Tuberculosis in children and adolescents with rheumatic diseases using biologic agents: an integrative review.

OBJECTIVE: To conduct a bibliographic review on tuberculosis (TB) disease in children and adolescents with rheumatic diseases, being managed with biologic therapy. DATA SOURCE: An integrative review with a search in the U.S. National Library of Medicine and the National Institutes of Health (PubMed) using the following descriptors and Boolean operators: (["tuberculosis"] AND (["children"] OR ["adolescent"]) AND ["rheumatic diseases"] AND (["tumor necrosis factor-alpha"] OR ["etanercept"] OR ["adalimumab"] OR ["infliximab"] OR ["biological drugs"] OR ["rituximab"] OR ["belimumab"] OR ["tocilizumab"] OR ["canakinumab"] OR ["golimumab"] OR ["secukinumab"] OR ["ustekinumab"] OR ["tofacitinib"] OR ["baricitinib"] OR ["anakinra"] OR ["rilonacept"] OR ["abatacept"]), between January 2010 and October 2021. DATA SYNTHESIS: Thirty-seven articles were included, with the total number of 36,198 patients. There were 81 cases of latent tuberculosis infection (LTBI), 80 cases of pulmonary tuberculosis (PTB), and four of extrapulmonary tuberculosis (EPTB). The main rheumatic disease was juvenile idiopathic arthritis. Among LTBI cases, most were diagnosed at screening and none progressed to TB disease during follow-up. Of the TB cases using biologics, most used tumor necrosis factor-alpha inhibitors (anti-TNFα) drugs. There was only one death. CONCLUSIONS: The study revealed a low rate of active TB in pediatric patients using biologic therapy. Screening for LTBI before initiating biologics should be done in all patients, and treatment, in cases of positive screening, plays a critical role in preventing progression to TB disease.

Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis.

The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single-nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.

Apoptosis induction of essential oils from Artemisia arborescens L. in human prostate cancer cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Prostate cancer originates from cells inside a gland, which begin to grow out of control. In the world, prostate cancer is the most common cancer in the male population. New therapeutic strategies are needed for this tumor which still has a high mortality. A. arborescens leaves and aerial parts have various ethnopharmacological uses such as anti-spasmodic, and their decoctions were used to resolve urticaria, neuralgia and several lung diseases. Often this species has been also used to treat different inflammatory-related diseases such as cancer. AIM OF THE STUDY: In a continuation of our research on essential oils from medicinal plants, we have selected, two essential oils from Artemisia arborescens L. (Compositae), an aromatic shrub widely used in traditional medicine. We evaluated their pro-apototic effect on androgen-sensitive (LNCaP) and androgen-insensitive (DU-145) human prostate cancer cells. In this study, we also evaluated the anti-Signal transducer and transcription factor 3 (STAT-3) activity of both essential oils in the human prostate cancer cell lines, and the treatment with Tumor necrosis factor (TNF)-Related Apoptosis (TRAIL). MATERIALS AND METHODS: The cells were exposed to essential oils for 72 h and cell viability and cell membrane integrity were evaluated. Genomic DNA and the activity of caspase-3 was tested to confirm the cell death for apoptosis. Western blot analysis was employed to evaluate the expression of Bcl-2, Bax, cleaved caspase-3, cleaved caspase-9, Hsp70, STAT-3 and SOD proteins. Assays to evaluate reactive oxygen species (ROS) and GSH levels were also performed. RESULTS: The results showed the capacity of two essential oils to activate an apoptotic process increasing the inhibition of Hsp70 and STAT-3 protein expression. In addition, our natural products sensitize LNCaP cells to Tumor necrosis factor (TNF)-Related Apoptosis (TRAIL)-induced apoptosis. CONCLUSIONS: In summary, our study provides a further contribution to the hypothesis of the use of essential oils, from traditional medicinal plants, for the treatment of tumors, and suggests that the combination of our samples with other anti-prostate cancer therapies could be used to affect prostate cancer.

Raw Lacquer Extract from Toxicodendron vernicifluum in Combination with ONC201 Enhances the Inhibitory Effects on Colorectal Cancer Cell Activity.

