the research emphasizes the significant potential of E2 as a therapeutic agent for liver injuries. It advocates for extensive clinical studies to validate E2 hepatoprotective properties and develop effective estrogen-based treatments.

The impact of NF-κB on inflammatory and angiogenic processes in age-related macular degeneration.

Age-related macular degeneration (AMD) is a prominent cause of vision loss, characterized by two different types, dry (atrophic) and wet (neovascular). Dry AMD is distinguished by the progressive deterioration of retinal cells, which ultimately causes a decline in vision. In contrast, wet AMD is defined by the abnormal development of blood vessels underneath the retina, leading to a sudden and severe vision impairment. The course of AMD is primarily driven by chronic inflammation and pathological angiogenesis, in which the NF-κB signaling pathway plays a crucial role. The activation of NF-κB results in the generation of pro-inflammatory cytokines, chemokines, and angiogenic factors like VEGF, which contribute to inflammation and the formation of new blood vessels in AMD. This review analyzes the intricate relationship between NF-κB signaling, inflammation, and angiogenesis in AMD and assesses the possibility of using NF-κB as a target for therapy. The evaluation involves a comprehensive examination of preclinical and clinical evidence that substantiates the effectiveness of NF-κB inhibitors in treating AMD by diminishing inflammation and pathological angiogenesis.

Low-molecular-weight heparin ameliorates intestinal barrier dysfunction in aged male rats via protection of tight junction proteins.

The intestinal barrier weakens and chronic gut inflammation occurs in old age, causing age-related illnesses. Recent research shows that low-molecular-weight heparin (LMWH), besides anticoagulation, also has anti-inflammatory and anti-apoptotic effects, protecting the intestinal barrier. This study aims to analyze the effect of LMWH on the intestinal barrier of old male rodents. This study assigned Sprague-Dawley male rats to four groups: young (3 months), young + LMWH, old (20 months), and old + LMWH. The LMWH groups received 1 mg/kg LMWH via subcutaneous injection for 7 days. Optical and transmission electron microscopy (TEM) were used to examine morphological changes in intestinal mucosa due to aging. Intestinal permeability was measured using fluorescein isothiocyanate (FITC)-dextran. ELISA kits were used to measure serum levels of IL-6 and IL-1ß, while Quantitative RT-PCR detected their mRNA levels in intestinal tissues. Western blotting and immunohistochemistry (IHC) evaluated the tight junction (TJ) protein levels such as occludin, zonula occludens-1 (ZO-1), and claudin-2. Western blotting assessed the expression of the apoptosis marker cleaved caspase 3, while IHC was used to detect LGR5+ intestinal stem cells. The intestinal permeability of aged rats was significantly higher than that of young rats, indicating significant differences. With age, the protein levels of occludin and ZO-1 decreased significantly, while the level of claudin-2 increased significantly. Meanwhile, our study found that the levels of IL-1ß and IL-6 increased significantly with age. LMWH intervention effectively alleviated age-related intestinal barrier dysfunction. In aged rats treated with LMWH, the expression of occludin and ZO-1 proteins in the intestine increased, while the expression of claudin-2 decreased. Furthermore, LMWH administration in aged rats resulted in a decrease in IL-1ß and IL-6 levels. LMWH also reduced age-related cleaved caspase3 expression, but IHC showed no difference in LGR5+ intestinal stem cells between groups. Research suggests that LMWH could potentially be a favorable therapeutic choice for age-related diseases associated with intestinal barrier dysfunction, by protecting TJ proteins, reducing inflammation, and apoptosis.

Improved synthesis, molecular modeling and anti-inflammatory activity of new fluorinated dihydrofurano-naphthoquinone compounds.

