Severe Inflammatory Response Research Articles

SARS-CoV-2 Omicron (B.1.1.529) infection in rhesus macaques, hamsters, and BALB/c mice with severe lung histopathological damage.

Since the first SARS-CoV-2outbreak in late 2019, the SARS-CoV-2genome has harbored multiple mutations, especially spike protein mutations. The currently fast-spreading Omicron variant that manifests without symptoms or with upper respiratory diseases has been recognized as a serious global public health problem. However, its pathological mechanism is largely unknown. In this work, rhesus macaques, hamsters, and BALB/Cmice were employed as animal models to explore the pathogenesis of Omicron (B.1.1.529). Notably, Omicron (B.1.1.529) infected the nasal turbinates, tracheae, bronchi, and lungs of hamsters and BALB/Cmice with higher viral loads than in those of rhesus macaques. Severe histopathological damage and inflammatory responses were observed in the lungs of Omicron (B.1.1.529)-infected animals. In addition, viral replication was found in multiple extrapulmonary organs. Results indicated that hamsters and BALB/cmice are potential animal models for studies on the development of drugs/vaccines and therapies for Omicron (B.1.1.529).

A comprehensive analysis of systematically screened laboratory tests: based on a COVID-19 cohort.

The study aimed at screening indicators with differential diagnosis values and investigating the characteristics of laboratory tests in COVID-19 patients. All the laboratory tests from COVID-19 patients and non-COVID-19 patients in this cohort were included. Test values from the groups during the course, days 1-7, and days 8-14 were analyzed. Mann-Whitney U test, univariate logistic regression analysis, and multivariate regression analysis were performed. Regression models were established to verify the diagnostic performance of indicators. 302 laboratory tests were included in this cohort, and 115 indicators were analyzed; the values of 61 indicators had significant differences (p < 0.05) between groups, and 23 indicators were independent risk factors of COVID-19. During days 1-7, the values of 40 indicators had significant differences (p < 0.05) between groups, while 20 indicators were independent risk factors of COVID-19. During days 8-14, the values of 45 indicators had significant differences (p < 0.05) between groups, and 23 indicators were independent risk factors of COVID-19. About 10, 12, and 12 indicators showed significant differences (p < 0.05) in multivariate regression analysis in different courses respectively, and the diagnostic performance of the model from them was 74.9%, 80.3%, and 80.8% separately. The indicators obtained through systematic screening have preferable differential diagnosis values. Compared with non-COVID-19 patients, the screened indicators indicated that COVID-19 patients had more severe inflammatory responses, organ damage, electrolyte and metabolism disturbance, and coagulation disorders. This screening approach could find valuable indicators from a large number of laboratory test indicators.

Dual modes reinforced silk adhesives for tissue repair: Integration of textiles and inorganic particles in silk gel for enhanced mechanical and adhesive strength

Skin wound healing in dynamic environments remains challenging. Conventional gels are not ideal dressing materials for wound healing due to difficulties in completely sealing wounds and the inability to deliver drugs quickly and precisely to the injury. To tackle these issues, we propose a multifunctional silk gel that rapidly forms strong adhesions to tissue, has excellent mechanical properties, and delivers growth factors to the wound. Specifically, the presence of Ca2+ in the silk protein leads to a solid adhesion to the wet tissue through a chelation reaction with water-trapping behavior; the integrated chitosan fabric and CaCO3 particles ensure enhanced mechanical strength of the silk gel for better adhesion and robustness during wound repair; and the preloaded growth factor further promoted wound healing. The results showed the adhesion and tensile breaking strength were as high as 93.79 kPa and 47.20 kPa, respectively. MSCCA@CaCO3-aFGF could remedy the wound model in 13 days, with 99.41 % wound shrinkage without severe inflammatory responses. Due to strong adhesion properties and mechanical strength, MSCCA@CaCO3-aFGF can be a promising alternative to conventional sutures and tissue closure staples for wound closure and healing. Therefore, MSCCA@CaCO3-aFGF is expected to be a strong candidate for the next generation of adhesives.