BACKGROUND: The purpose of the present research was to explore the therapeutic impact of raw lacquer extract from Toxicodendron vernicifluum on colorectal cancer cells and to investigate the outcome of raw lacquer extract and ONC201 co-treatment on the activity of colorectal cancer cells. METHODS: The cells of HCT116 were treated with raw lacquer extract, ONC201, or co-treatment. Subsequently, MTT, trypan blue staining, colony formation, annexin V/propidium iodide staining, wound healing, and transwell assays were performed to assess the effects of raw lacquer extract, ONC201 and the synthesis effect of co-treatment on cell activity, survival, proliferation, apoptosis, migration, and invasion in HCT116 cells. Western blotting and immunostaining assay were also performed to detect the expressions of tumor necrosis factor-related apoptosis-inducing ligand, death receptor-5, cleaved caspase-8, p-mTOR/mTOR, and p-S6K/S6K in cells. RESULTS: The results showed that ONC201 and raw lacquer extract had effective anti-cancer effects on HCT116 cells. ONC201 and raw lacquer extract treatment on colorectal cancer cells inhibited cell viability and growth, as well as induced cell apoptosis and cell death of HCT116. The migration and invasion of HCT116 cells were also inhibited. Significantly, raw lacquer extract and ONC201 cotreatment further enhanced the anti-colorectal cancer cell activity in HCT116 cells. Western blotting and immunostaining assay showed that raw lacquer extract in combination with ONC201 induced tumor necrosis factor-related apoptosis-inducing ligand/death receptor-5 expression activation, inhibited the expression of cleaved caspase-8/procaspase-8, and reduced the expression of p-mTOR/mTOR and p-S6K/S6K. CONCLUSION: These results indicated that raw lacquer extract in combination with ONC201 enhanced the inhibitory effects on colorectal cancer cell activity.

A single-center randomized controlled study of intraperitoneal hyperthermic chemoperfusion in combination of recombinant human tumor necrosis factor (TNF) in treatment of malignant ascites caused by advanced abdominal cancers.

INTRODUCTION: Malignant peritoneal effusion is a common complication of advanced malignancies, which has a poor prognosis for patients. Hyperthermic intraperitoneal chemotherapy (HIPEC) has been widely used in the treatment of advanced gynecological tumors, especially ovarian cancer (OC). Relative studies have indicated that HIPEC allows for direct exposure of tumor cells to high peritoneal concentrations of cytotoxic drugs without increasing systemic toxicity compared with intravenous treatment. Recombinant human tumor necrosis factor for injection (rmhTNF-NC) is a safely tolerated immunotherapeutic drug that has becoming a mainstay of treatment for malignant effusions. Currently, a prospective study is required to determining the efficacy of rmhTNF-NC plus cisplatin for the treatment of malignant peritoneal effusion for OC. METHODS: Design and setting: This is a single-center, open trial will be performed in Zhongshan Affiliated Hospital, Guangzhou University of Chinese Medicine. PARTICIPANTS: Eligible patients will be those with advanced gynecologic cancers and who would be suitable for HIPEC. INTERVENTION AND CONTROL: HIPEC with cisplatin and intraperitoneal perfusion with rmhTNF-NC. COINTERVENTIONS: Further chemotherapy will be offered to patients as per current practice.OutcomesPilot study: Patients and clinicians' acceptability of the trial to assist in optimization of recruitment.Primary outcome: One-year overall survival (OS).Secondary outcomes: Progression-free survival (PFS), adverse events.Follow-up: One-year follow-up for OS.Sample size: Twenty patients to demonstrate therapeutic effect of peritoneal effusion caused by OC. DISCUSSION: This trial will determine the effectiveness of HIPEC with cisplatin and intraperitoneal perfusion with rmhTNF-NC for advanced gynecologic cancers, and guide the optimal treatment for these patients.

Intercellular Communication Reveals Therapeutic Potential of Epithelial-Mesenchymal Transition in Triple-Negative Breast Cancer.