A series of new fluorinated dihydrofurano-napthoquinone compounds were sucessfully synthesized in good yields using microwave-assisted multi-component reactions of 2-hydroxy-1,4-naphthoquinone, fluorinated aromatic aldehydes, and pyridinium bromide. The products were fully characterized using spectroscopic techniques and evaluated for their anti-inflammatory activity using lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Among 12 new compounds, compounds 8b, 8d, and 8e showed high potent NO inhibitory activity in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells with IC50 values ranging from 1.54 to 3.92 µM. The levels of pro-inflammatory cytokines IL-1ß and IL-6 in LPS-stimulated RAW264.7 macrophages were remarkably decreased after the application of 8b, 8d, 8e and 8k. Molecular docking simulations revealed structure-activity relationships of 8b, 8d, and 8e toward NO synthase, cyclooxygenase (COX-2 over COX-1), and prostaglandin E synthase-1 (mPGES-1). Further physicochemical and pharmacokinetic computations also demonstrated the drug-like characteristics of synthesized compounds. These findings demonstrated the importance of fluorinated dihydrofurano-napthoquinone moieties in the development of potential anti-inflammatory agents.

Mac-2-Binding Protein Glycosylation Isomer to Albumin Ratio Predicts Bacterial Infections in Cirrhotic Patients.

INTRODUCTION: Mac-2-binding protein glycosylation isomer (M2BPGi) is a novel biomarker for liver fibrosis, but little is known about its role in cirrhosis-associated clinical outcomes. This study aimed to investigate the predictive role of M2BPGi in cirrhosis-associated complications. METHODS: One hundred and forty-nine cirrhotic patients were retrospectively enrolled. Patients were followed up for 1 year, and cirrhosis-associated clinical events were recorded. Receiver operating characteristic curve (ROC) analysis was used to establish the values of the predictive models for cirrhotic outcomes, and Cox proportional hazards regression models were used to identify predictors of clinical outcomes. RESULTS: Sixty (40.3%) patients experienced cirrhosis-associated clinical events and had higher M2BPGi levels compared to those without events (8.7 vs. 5.1 cutoff index, p < 0.001). The most common cirrhosis-associated complications were bacterial infections (24.2%). On ROC analysis, M2BPGi to albumin ratio (M2BPGi/albumin) had comparable discriminant abilities for all cirrhosis-associated events (area under the ROC curve [AUC] = 0.74) compared with M2BPGi, Child-Pugh, model for end-stage liver disease, albumin-bilirubin scores, and neutrophil-to-lymphocyte ratio and was superior to M2BPGi alone for all bacterial infectious events (AUC = 0.80). Cox regression analysis revealed that the M2BPGi/albumin, but not M2BPGi alone, independently predicted all cirrhosis-associated events (hazard ratio [HR] = 1.34, p = 0.038) and all bacterial infectious events (HR = 1.51, p = 0.011) within 1 year. However, M2BPGi/albumin did not predict other cirrhotic complications and transplant-free survival. DISCUSSION/CONCLUSION: M2BPGi/albumin might serve as a potential prognostic indicator for patients with cirrhosis, particularly for predicting bacterial infections.

The role of periodontitis in cancer development, with a focus on oral cancers.

Periodontitis is a severe gum infection that begins as gingivitis and can lead to gum recession, bone loss, and tooth loss if left untreated. It is primarily caused by bacterial infection, which triggers inflammation and the formation of periodontal pockets. Notably, periodontitis is associated with systemic health issues and has been linked to heart disease, diabetes, respiratory diseases, adverse pregnancy outcomes, and cancers. Accordingly, the presence of chronic inflammation and immune system dysregulation in individuals with periodontitis significantly contributes to the initiation and progression of various cancers, particularly oral cancers. These processes promote genetic mutations, impair DNA repair mechanisms, and create a tumor-supportive environment. Moreover, the bacteria associated with periodontitis produce harmful byproducts and toxins that directly damage the DNA within oral cells, exacerbating cancer development. In addition, chronic inflammation not only stimulates cell proliferation but also inhibits apoptosis, causes DNA damage, and triggers the release of pro-inflammatory cytokines. Collectively, these factors play a crucial role in the progression of cancer in individuals affected by periodontitis. Further, specific viral and bacterial agents, such as hepatitis B and C viruses, human papillomavirus (HPV), Helicobacter pylori (H. pylori), and Porphyromonas gingivalis, contribute to cancer development through distinct mechanisms. Bacterial infections have systemic implications for cancer development, while viral infections provoke immune and inflammatory responses that can lead to genetic mutations. This review will elucidate the link between periodontitis and cancers, particularly oral cancers, exploring their underlying mechanisms to provide insights for future research and treatment advancements.