The Protective Rolls of Taraxacum officinale against Carbone Tetrachloride Infarction in the Liver

Carbon tetrachloride (CCl4) is a liquid that is colorless, transparent, inflammable, and volatile. Its central carbon atom is surrounded by four Cl- atoms. As a result, the objective of this effort was to estimate the anti-oxidant properties of silver nanoparticles (AgNPs) made utilizing aqueous plant extracts from Taraxacum officinale leaves. A green synthesis of AgNPs using a synergistic aqueous extract from T. officinale leaves was tested against liver damage in rats caused by CCl4. The rats were randomly distributed into seven groups: Group 1: Control group, Group 2: Olive oil group, Group 3: AgNPs-treated group (100 mg/kg BW.), Group 4: AgNPs-treated group (200 mg/kg BW.), Group 5: CCl4 + Olive oil group, Group 6: (CCl4 + Olive Oil) + 100 mg/kg of AgNPs-treated group, and Group 7: (CCl4 + Olive oil) + 200 mg/kg of AgNPs-treated group one a week for 6 weeks. This study demonstrated a sustainable method for synthesizing AgNPs utilizing T. officinale leaf (TOL) extract. To characterize the synthesized T. officinale leaf-silver nanoparticles (TOL-AgNPs), various microscopic and spectroscopic methods were used. The effectiveness of the biosynthesized TOL-AgNPs against CCl4 was tested to assess their antioxidant potential. The antioxidant properties of synthetic TOL-AgNPs were also evaluated. Histopathological research showed that all groups treated with nano-extract had less severe inflammatory responses. Our findings demonstrated that AgNPs synthesized using the leaves of T. officinale possess a potential anti-oxidant activity against CCl4-induced liver injury in rats.

COVID-19 musculoskeletal involvement in children.

Since the early phases of the COVID-19 pandemic, it has become clear that children are affected by mild respiratory symptoms rather than the critical pneumonia typical in adults. Nevertheless, it took longer to understand that pediatric patients with SARS-COV2 may develop a severe multisystem inflammatory response (a.k.a. multisystem inflammatory syndrome in children (MIS-C)), which can include musculoskeletal symptoms, and/or arthritis and myositis independently from MIS-C. Diagnostic imaging significantly contributed to the assessment of pulmonary disease due to COVID-19 but it has been rarely applied to evaluate musculoskeletal involvement in children with or without previous rheumatic diseases. Despite the paucity of radiological literature, muscle edema at magnetic resonance and synovitis at ultrasound have been described. Further use of diagnostic imaging for children with articular and muscular symptoms due to COVID-19 is strongly encouraged.

Mesenchymal stem cells transplantation combined with IronQ attenuates ICH-induced inflammation response via Mincle/syk signaling pathway

BackgroundIntracerebral hemorrhage (ICH) is a severe brain-injured disease accompanied by cerebral edema, inflammation, and subsequent neurological deficits. Mesenchymal stem cells (MSCs) transplantation has been used as a neuroprotective therapy in nervous system diseases because of its anti-inflammatory effect. Nevertheless, the biological characteristics of transplanted MSCs, including the survival rate, viability, and effectiveness, are restricted because of the severe inflammatory response after ICH. Therefore, improving the survival and viability of MSCs will provide a hopeful therapeutic efficacy for ICH. Notably, the biomedical applications of coordination chemistry-mediated metal-quercetin complex have been verified positively and studied extensively, including growth-promoting and imaging probes. Previous studies have shown that the iron-quercetin complex (IronQ) possesses extraordinary dual capabilities with a stimulating agent for cell growth and an imaging probe by magnetic resonance imaging (MRI). Therefore, we hypothesized that IronQ could improve the survival and viability of MSCs, displaying the anti-inflammation function in the treatment of ICH while also labeling MSCs for their tracking by MRI. This study aimed to explore the effects of MSCs with IronQ in regulating inflammation and further clarify their potential mechanisms.MethodsC57BL/6 male mice were utilized in this research. A collagenase I-induced ICH mice model was established and randomly separated into the model group (Model), quercetin gavage group (Quercetin), MSCs transplantation group (MSCs), and MSCs transplantation combined with IronQ group (MSCs + IronQ) after 24 h. Then, the neurological deficits score, brain water content (BWC), and protein expression, such as TNF-α, IL-6, NeuN, MBP, as well as GFAP, were investigated. We further measured the protein expression of Mincle and its downstream targets. Furthermore, the lipopolysaccharide (LPS)-induced BV2 cells were utilized to investigate the neuroprotection of conditioned medium of MSCs co-cultured with IronQ in vitro.ResultsWe found that the combined treatment of MSCs with IronQ improved the inflammation-induced neurological deficits and BWC in vivo by inhibiting the Mincle/syk signaling pathway. Conditioned medium derived from MSCs co-cultured with IronQ decreased inflammation, Mincle, and its downstream targets in the LPS-induced BV2 cell line.ConclusionsThese data suggested that the combined treatment exerts a collaborative effect in alleviating ICH-induced inflammatory response through the downregulation of the Mincle/syk signaling pathway following ICH, further improving the neurologic deficits and brain edema.