(1) Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high intra-tumoral heterogeneity. The epithelial-mesenchymal transition (EMT) is one of the inducers of cancer metastasis and migration. However, the description of the EMT process in TNBC using single-cell RNA sequencing (scRNA-seq) remains unclear. (2) Methods: In this study, we analyzed 8938 cellular gene expression profiles from five TNBC patients. We first scored each malignant cell based on functional pathways to determine its EMT characteristics. Then, a pseudo-time trajectory analysis was employed to characterize the cell trajectories. Furthermore, CellChat was used to identify the cellular communications. (3) Results: We identified 888 epithelium-like and 846 mesenchyme-like malignant cells, respectively. A further pseudo-time trajectory analysis indicated the transition trends from epithelium-like to mesenchyme-like in malignant cells. To characterize the potential regulators of the EMT process, we identified 10 dysregulated transcription factors (TFs) between epithelium-like and mesenchyme-like malignant cells, in which overexpressed forkhead box protein A1 (FOXA1) was recognized as a poor prognosis marker of TNBC. Furthermore, we dissected the cell-cell communications via ligand-receptor (L-R) interactions. We observed that tumor-associated macrophages (TAMs) may support the invasion of malignant epithelial cells, based on CXCL-CXCR2 signaling. The tumor necrosis factor (TNF) signaling pathway secreted by TAMs was identified as an outgoing communication pattern, mediating the communications between monocytes/TAMs and malignant epithelial cells. Alternatively, the TNF-related ligand-receptor (L-R) pairs showed promising clinical implications. Some immunotherapy and anti-neoplastic drugs could interact with the L-R pairs as a potential strategy for the treatment of TNBC. In summary, this study enhances the understanding of the EMT process in the TNBC microenvironment, and dissections of EMT-related cell communications also provided us with potential treatment targets.

Antidyslipidemic, Antioxidant, and Anti-inflammatory Effects of Jelly Drink Containing Polyphenol-Rich Roselle Calyces Extract and Passion Fruit Juice with Pulp in Adults with Dyslipidemia: A Randomized, Double-Blind, Placebo-Controlled Trial.

Oxidative stress and inflammation play key roles in the pathophysiology in the pathophysiology of dyslipidemia, which are positive risks that increase atherosclerosis leading to important healthcare problems. Therefore, we aimed to study the antioxidant, anti-inflammatory, and lipid-lowering effects of jelly drink containing polyphenol-rich roselle calyces extract and passion fruit juice with pulp concentrate (RP jelly drink) in comparison to a placebo jelly drink for 8 weeks. Forty-three adults with dyslipidemia were randomly assigned into two groups: the RP jelly drink group and the placebo group. Glucose, total cholesterol (TC) triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), oxidative stress biomarkers, inflammatory parameters, and monocyte chemotactic protein-1 (MCP-1) were measured with fasting blood samples at baseline, 4 weeks and 8 weeks of intervention. Results showed a significant decrease in LDL-C and TG, respectively, after 8 weeks of RP jelly drink consumption (LDL-C: 107.63 ± 22.98 mg/dL; TG: 109.79 ± 38.83 mg/dL) compared to baseline measurements (LDL-C: 128.43 ± 32.74 mg/dL; TG: 132.33 ± 75.11 mg/dL). These may be possible due to reduced inflammation and improvements in oxidative stress, as demonstrated by the reduction of tumor necrosis factor- (TNF-) α and malondialdehyde (MDA), and the enhancement of glutathione (GSH) after consuming the RP jelly drink for 8 weeks. However, no significant differences of treatment on glucose, total cholesterol, MCP-1, interleukin-6, and interleukin-10 were observed. In conclusion, daily consumption of RP jelly drink for 8 weeks resulted in significant improvement in lipid profiles in subjects with dyslipidemia. However, more research is needed to assess its nutritional and functional potential.

Didymin Alleviates Cerebral Ischemia-Reperfusion Injury by Activating the PPAR Signaling Pathway.