Ceramides and pro-inflammatory cytokines for the prediction of acute coronary syndrome: a multi-marker approach.

BACKGROUND: There is a growing body of evidence supporting the significant involvement of both ceramides and pro-inflammatory cytokines in the occurrence and progression of acute coronary syndrome (ACS). METHODS: This study encompassed 216 participants whose laboratory variables were analysed using standardised procedures. Parameters included baseline serum lipid markers, comprising total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, triglycerides (TGs), lipoprotein(a) (LPa), fasting blood glucose, B-natriuretic peptide and hypersensitive C-reactive protein. Liquid chromatography-tandem mass spectrometry measured the concentrations of plasma ceramides. Enzyme-linked immunosorbent assay quantified tumour necrosis factor-α (TNF-α), interleukin 6 (IL6) and IL8. The correlation between ceramides and inflammatory factors was determined through Pearson's correlation coefficient. Receiver operating characteristic (ROC) curve analysis and multivariate logistic regression evaluated the diagnostic potential of models incorporating traditional risk factors, ceramides and pro-inflammatory cytokines in ACS detection. RESULTS: Among the 216 participants, 138 (63.89%) were diagnosed with ACS. Univariate logistic regression analysis identified significant independent predictors of ACS, including age, gender, history of diabetes, smoking history, TGs, TNF-α, IL-6, ceramide (d18:1/16:0), ceramide (d18:1/18:0), ceramide (d18:1/24:0), ceramide (d18:1/20:0) and ceramide (d18:1/22:0). Multivariate logistic regression analysis revealed significant associations between gender, diabetes mellitus history, smoking history, LPa, IL-6, ceramide (d18:1/16:0) and ACS. Receiver operating characteristic analysis indicated that model 4, which integrated traditional risk factors, IL-6 and ceramide (d18:1/16:0), achieved the highest area under the curve (AUC) of 0.827 (95% CI 0.770-0.884), compared with model 3 (traditional risk factors and ceramide [d18:1/16:0]) with an AUC of 0.782 (95% CI 0.720-0.845) and model 2 (traditional risk factors and IL-6), with an AUC of 0.785 (95% CI 0.723-0.846) in ACS detection. CONCLUSIONS: In summary, incorporating the simultaneous measurement of traditional risk factors, pro-inflammatory cytokine IL-6 and ceramide (d18:1/16:0) can improve the diagnostic accuracy of ACS.

The influence of time-restricted eating/feeding on Alzheimer's biomarkers and gut microbiota.

OBJECTIVES: Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting approximately 55 million individuals globally. Diagnosis typically occurs in advanced stages, and there are limited options for reversing symptoms. Preventive strategies are, therefore, crucial. Time Restricted Eating (TRE) or Time Restricted Feeding (TRF) is one such strategy. Here we review recent research on AD and TRE/TRF in addition to AD biomarkers and gut microbiota. METHODS: A comprehensive review of recent studies was conducted to assess the impact of TRE/TRF on AD-related outcomes. This includes the analysis of how TRE/TRF influences circadian rhythms, beta-amyloid 42 (Aß42), pro-inflammatory cytokines levels, and gut microbiota composition. RESULTS: TRE/TRF impacts circadian rhythms and can influence cognitive performance as observed in AD. It lowers beta-amyloid 42 deposition in the brain, a key AD biomarker, and reduces pro-ininflammatory cytokines. The gut microbiome has emerged as a modifiable factor in AD treatment. TRE/TRF changes the structure and composition of the gut microbiota, leading to increased diversity and a decrease in harmful bacteria. DISCUSSION: These findings underscore the potential of TRE/TRF as a preventive strategy for AD. By reducing Aß42 plaques, modulating pro-inflammatory cytokines, and altering gut microbiota composition, TRE/TRF may slow the progression of AD. Further research is needed to confirm these effects and to understand the mechanisms involved. This review highlights TRE/TRF as a promising non-pharmacological intervention in the fight against AD.

Effect of duloxetine on changes in serum proinflammatory cytokine levels in patients with major depressive disorder.