Combined effects of microplastics and chlortetracycline on the intestinal barrier, gut microbiota, and antibiotic resistome of Muscovy ducks (Cairina moschata)

Antibiotics and microplastics (MPs) have become critical concerns worldwide because of their increasing amount and ecological risks to ecosystems. However, how MPs exposure affects the bioaccumulation and risks of antibiotics in waterfowls remains poorly understood. In this study, Muscovy ducks were exposed to single and combined contamination with polystyrene MPs and chlortetracycline (CTC) for 56 days, and the effects of MPs on CTC bioaccumulation and their risks in duck intestines were investigated. MPs exposure reduced the bioaccumulation of CTC in the intestine and liver of ducks and increased their fecal CTC excretion. MPs exposure caused severe oxidative stress, inflammatory response, and intestinal barrier damages. Microbiome analysis showed that MPs exposure induced microbiota dysbiosis by increasing the abundance of Streptococcus and Helicobacter, the increase of which may exacerbate intestinal damages. Co-exposure to MPs and CTC alleviated the intestinal damage by regulating the gut microbiome. Metagenomic sequencing revealed that the combined exposure to MPs and CTC increased the abundance of Prevotella, Faecalibacterium, and Megamonas and incidence of total antibiotic resistance genes (ARGs), especially tetracycline ARGs subtypes in the gut microbiota. The results obtained herein provide new insights into the potential risks of polystyrene MPs and antibiotics in waterfowls living in aquatic environments.

Genotype 4 Hepatitis E virus replicates in the placenta, causes severe histopathological damage, and vertically transmits to fetuses

Hepatitis E virus (HEV) infection in pregnant women causes adverse pregnancy outcomes, including maternal death, premature delivery, stillbirth, and fetal infection. However, the pathogenesis of maternal and fetal HEV infection is unclear. Placenta and placental appendixes were collected from HEV-4 infected pregnant women to explore the vertical transmission of HEV from mothers to fetuses. HEV-4 replicated in the placenta, placental membrane, and umbilical cord and was vertically transmitted from mothers to fetuses. HEV-4 placental infection resulted in serious histopathological damage, such as fibrosis and calcification, and severe inflammatory responses. Adverse maternal outcomes were observed in 38.5% of HEV-4 infected pregnant women. The distinct cytokine/chemokine expression patterns of HEV-infected pregnant women and nonpregnant women may contribute to the adverse pregnancy outcomes. Furthermore, the impaired maternal and fetal innate immune responses against HEV-4 facilitated viral replication during pregnancy. HEV-4 replicates in the placenta and is vertically transmitted from mothers to fetuses, causing severe histopathological damage.

Involvement of baroreflex deficiency in the age-related loss of estrogen efficacy against cerebral ischemia.

For post-menopausal women, stroke is complicated by the variable effects of estrogen therapy and the age-related therapeutic consequences involved. Estrogen therapy has been shown to have an age-dimorphic effect, which is neuroprotective in young females, but non-neuroprotective, even neurotoxic in acyclic females. We hypothesized that arterial baroreflex (ABR) and its downstream acetylcholine-α7 nicotinic acetylcholine receptor (α7nAChR) anti-inflammatory pathways are involved in estrogen efficacy toward cerebral ischemic damage. Our data showed that estrogen supplements contributed to ABR improvement and neuroprotection in adult, not aged, ovariectomized (OVX) rats. In adult rats, OVX-induced estrogen deficiency aggravated middle cerebral artery occlusion (MCAO), which induced brain infarction and reduced ABR function, with decreased α7nAChR expression of the brain and exaggerated inflammation following MCAO; these effects were significantly prevented by supplementation with estrogen. ABR impairment by sinoaortic denervation partly attenuated the estrogen effect on baroreflex sensitivity (BRS) and ischemic damage in adult rats, as well as α7nAChR expression and inflammatory response. These data suggested that ABR and acetylcholine-α7nAChR anti-inflammatory pathways are involved in the neuroprotection of estrogen in adult OVX rats. In contrast, aged rats exhibited more severe ischemic damage and inflammatory response than adult rats, as well as poorer baroreflex function and lower α7nAChR expression. Estrogen supplements did not improve BRS or confer neuroprotection in aged rats without affecting brain α7nAChR and post-ischemic inflammation. Most importantly, ketanserin restored ABR function and significantly postponed the onset of stroke in aged female strokeprone spontaneously hypertensive rats, whereas estrogen treatment failed to delay the development of stroke. Our findings reveal that estrogen is protective against ischemic stroke (IS) in adult female rats and that ABR played a role in this beneficial action. Dysfunction of ABR and unresponsiveness to estrogen in aged female rats may contribute to a reduced estrogen efficacy against cerebral ischemia.