PURPOSE: Cerebral ischemia-reperfusion (IR) injury is a severe secondary injury induced by reperfusion after stroke. Didymin has been reported to have a protective effect on intracerebral hemorrhage. However, the underlying mechanism of didymin on regulating cerebral IR injury remains largely unknown. MATERIALS AND METHODS: A rat cerebral IR model and oxygen-glucose deprivation/reperfusion (OGD/R) model in PC12 cells were established. Hematoxylin and eosin (H&E) was used to detect the pathological changes in brain tissues, and TUNEL staining was performed to detect apoptosis of brain tissues. MTT and flow cytometry were used to measure the viability and apoptosis of PC12 cells. QRT-PCR and western blot were used to detect inflammation cytokines in PC12 cells. Western blot was used to measure the expression of PPAR-γ, RXRA, Bax, c-caspase-3, and Bcl-2. RESULTS: Didymin pretreatment decreased apoptotic rates, reduced levels of Bax and c-caspase-3, and increased Bcl-2 level in vivo and in vitro. Additionally, didymin pretreatment increased viability and decreased the inflammation levels [interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, and monocyte chemotactic protein (MCP)-1] of OGD/R treated PC12 cells. Moreover, didymin activated the peroxisome proliferator-activated receptors (PPAR) signaling pathway and increased the expression of PPAR-γ and RXRA in OGD/R treated PC12 cells. Inhibition of PPAR-γ eliminated the protective effect of didymin on OGD/R treated cells. CONCLUSION: Didymin protected neuron cells against IR injury in vitro and in vivo by activation of the PPAR pathway. Didymin may be a candidate drug for IR treatment.

Network Pharmacology-Integrated Molecular Docking Reveals the Expected Anticancer Mechanism of Picrorhizae Rhizoma Extract.

This study sought to explore the anticancer mechanism of Picrorhizae Rhizoma (PR) extract based on network pharmacology and molecular docking. The potential chemicals of PR were screened through the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and relevant literatures. Corresponding targets of active ingredients were found with the help of the UniProtKB database, and therapeutic targets for cancer action were screened with the help of the GeneCards database. We used Cytoscape software to construct the compound-target-pathway network of PR extract. We utilized the STRING database to obtain the protein-protein interaction (PPI) network. We used DAVID database combining Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Finally, molecular docking was employed for initial efficacy checking. We have identified 16 potential active components of PR through screening, involving 112 disease action targets. Utilizing the GeneCards database, 112 intersecting targets between PR extract and cancer were found, which mainly exerts anticancer effects by regulating tumor necrosis factor (TNF), recombinant caspase 3 (CASP3), c-Jun NH2-terminal kinase (JNK)/JUN, epidermal growth factor receptor (EGFR), and estrogen receptor-1 (ESR1) with some other target genes and pathways associated with cancer. The major anticancer species are prostate cancer, colorectal cancer, small cell lung cancer, etc. In the molecular docking study, herbactin had a strong affinity for TNF. Based on network pharmacology and molecular docking studies, PR and their compounds have demonstrated potential anticancer activities against several key targets. Our preliminary findings provide a strong foundation for further experiments with PR constituents.

From Hair to Colon: Hair Follicle-Derived MSCs Alleviate Pyroptosis in DSS-Induced Ulcerative Colitis by Releasing Exosomes in a Paracrine Manner.

Ulcerative colitis (UC) has attracted intense attention due to its high recurrence rate and the difficulty of treatment. Pyroptosis has been suggested to be crucial in the development of UC. Although mesenchymal stem cells (MSCs) are broadly used for UC therapy, they have rarely been studied in the context of UC pyroptosis. Hair follicle-derived MSCs (HFMSCs) are especially understudied with regard to UC and pyroptosis. In this study, we aimed to discover the effects and potential mechanisms of HFMSCs in UC. We administered HFMSCs to dextran sulfate sodium- (DSS-) treated mice and found that the HFMSCs significantly inhibited pyroptosis to alleviate DSS-induced UC. A transwell system and GW4869, an exosome inhibitor, were used to prove the paracrine mechanism of HFMSCs. HFMSC supernatant reduced pyroptosis-related protein expression and promoted cell viability, but these effects were attenuated by GW4869, suggesting a role for HFMSC-released exosomes (Exos) in pyroptosis. Next, Exos were extracted and administered in vitro and in vivo to explore their roles in pyroptosis and UC. In addition, the biodistribution of Exos in mice was tracked using an imaging system and immunofluorescence. The results suggested that Exos not only improved DSS-induced pyroptosis and UC but also were internalized into the injured colon. Furthermore, the therapeutic efficacy of Exos was dose dependent. Among the Exo treatments, administration of 400 µg of Exos per mouse twice a week exhibited the highest efficacy. The differentially expressed miRNAs (DEmiRNAs) between MSCs and MSC-released Exos suggested that Exos might inhibit pyroptosis through tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) signalling and interferon- (IFN-) gamma pathways. Our study reveals that HFMSCs can alleviate pyroptosis in UC by releasing DEmiRNA-containing Exos in a paracrine manner. This finding may lead to new treatments for UC.