OBJECTIVE: Accumulating evidence supports the idea that inflammation may contribute to the pathophysiology of major depressive disorder (MDD). Duloxetine, a serotonin-norepinephrine reuptake inhibitor, exhibits anti-inflammatory effects both in vitro and in vivo. In this study, we investigated the impact of duloxetine on changes in serum proinflammatory cytokine levels among individuals diagnosed with MDD. METHODS: A cohort of 23 drug-naïve individuals diagnosed with MDD and 23 healthy controls were included in this study. The severity of depressive symptoms was evaluated using the 24-item Hamilton Depression Scale (HAMD-24). A panel of 7 proinflammatory cytokines, including interleukin-1ß (IL-1ß), IL-2, IL-6, IL-8, IL-12, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), were quantified using multiplex Luminex assays. The levels of serum cytokines in healthy controls and patients with MDD were compared at baseline. All patients received duloxetine at a dosage range of 40-60 mg/day for a duration of 4 weeks. The HAMD-24 scores and serum cytokine levels were compared before and after duloxetine treatment. RESULTS: Compared with healthy controls, patients with MDD had significantly greater levels of IL-2, IL-6, IL-8, IL-12, TNF-α, and IFN-γ (P < 0.05). Moreover, there was a significant decrease in HAMD-24 scores observed pre- and post-treatment (t = 13.161, P < 0.001). Furthermore, after 4 weeks of treatment, the serum levels of IL-8 (t = 3.605, P = 0.002), IL-12 (t = 2.559, P = 0.018), and IFN-γ (t = 3.567, P = 0.002) decreased significantly. However, there were no significant differences in other cytokines, including IL-1ß, IL-2, IL-6, and TNF-α, before and after treatment (P > 0.05). CONCLUSIONS: These findings present compelling evidence, potentially for the first time, indicating that duloxetine treatment may effectively reduce the serum concentrations of IL-8, IL-12, and IFN-γ in individuals diagnosed with MDD. However, the precise mechanisms underlying this effect remain unclear and warrant further investigation.

The association between physical activity and delayed neurocognitive recovery in elderly patients: a mediation analysis of pro-inflammatory cytokines.

BACKGROUND: Delayed neurocognitive recovery (dNCR) can result in unfavorable outcomes in elderly surgical patients. Physical activity (PA) has been shown to improve cognitive function, potentially by reducing systemic inflammatory responses. However, there is a lack of supportive data indicating whether PA has a protective effect against dNCR. AIMS: To examine the correlation between dNCR and PA, and to further analyze if pro-inflammatory cytokines mediate this relationship. METHODS: This study is a prospective nested case-control investigation of elderly patients who had knee replacement surgery. dNCR was defined as a decline in cognitive function compared with baseline by using a battery of neuropsychological tests. PA was assessed with the Physical Activity Scale for the Elderly (PASE). Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum concentrations of IL-6, IL-1ß, and TNF-α. Multivariable logistic regression analysis was conducted to assess the association between PA and dNCR. Mediation analysis was employed to evaluate whether pro-inflammatory cytokines mediate the relationship between them. RESULTS: A cohort of 152 patients was included, resulting in an incidence rate of dNCR of 23.68%. PA was associated with dNCR after full adjustment [OR = 0.199, (95% CI, 0.061; 0.649), P = 0.007]. Mediation analysis showed that the IL-6 mediated the statistical association between PA and dNCR, with mediation proportions (%) of 77.68 (postoperative concentration of IL-6) or 27.58 (the absolute change in IL-6 before and after surgery). CONCLUSIONS: PA serves as a protective factor against dNCR, possibly through the reduction of pro-inflammatory cytokine concentrations. THE CHINESE CLINICAL TRAIL REGISTRY: : www.http://chictr.org.cn , Registration No. ChiCTR2300070834, Registration date: April 24, 2023.

Porphyran Attenuates Neuronal Loss in the Hippocampal CA1 Subregion Induced by Ischemia and Reperfusion in Gerbils by Inhibiting NLRP3 Inflammasome-Mediated Neuroinflammation.