Hospitalized COVID-19 patients exhibit increased numbers of low density neutrophils expressing the transcription factor ARID3a

Abstract We previously showed that individuals with systemic lupus erythematosus (SLE) and high levels of Type I inflammatory cytokines had increased numbers of low density neutrophils (LDNs) in their peripheral blood compared to healthy donors. Increased numbers of LDNs were associated with increased expression of the transcription factor ARID3a and increased interferon alpha (IFNα) production. Data from other cell types suggest that ARID3a expression occurs upstream of IFNα expression. Therefore, we sought to determine if increases in ARID3a-expressing LDNs might also occur in other severe inflammatory responses, such as infection with SARS-CoV2 where IFNα expression was known to be increased. Subjects admitted to the hospital with a confirmed diagnosis of SARS-CoV2 infection were enrolled in our IRB approved study and peripheral blood mononuclear cells from 24 patients were evaluated via flow cytometry for numbers of LDNs and ARID3a expression at the time of admission and at various time points after hospitalization. Numbers of circulating LDNs were dramatically increased in COVID patient samples at the time of hospitalization, as were percentages of those cells expressing ARID3a protein. IL-6 expression was also high in the LDNs, while IFNα expression was more variable. Over the course of two weeks, IFNα expression appeared to be associated with, or to lag just behind ARID3a expression in most patients, while IL-6 expression levels were not associated with ARID3a or IFNα expression. These data suggest that ARID3a expression is induced in LDNs in association with severe viral infection and may implicate ARID3a as a potential regulator of inflammatory pathways in infection as well as autoimmunity. Supported in part by grant NIH U19 AI06269

Farnesoid X receptor protects against lipopolysaccharide-induced endometritis by inhibiting ferroptosis and inflammatory response

Endometritis is an inflammatory condition that affects the endometrium; it is induced by bacterial infection and often leads to infertility and repeated abortions. FarnesoidXreceptor (FXR) is a member of the nuclear receptor superfamily that mediates a variety of inflammatory diseases. In the present study, we determined the protective effects of FXR on lipopolysaccharide (LPS)-induced endometritis in mice and the underlying mechanisms. The results showed that LPS administration reduced the expression of FXR in the uterus, and treatment with the FXR agonist GW4064 and fexaramine significantly alleviated the endometritis induced by LPS. In addition, compared with wild-type (WT) mice, FXR-knockout mice had more severe inflammatory responses in their uteri after LPS treatment. Moreover, ferroptosis was increased during LPS-induced endometritis, as shown by increased levels of malondialdehyde (MDA) and iron, and decreased levels of superoxide dismutase (SOD), glutathione (GSH), GXP4 and SLC7A11. In addition, inhibition of ferroptosis by treatment with ferrostation-1 (Fer-1) and liproxstatin (Lip-1) alleviated LPS-induced endometritis. Additionally, FXR-knockout mice were used to determine the relationship between FXR and ferroptosis. The results showed that knockout of FXR induced ferroptosis, and an FXR agonist inhibited LPS-induced ferroptosis. Finally, the regulatory effects of obeticholic acid (OCA) on FXR/ferroptosis and endometritis were assessed. The results showed that treatment with OCA increased the expression of FXR, decreased the levels of ferroptosis, and inhibited the endometritis induced by LPS. In conclusion, the results showed that activation of FXR can alleviate LPS-induced endometritis by inhibiting ferroptosis, and FXR may be a potential therapeutic target for treating endometritis.