Fructus ligustri lucidi suppresses inflammation and restores the microbiome profile in murine colitis models.

BACKGROUND: Ulcerative colitis (UC) is pathologically characterized by an inappropriate immune response to the gut commensal microbes accompanied by persistent epithelial barrier dysfunction, and its progression increases the susceptibility to colitis-associated cancer (CAC), as well as other complications. Fructus ligustri lucidi (FLL) has a long historical application in traditional Chinese medicine due to its various pharmacological effects, including antioxidation and anti-inflammation. The present study aimed to explore the molecular and cellular mechanisms of FLL in treating colitis. METHODS: A high-performance liquid chromatography (HPLC) combined with ultraviolet (UV) was performed to validate the quality of FLL; Network pharmacology analysis and weighted gene co-expression network analysis (WGCNA) based on The Cancer Genome Atlas (TCGA) database predicted the therapeutic value of FLL against UC and CAC; 2% dextran sodium sulfate (DSS) was administered to mice to establish murine models of experimental colitis, and FLL was given for the next 14 days at different concentrations; 16S rRNA sequencing and untargeted metabolomics were performed on fecal samples to delineate the alteration in microbiome profile; Western blotting, flow cytometry, and immunocytochemistry experiments were conducted to confirm the predicted cellular mechanisms. RESULTS: Network pharmacology analysis and WGCNA predicted that the targets of the FLL were associated with the progression of UC and the survival of patients with colorectal cancer by regulating tumor necrosis factor (TNF) and IL-17 signaling pathways, immune cell functions, responses to bacterial and reactive oxygen species (ROS), and cell proliferation. In vivo experiments corroborated that the high dose of FLL significantly attenuated the progression of experimental colitis by reversing the weight loss and bloody stool, reconstructing the integrity of colorectal epithelium, and suppressing the concentration of pro-inflammatory cytokines. Moreover, FLL treatment reduced the transition of macrophages (Mφs) to the proinflammatory phenotype and promoted Mφs-regulated wound healing, and suppressed the production of ROS in intestinal organoids (IOs) and crypts. 16S rRNA and untargeted metabolomics showed that the administration of FLL inhibited DSS-caused colonization of the potentially pathogenic gut microorganisms and reversed DSS-influenced metabolic profile. CONCLUSION: FLL is a potent anti-colitis drug by suppressing inflammation and rescuing dysbiosis.

Carvacrol preserves antioxidant status and attenuates kidney fibrosis via modulation of TGF-ß1/Smad signaling and inflammation.

Chronic kidney disease (CKD) with diverse aetiologies is emerging as a challenging kidney disorder associated with inflammation and interstitial fibrosis. Carvacrol (CVL) is a bioactive monoterpenoid found abundantly in oregano, thyme, and bergamot, having diverse pharmacological benefits. However, the effect of CVL against fibrotic changes in the kidneys is poorly defined. In the current study, a robust mouse model of renal fibrosis induced through unilateral ureteral obstruction (UUO) is used to investigate the anti-fibrotic activity of CVL. The mice were treated with two different oral doses of CVL (25 mg kg-1 and 50 mg kg-1 body weight) for 14 consecutive days. The UUO induction resulted in impaired renal function, severe histological damage, and collagen deposition in the obstructed kidney. Our findings revealed profound activation of transforming growth factor-ß1 (TGF-ß1) and NF-κB (p65) signaling along with the downregulation of antioxidant proteins, nuclear factor-erythroid factor 2-related factor 2 (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO1), and superoxide dismutase (SOD) in the obstructed kidney. CVL administration markedly recovered antioxidant proteins and kidney histological changes. In addition, CVL blunted the NF-κB (p65) phosphorylation and reduced the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and cyclooxygenase 2 (COX-2) compared to the UUO control group. CVL also alleviated the increased fibrotic protein levels of TGF-ß1, pSmad2/3, collagen I, collagen III, fibronectin, and myofibroblast activation and epithelial-mesenchymal transition (EMT) markers, including alpha-smooth muscle actin (α-SMA), E-cadherin, and vimentin in the kidneys. Findings from in vitro study also confirmed that CVL inhibits the EMT process in TGF-ß1 stimulated renal tubular epithelial cells (NRK 52E cells). Collectively, our findings indicate that CVL administration attenuates kidney fibrosis by targeting oxidative stress and inflammation.