Porphyran, a sulfated polysaccharide found in various species of marine red algae, has been demonstrated to exhibit diverse bioactivities, including anti-inflammatory effects. However, the protective effects of porphyran against cerebral ischemia and reperfusion (IR) injury have not been investigated. The aim of this study was to examine the neuroprotective effects of porphyran against brain IR injury and its underlying mechanisms using a gerbil model of transient forebrain ischemia (IR in the forebrain), which results in pyramidal cell (principal neuron) loss in the cornu ammonis 1 (CA1) subregion of the hippocampus on day 4 after IR. Porphyran (25 and 50 mg/kg) was orally administered daily for one week prior to IR. Pretreatment with 50 mg/kg of porphyran, but not 25 mg/kg, significantly attenuated locomotor hyperactivity and protected pyramidal cells located in the CA1 area from IR injury. The pretreatment with 50 mg/kg of porphyran significantly suppressed the IR-induced activation and proliferation of microglia in the CA1 subregion. Additionally, the pretreatment significantly inhibited the overexpressions of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing protein-3 (NLRP3) inflammasome complex, and pro-inflammatory cytokines (interleukin 1 beta and interleukin 18) induced by IR in the CA1 subregion. Overall, our findings suggest that porphyran exerts neuroprotective effects against brain IR injury, potentially by reducing the reaction (activation) and proliferation of microglia and reducing NLRP3 inflammasome-mediated neuroinflammation.

The changes of blood-based inflammatory biomarkers after non-pharmacologic interventions for chronic low back pain: a systematic review.

BACKGROUND: Chronic low back pain (CLBP) is a prevalent and debilitating condition, leading to significant challenges to both patients and the governmental healthcare system. Non-pharmacologic interventions have received increasing attention as potential strategies to alleviate chronic low back pain and improve patient outcomes. The aim of this systematic review was to comprehensively assess the changes in blood inflammatory biomarkers after non-pharmacologic interventions for CLBP patients, thus trying to understand the complex interactions between non-pharmacologic interventions and inflammatory biomarker changes in CLBP. METHODS: A thorough search (from January 1st, 2002 to October 5th, 2022) of PubMed, Medline (platform Web of Science), and the Cochrane Library (platform Wiley Online Library) were conducted, and inclusion criteria as well as exclusion criteria were refined to selection of the studies. Rigorous assessments of study quality were performed using RoB 2 from Cochrane or an adaptation of the Downs and Black checklist. Data synthesis includes alterations in inflammatory biomarkers after various non-pharmacologic interventions, including exercise, acupressure, neuro-emotional technique, and other modalities. RESULTS: Thirteen primary studies were included in this systematic review, eight randomized controlled trials, one quasi-randomized trial, and four before-after studies. The interventions studied consisted of osteopathic manual treatment (one study), spinal manipulative therapy (SMT) (three studies), exercise (two studies), yoga (two studies) and acupressure (two studies), neuro-emotional technique (one study), mindfulness-based (one study) and balneotherapy study (one study). Four studies reported some changes in the inflammatory biomarkers compared to the control group. Decreased tumor necrosis factor-alpha (TNF-α) after osteopathic manual treatment (OMT), neuro-emotional technique (NET), and yoga. Decreased interleukin (IL)-1, IL-6, IL-10, and c-reactive protein (CRP) after NET, and increased IL-4 after acupressure. Another five studies found changes in inflammatory biomarkers through pre- and post-intervention comparisons, indicating improvement outcomes after intervention. Increased IL-10 after balneotherapy; decreased TNF-α, IL-1ß, IL-8, Interferon-gamma, interferon-γ-induced protein 10-γ-induced protein 10 after exercise; decreased IL-6 after exercise and SMT; decreased CRP and chemokine ligand 3 after SMT. CONCLUSION: Results suggest a moderation of inflammatory biomarkers due to different non-pharmacologic interventions for CLBP, generally resulting in decreased pro-inflammatory markers such as TNF-α and IL-6 as well as increased anti-inflammatory markers such as IL-4, thus revealing the inhibition of inflammatory processes by different non-pharmacologic interventions. However, a limited number of high-quality studies evaluating similar interventions and similar biomarkers limits the conclusion of this review.