Role of IgG glycans in severe COVID-19 inflammatory cytokine responses

Abstract Severe COVID-19 and multisystem inflammatory syndrome in children (MIS-C) are characterized by hyperinflammation. Severe COVID in adults is associated with development of afucosylated SARS-CoV-2 IgG that induce monocytes to secrete inflammatory cytokines. This study aimed to analyze the relationship between spike IgG Fc glycosylation and inflammatory markers during acute pediatric COVID or MIS-C or following COVID vaccination in adults. We assessed cross-sectional and longitudinal samples from 195 participants: Adult vaccinees, acute COVID patients, and healthy controls, as well as pediatric acute COVID patients, MIS-C patients, and healthy controls. We developed capillary electrophoresis (CE) methods to analyze bulk and spike IgG Fc glycans and measured ten relevant cytokines/chemokines by multiplexed assay. Analysis of healthy control bulk IgG by CE found 95.3–99.6% fucosylated, 2.7–6.9% bisected, 55.8–66.8% galactosylated, and 4.6–15.6% sialylated Fc glycans, compared to 99.8%, 6.7%, 45.4%, and 8.2% by mass spectrometry, respectively. IFN-γ, IL-10, CXCL10, and CCL3 were significantly increased in MIS-C compared to pediatric healthy controls; IL-10, CCL2, and TNF were only increased in severe adult COVID compared to healthy controls or less severe COVID. Initial results confirmed significantly more afucosylated spike IgG in adult severe COVID than afucosylated bulk IgG in controls. Our high-throughput methods for IgG Fc glycan profiling generated comparable results to mass spectrometry. Continued assessment will determine if COVID- or vaccine-induced spike IgG glycoforms correlate with inflammatory markers. Future mechanistic work will examine how modified glycosylation induces inflammatory cytokines. Supported by an IDCRC New Investigator Pilot Award to E.M.S. (NIH UM1AI148684), by the Centers for Disease Control and Prevention through a cooperative agreement with the Georgia Emerging Infection Program (grant no. U50CK000485), and by grant from NIH to P.A. (R24GM137782).

Hepatoprotective potential of gabapentin in cecal ligation and puncture-induced sepsis; targeting oxidative stress, apoptosis, and NF-kB/MAPK signaling pathways.

Sepsis is a severe inflammatory response to infection with an incidence rate exceeding 48 million cases and 11 million sepsis-related deaths yearly. Furthermore, sepsis remains the fifth most common cause of death worldwide. The present study aimed to examine, for the first time, the potential hepatoprotective activity of gabapentin on cecal ligation and puncture (CLP)-induced sepsis in rats at the molecular level. CLP was used as a model of sepsis in male Wistar rats. Histological examination and liver functions were evaluated. Levels of MDA, GSH, SOD, IL-6, IL-1β, and TNF-α were investigated using ELISA. mRNA levels of Bax, Bcl-2, and NF-kB were assessed by qRT-PCR. Western blotting investigated the expression of ERK1/2, JNK1/2, and cleaved caspase 3 proteins. CLP resulted in liver damage, elevated serum levels of ALT, AST, ALP, MDA, TNF-α, IL-6, and IL-1β, increased expression of ERK1/2, JNK1/2, and cleaved caspase 3 proteins, and upregulated Bax and NF-κB genes expression while it down-regulated Bcl-2 gene expression. However, gabapentin treatment significantly reduced the severity of CLP-induced biochemical, molecular, and histopathological changes. Gabapentin attenuated the levels of the proinflammatory mediators, decreased the expression of JNK1/2, ERK1/2, and cleaved caspase 3 proteins, suppressed Bax and NF-κB genes expression and increased the expression of the Bcl-2 gene. Consequently, Gabapentin reduced hepatic injury resulting from CLP-induced sepsis by reducing proinflammatory mediators, attenuating apoptosis, and inhibiting the intracellular MAPK (ERK1/2, JNK1/2)-NF-kB signaling pathway.

Plasma Cytokine Expression and Immune Reconstitution in Early and Delayed Anti-HIV 96-Weeks Treatment: A Retrospective Study.

HIV is an immunodeficiency disease with emergence of inadequate corresponding reconstruction therapies. Pyroptosis of CD4+T cell is mainly caused by immune activation and inflammation that cannot be reduced by successful antiretroviral therapy (ART) alone. Coinfections because of CD4+T cell reconstitution failure can occur. Anti-inflammatory treatment determines the success of immune reconstitution. In our experiment, only a few cytokines could recover to normal level following a 2-year antiretroviral treatment in early ART initiation, which is consistent with current findings about adjuvant HIV anti-inflammatory therapy. Early infection is often accompanied by a more severe inflammatory response. Innate immunity cytokines like granulocyte macrophage-colony stimulating factor, IFN-γ induced protein 10 kDa, and tumor necrosis factor-α exhibited the most elevated levels among all kinds of inflammatory cytokines. The correlation analysis showed at least eight cytokines contributing to the changes of CD4/CD8 ratio.