ß-Caryophyllene, a Dietary Cannabinoid, Protects Against Metabolic and Immune Dysregulation in a Diet-Induced Obesity Mouse Model.

Obesity is an abnormal or excessive accumulation of fat in the body that exacerbates metabolic and inflammatory processes, and impairs the health of afflicted individuals. ß-caryophyllene is a natural sesquiterpene that is a dietary cannabinoid with anti-inflammatory properties and potential activity against metabolic diseases. In the present study, we evaluated the effect of ß-caryophyllene on C57BL/6 mice using a diet-induced obesity model. Male mice were randomly assigned to the following groups over a 16-week period: (1) standard diet as lean control, (2) high-fat diet (HFD) as obese control, and (3) HFD + ß-caryophyllene with ß-caryophyllene at 50 mg/kg. Treatment with ß-caryophyllene improved various metabolic parameters including increased total body weight, fasting glucose levels, oral-glucose tolerance, insulin tolerance, fasting triglycerides, adipocyte hypertrophy, and liver macrovesicular steatosis. ß-caryophyllene also modulated the levels and expression of immune response factors including adiponectin, leptin, insulin, interleukin-6, tumor necrosis factor-a, and Toll-like receptor-4. Our data indicate that chronic supplementation with ß-caryophyllene can improve relevant metabolic and immunological processes in obese mice. This protocol was approved by the Institutional Committee for Care and Use of Laboratory Animals from the University of Guadalajara with protocol code CUCEI/CINV/CICUAL-01/2022.

Clinical outcomes of patients with COVID-19 and inflammatory rheumatic diseases receiving biological/targeted therapy.

BACKGROUND: Anti-cytokine treatments are used in the treatment of severe COVID-19. Other studies have shown statistical significance with TNF inhibitors but not with other biological/targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARD). OBJECTIVES: Compare the rate of severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) infection and the course and incidence of COVID-19 infection in patients who received b/tsDMARD with control patients. DESIGN: Analytical cross-sectional SETTINGS: Tertiary care hospital PATIENTS AND METHODS: All patients who applied to the rheumatology outpatient clinic between June 2020-March 2021 and received b/tsDMARD were included in the study. All patients with rheumatoid arthritis, psoriatic arthritis and spondyloarthritis who applied to the rheumatology outpatient clinic in the three months before March 2021 and did not receive b/tsDMARD were included as the control group. History of COVID-19 infection and treatments were recorded. Multivariate analysis was performed to assess factors associated with use of tumor necrosis factor (TNF) inhibitors and differences between specific biologic drugs. MAIN OUTCOME MEASURES: Rate of COVID-19 disease among patients using biological/targeted synthetic therapy and non-biological/targeted synthetic therapy. COVID-19 clinical outcomes (hospitalization, intensive care admission, mechanical ventilation and death). SAMPLE SIZE: 533 in total; 341 received b/tsDMARD, 212 in the control group that did not receive b/tsDMARD. RESULTS: One hundred patients (18%) had been infected with SARS-COV-2. The difference in SARS-COV-2 infection between b/tsDMARD and the control was statistically significant (13, 2% vs. 25, 9%, respectively) (P<.001). The hospital stays were longer in the controls (P<.001). Multinomial regression analysis revealed that COVID-19 negative patients were more likely to use tumor necrosis factor (TNF) inhibitors (OR: 2, 911; 95% CI: 1.727-4.908; P<.001) compared to COVID-19 positive participants. Multinomial logistic regression analysis indicated that hospitalized patients were more likely to use TNF inhibitors (OR: 11, 006; 95% CI: 3.447-35.138; P<.001) and there was no significant difference between b/tsDMARDs other than TNF inhibitors in frequency of hospitalization. CONCLUSIONS: Patients who were medicated with b/tsDMARD were less likely to be infected with COVID-19 and be hospitalized due to the infection. We have found that this effect was particularly dependent on the use of TNF inhibitors. LIMITATIONS: Conducted in a single center and unable to provide a homogeneous study population. CONFLICT OF INTEREST: None.