Reduced IL-8 Secretion by NOD-like and Toll-like Receptors in Blood Cells from COVID-19 Patients

Severe inflammatory responses are associated with the misbalance of innate and adaptive immunity. TLRs, NLRs, and cytokine receptors play an important role in pathogen sensing and intracellular control, which remains unclear in COVID-19. This study aimed to evaluate IL-8 production in blood cells from COVID-19 patients in a two-week follow-up evaluation. Blood samples were taken at admission (t1) and after 14 days of hospitalization (t2). The functionality of TLR2, TLR4, TLR7/8, TLR9, NOD1, and NOD2 innate receptors and IL-12 and IFN-γ cytokine receptors was evaluated by whole blood stimulation with specific synthetic receptor agonists through the quantification of IL-8, TNF-α, or IFN-γ. At admission, ligand-dependent IL-8 secretion was 6.4, 13, and 2.5 times lower for TLR2, TLR4, and endosomal TLR7/8 receptors, respectively, in patients than in healthy controls. Additionally, IL-12 receptor-induced IFN-γ secretion was lower in COVID-19 patients than in healthy subjects. We evaluated the same parameters after 14 days and observed significantly higher responses for TLR2, TLR4, TLR7/8, TLR9, and NOD1, NOD2, and IFN-γ receptors. In conclusion, the low secretion of IL-8 through stimulation with agonists of TLR2, TLR4, TLR7/8, TLR9, and NOD2 at t1 suggests their possible contribution to immunosuppression following hyperinflammation in COVID-19 disease.

Could the Systemic Immune Inflammation Index Predict Diagnosis, Recovery Time, Hypothyroidism, and Recurrence Rates in Subacute Thyroiditis?

Subacute thyroiditis (SAT) is a non-infectious inflammatory disease of the thyroid. The Systemic Immune-Inflammation Index (SII), also known as an easy economical marker, correlates with the severity of inflammatory responses. We aimed to evaluate the clinical significance of the SII and to compare it to other inflammatory markers in terms of diagnosis, recovery time, and recurrence of SAT. The current non-interventional observational prospective study was performed at Outpatient Department of Endocrinology, Erzurum Training and Research Hospital. Sixty-nine patients with SAT and fifty-nine healthy individuals in total were enrolled in our study. The follow-up period was 6-12 months for all patients regarding treatment response, recurrence, and hypothyroidism. The SII level was found to be significantly higher at the time of diagnosis in the SAT group compared to the control group (p=0.000). There was a significant positive correlation between the SII and SAT recovery time (p=0.000), particularly in patients receiving methyl prednisolone treatment (p=0.002). SII was not found to be significantly associated with hypothyroidism and recurrence in patients with SAT (p=0.261, p=0.568). However, compared to the ones without recurrence, thyroid stimulating hormone (TSH) and erythrocyte sedimentation rate levels at the time of diagnosis were found to be higher in those patients with recurrence (p=0.035, p=0.046). SII is a low-cost, widely available, universal indicator of inflammatory processes in SAT. It could provide many benefits in the follow-up process and the selection of aggressive anti-inflammatory treatment by estimating recovery time. SII, as a practical biomarker, may be a new diagnostic and prognostic tool for SAT.

Multi-modulation of immune-inflammatory response using bioactive molecule-integrated PLGA composite for spinal fusion.

Despite current developments in bone substitute technology for spinal fusion, there is a lack of adequate materials for bone regeneration in clinical applications. Recombinant human bone morphogenetic protein-2 (rhBMP-2) is commercially available, but a severe inflammatory response is a known side effect. Bone graft substitutes that enhance osteogenesis without adverse effects are needed. We developed a bioactive molecule-laden PLGA composite with multi-modulation for bone fusion. This bioresorbable composite scaffold was considered for bone tissue engineering. Among the main components, magnesium hydroxide (MH) aids in reduction of acute inflammation affecting disruption of new bone formation. Decellularized bone extracellular matrix (bECM) and demineralized bone matrix (DBM) composites were used for osteoconductive and osteoinductive activities. A bioactive molecule, polydeoxyribonucleotide (PDRN, PN), derived from trout was used for angiogenesis during bone regeneration. A nano-emulsion method that included Span 80 was used to fabricate bioactive PLGA-MH-bECM/DBM-PDRN (PME2/PN) composite to obtain a highly effective and safe scaffold. The synergistic effect provided by PME2/PN improved not only osteogenic and angiogenic gene expression for bone fusion but also improved immunosuppression and polarization of macrophages that were important for bone tissue repair, using a rat model of posterolateral spinal fusion (PLF). It thus had sufficient biocompatibility and bioactivity for spinal fusion.

The Presence of Pneumonia Is Strongly Associated With Higher Prevalence of Non-ST-Elevation Myocardial Infarction Using a Large NIS Database.

Inflammation is a risk factor for myocardial infarction. Pneumonia leads to severe inflammatory response. Some studies suggest higher risk of myocardial infarction in patients with pneumonia. We used a large inpatient database (National Inpatient Sample) to evaluate this association. This study includes patients from a Nationwide Inpatient Sample hospital in 2005 to 2014 with International Classification of Diseases, Ninth Revision, and Clinical Modification codes consistent with pneumonia and non-ST elevation myocardial infarction (NSTEMI). Subjects were stratified into all hospitalized patients aged 30 and above. Univariate and multivariate analysis was performed adjusting for age, race, gender, tobacco use, diabetes mellitus, hypertension, and hyperlipidemia. NSTEMI was present in 3.2% of pneumonia patients versus 1.8% in the non-pneumonia population over 10-year period. For example, the 2005 database: [odds ratio (OR), 1.77; 95% confidence interval (CI), 1.73-1.80; P < 0.001]. For 2014, NSTEMI was present in 4.1% of pneumonia patients (PNA) versus 2.4% in the non-pneumonia population (OR, 1.72; 95% CI, 1.70-1.75; P < 0.001). NSTEMI remained independently associated with pneumonia following a multivariate analysis in 2005 (OR, 1.477; 95% CI, 1.447-1.508; P < 0.001) with a similar value in 2014 (OR, 1.445; 95% CI, 1.421-1.469; P < 0.001). Using a large inpatient database, we found that NSTEMI was strongly associated with PNA versus non-pneumonia population over a 10-year period. Suggesting acute inflammatory cytokines or hypoxia which occurs during lung infection may play a role in NSTEMI development, reinforcing the importance of acute cardiac monitoring in patients with PNA.

Effect of allyl isothiocyanate on oxidative stress in COPD via the AhR / CYP1A1 and Nrf2 / NQO1 pathways and the underlying mechanism

BackgroundChronic obstructive pulmonary disease (COPD) is currently the third leading cause of death globally. Oxidative stress affects various molecular mechanisms and is the main driving factor of COPD. Ally isothiocyanate (AITC) is an effective component of Semen Sinapis Albae, which has favorable effects for the treatment of COPD, but its mechanism has not been fully elucidated. PurposeThis study aimed to elucidate the antioxidant effect of AITC on COPD and its molecular mechanism, and preliminarily determine the role of AhR in the progression of COPD. Study DesignThe COPD rat model was established by smoking combined with intratracheal instillation of lipopolysaccharide. Different doses of AITC, positive control drug acetylcysteine, AhR inhibitor alpha-naphthoflavone, and agonist beta-naphthoflavone were administered by gavage. Human bronchial epithelial cells induced by cigarette smoke extract (CSE) were used in an in vitro model to explore the molecular mechanisms of AITC. MethodsThe effects of AITC on lung function and oxidative stress in rats were evaluated in vivo using the respiratory function test, white blood cell count, enzyme-linked immunosorbent assay, and histological staining. The changes in protein expression in the lung tissue were detected by immunohistochemistry and Western blotting. RT-PCR, western blotting, and immunofluorescence were used to explore the molecular mechanisms of AITC. Enzyme-linked immunosorbent assay, reactive oxygen species probing, and flow cytometry were used to determine the antioxidant effect of AITC. ResultsAITC can improve the lung function of rats with COPD, restore lung tissue structure, improve oxidative stress, reduce inflammation, and inhibit lung cell apoptosis. AITC reversed the upregulation of AhR and CYP1A1 and the down-regulation of Nrf2 and NQO1 in the lung tissues of rats with COPD. CSE stimulation can increase the expressions of AhR and CYP1A1 and decrease the expressions of Nrf2 and NQO1 in 16HBE cells, leading to severe oxidative stress and inflammatory response and, ultimately, apoptosis. AITC inhibited AhR and CYP1A1 expressions, induced Nrf2 and NQO1 expressions, promoted Nrf2 nuclear translocation, and improved CSE-induced toxicological effects. ConclusionAITC may improve lung oxidative stress by inhibiting the AhR / CYP1A1 and activating the Nrf2 / NQO1 pathways, thereby delaying the pathological progression of COPD.