CTRP3 protects hippocampal neurons from oxygen-glucose deprivation-induced injury through the AMPK/Nrf2/ARE pathway.

OBJECTIVE: C1q/TNF-related protein 3 (CTRP3), a member of CTRP family, has been found to have neuroprotective effect. In the current study, we investigated the protective role of CTRP3 in hippocampal neurons exposed to oxygen-glucose deprivation/reperfusion (OGD/R). MATERIALS AND METHODS: The mRNA and protein levels of CTRP3 in OGD/R-stimulated hippocampal neurons were measured using qRT-PCR and western blot analysis, respectively. CCK-8 assay was performed to assess cell viability. ROS production was measured using the fluorescence probe 2',7'-dichlorofluorescein diacetate (H2DCFDA). The activities of SOD and GPx were determined using ELISA. Cell apoptosis was assessed. Luciferase reporter assay was carried out to assess the activation of ARE). The levels of p-AMPK and Nrf2 were measured using western blot. RESULTS: Our results showed that the expression of CTRP3 was significantly downregulated in hippocampal neuronal cells exposed to OGD/R. Overexpression of CTRP3 improved cell viability of OGD/R-induced hippocampal neurons. In addition, overexpression of CTRP3 attenuated the OGD/R-caused oxidative stress with decreased ROS production and increased activities of SOD and GPx. Moreover, CTRP3 caused a significant increase in bcl-2 expression and decreases in bax expression and caspase-3 activity. Furthermore, CTRP3 overexpression significantly upregulated the levels of p-AMPK and Nrf2, as well induced the activation of ARE in OGD-R-induced hippocampal neurons. CTRP3 upregulated the mRNA expression levels of HO-1, NQO-1 and GPx-3. Additionally, treatment with the inhibitor of AMPK partially reversed the neuroprotective effect of CTRP3 in OGD/R-exposed neurons. CONCLUSION: CTRP3 exerted protective effect on OGD/R-induced cerebral injury, which was regulated by AMPK/Nrf2/ARE pathway.

Association between Antiretroviral Treatment and Markers of Systemic Inflammation among HIV Patients in Ghana.

BACKGROUND: Studies from high-income countries have reported that even after receiving antiretroviral treatment (ART), HIV-infected adults may not achieve normal levels of certain inflammatory markers that are known to be associated with the onset and development of non-communicable diseases. OBJECTIVE: The aim of this study is to examine the relationship between ART and markers of systemic inflammation in HIV/AIDS patients at an urban antiretroviral clinic in Ghana. METHODS: We examined serum levels of high sensitivity CRP (hsCRP), interleukin-6 (IL-6), interleukin- 18(IL-18), and tumor necrosis factor-α (sTNFR1 and sTNFR2) from 40 HIV infected patients. Kruskal-Wallis Test was used to examine the differences in markers of systemic inflammation according to the types of ART medication taken. We then utilized generalized additive models (GAM) with non-linear function to examine the association between ART and markers of systemic inflammation after adjusting for potential confounders. RESULTS: Overall, 30 (75.0%) of the participants received ART and 35 (85%) were female. Kruskal- Wallis Test revealed no significant differences in the markers of systemic inflammation among the three categories of ART (none, AZT, 3TC, EFV/NVP, and TDF, 3TC/FTC, EFV/NVP). In the multivariable- adjusted GAM model, we found a significant but non-linear association between time since diagnosis and CRP levels (p=0.006). CONCLUSION: Although the relatively small sample size limits the scope of the study's findings, these results suggest that individuals on ART need to be screened periodically for the development of chronic conditions. This line of investigation has the potential to influence treatment and clinical guidelines that will improve the quality of care for HIV-infected patients.