Levels of Complement Components in Children With Acute COVID-19 or Multisystem Inflammatory Syndrome

Multisystem inflammatory syndrome in children (MIS-C) is a severe and unrestrained inflammatory response with multiorgan involvement, which occurs within a few weeks following the resolution of acute SARS-CoV-2 infection. The complement system is a vital part of the innate immune system and plays a role in COVID-19 pathogenesis. To examine and compare the levels of complement components and regulators along with complement activation products in the different clinical spectrum of children with SARS-CoV-2 and a control group. This cross-sectional study analyzed children with MIS-C admitted to a single hospital in India from June through September 2020. Eligible participants were children who were hospitalized of either sex, aged 1 to 18 years. Data were analyzed August 2022. Levels of complement components and regulators along with complement activation products in all the groups of children. Mann-Whitney U test and Kruskal-Wallis analysis were used to compare the complement component levels, and Spearman rank correlation analysis was used to describe the association between complement components and laboratory and biochemical parameters. A total 145 children were included (median age, 5 years [range, 1 month-17 years); 84 [58%] male): 44 children with MIS-C, 33 with acute COVID-19 (reverse transcriptase-polymerase chain reaction [RT-PCR] positive), 47 with convalescent COVID-19 (immunoglobulin G-positive non-MIS-C) and 21 children for a control group (both serology and RT-PCR negative). Children with MIS-C and COVID-19 had higher levels of C1q (geometric mean [SD]: MIS-C, 61.5 [18.5] ng/mL; acute COVID-19, 56.9 [18.6] ng/mL; controls, 24.1 [3.3] ng/mL), C2 (MIS-C, 605.8 [219.7] ng/mL; acute COVID-19, 606.4 [167.7] ng/mL; controls, 255.9 [73.3] ng/mL), C3 (MIS-C, 318.2 [70.7] ng/mL; acute COVID-19, 237.7 [61.8] ng/mL; controls, 123.4 [15.7] ng/mL), C4b (MIS-C, 712.4 ng/mL; acute COVID-19, 640.7 ng/mL; controls, 351.5 ng/mL), C5 (MIS-C, 1487 ng/mL; acute COVID-19, 1364 ng/mL; controls, 561.9 ng/mL), C5a, (MIS-C, 2614.0 [336.2] ng/mL; acute COVID-19, 1826.0 [541.0] ng/mL; controls, 462.5 [132.4] ng/mL), C3b/iC3b (MIS-C, 3971.0 [635.1] ng/mL; acute COVID-19, 3702.0 [653.9] ng/mL; controls, 2039.0 [344.5] ng/mL), and factor B (MIS-C, 47.6 [7.8] ng/mL; acute COVID-19, 44.6 [6.3] ng/mL; controls, 27.5 [5.0] ng/mL), factor D (MIS-C, 44.0 [17.2] ng/mL; acute COVID-19, 33.8 [18.4] ng/mL; controls, 21.3 [6.1] ng/mL), and factor H (MIS-C, 53.1 [4.0] ng/mL; acute COVID-19, 50.8 [5.7] ng/mL; controls, 43.6 [3.8] ng/mL) in comparison with convalescent and control children. In addition, children with MIS-C had significantly elevated levels of C3 (318.2 [70.7] ng/mL vs 237.7 [61.8] ng/mL), C5a (2614 [336.2] ng/mL vs 1826 [541.0] ng/mL), and mannose-binding lectin (79.4 [12.4] ng/mL vs 69.6 [14.7] ng/mL) in comparison to children with acute COVID-19. Levels of some of these analytes at admission (ie, pretreatment) were more elevated in children with MIS-C who needed pediatric intensive care unit (PICU) support as compared with those who did not require PICU support, and in children with COVID-19 who developed moderate to severe disease compared with those who developed mild disease. Overall, MIS-C and acute COVID-19 were associated with the hyperactivation of complement components and complement regulators. In this cross-sectional study, the complement system was associated with the pathogenesis of MIS-C and COVID-19 in children; complement inhibition could be further explored as a potential treatment option.