Artritis Idiopática Juvenil: manifestaciones clínicas y tratamiento / Juvenile Idiopathic Arthritis: clinical manifestation and treatment

Resumen La Artritis Idiopática Juvenil es la enfermedad reumática más frecuente en niños. Es una enfermedad crónica, degenerativa y de etiología desconocida; que puede dejar múltiples secuelas en la población pediátrica. Consta de siete afecciones definidas por la International League of Associations for Rheumatology del 2001: Artritis Sistémica, Oligoartritis, Artritis con Factor Reumatoide positivo o Factor Reumatoide negativo, Artritis relacionada a entesitis, Artritis psoriasica y Artritis indiferenciada; distintas tanto en el aspecto clínico, patogénico como evolutivo. Esta enfermedad se caracteriza por una alteración de la regulación del sistema inmunitario innato con una falta de linfocitos T autorreactivos y autoanticuerpos. La inflamación continua estimula el cierre rápido y prematuro del cartílago de crecimiento provocando un acortamiento óseo. Para llegar a su diagnóstico no se requiere más que una buena historia clínica y examen físico, ya que no hay laboratorios o gabinete lo bastante sensible que nos puedan ayudar. Fármacos como el metrotexate y los inhibidores del factor de necrosis tumoral han venido a modificar la evolución de la enfermedad y mejorar la calidad de vida de estos pacientes.

Abstract Juvenile idiopathic arthritis is the most common rheumatic disease in children. It is a chronic and degenerative disease, with an unknown etiology; that can leave multiple sequels in the pediatric population. There are seven conditions defined by 2001 International League of Associations for Rheumatology: Systemic Arthritis, Oligoarthritis, Arthritis with positive rheumatoid factor or negative rheumatoid factor, enthesitis-related arthritis and undifferentiated arthritis; distinct in clinical, pathogenetic and evolutionary aspects. This disease is characterized by an alteration on the regulation of the innate immune system with a lack of autoreactive lymphocytes T and autoantibodies. Continuous inflammation stimulates the rapid and premature closure of the growth cartilage causing bone shortening. To arrive at the diagnosis, it is only necessary to have a good medical history and physical exam, since there are no laboratory test sensitive enough to help us. Drugs such as methotrexate and tumor necrosis factor inhibitors have come to modify the evolution of the disease and improve the quality of life of these patients.

Tumour necrosis factor superfamily members in ischaemic vascular diseases.

Current treatment of ischaemic vascular diseases such as coronary and peripheral artery disease includes angioplasty and bypass grafting, as well as lipid lowering therapies and control of other cardiovascular risk factors. Numerous members of the tumour necrosis factor superfamily (TNFSF) have recently shown emerging roles in both the protection and progression of such diseases. Understanding the role TNFSF members play in ischaemic vascular disease may provide insight into the development of novel therapeutics to prevent or treat diseases relating to atherosclerosis and ischaemia. This review summarizes the most recent findings relating to TNFSF members and the mechanisms that precede ischaemic vascular disease progression, particularly endothelial dysfunction, chronic inflammation, and atherosclerotic plaque development. This review also explores recent translational research on the role of TNFSF therapies in cardiovascular disease.

CTRP3 attenuates high-fat diet-induced male reproductive dysfunction in mice.

Recent studies have suggested a role for abdominal obesity in male infertility. Previous studies have found that cell apoptosis exerts an important role in obesity-related male infertility. C1q/TNF-related protein 3 (CTRP3), a paralog of adiponectin, has been proposed to exert anti-apoptotic effects and to attenuate diabetes-related cardiac injuries. However, the role of CTRP3 in high-fat diet (HFD)-induced spermatogenic impairment remains unclear. In the present study, we fed male mice an HFD for 24 weeks to induce obesity. The expression of CTRP3 was decreased by HFD feeding. Supplementation with the recombinant human globular domain of CTRP3 (0.25 µg/g/day) for 4 weeks beginning at 20 weeks of the HFD improved spermatogenic function in the HFD-fed mice, which were characterized by improved testis morphology, increased testis weight/body weight ratio, and increased sperm count, sperm viability, and sperm motility. We also found that CTRP3 infusion resulted in the attenuation of endoplasmic reticulum (ER) stress and the activation of silence information regulator 1 (SIRT1) in the testes of obese mice. Our in vitro study also suggested that CTRP3 attenuated the palmitic acid (PA)-induced reductions in sperm viability and motility via the inhibition of ER stress. Moreover, germ cell-specific Sirtuin1 knockout abolished the protective effects of CTRP3 in vivo and in vitro. In vitro studies of human sperm showed that the protective effects of CTRP3 on sperm viability and motility were abrogated by a specific inhibitor of SIRT1. Thus, our results demonstrated that CTRP3 expression protected against HFD-induced spermatogenic deficiency through the SIRT1/ER stress pathway.