Strong Inflammatory Response Research Articles

Painless photodynamic therapy for facial actinic keratoses: A retrospective cohort study of the post-treatment inflammatory response

IntroductionPhotodynamic therapy (PDT) is a safe, non-mutagenic, and non-scarring treatment for actinic keratoses (AK). Background‘Painless’ photodynamic therapy (p-PDT) is a regimen for AK that employs simultaneous aminolevulinate incubation and blue light illumination. The efficacy of p-PDT resembles that of traditional PDT, but detailed mechanisms of action for p-PDT are not well understood. MethodsTo characterize the inflammatory effects of the p-PDT procedure 48 h following treatment and determine the association of inflammation with precancer burden, we performed a retrospective cohort study of 104 patients with AK of face or scalp treated with p-PDT between 2017 and 2019. Patients self-reported their side effects 48 h following p-PDT and took photographs of their face and scalp. Photographs were edited to define seven anatomic regions, and erythema was scored by four investigators. ResultsNinety-eight patients provided photographs suitable for erythema evaluation. Most patients experienced 2 or more side effects and some pain 48 h post-procedure. Females experienced more pain (p = 0.01) and side effects (p = 0.002) compared to males. AK burden was positively associated with post p-PDT erythema response (p < 0.0001) at all sites, but particularly in the temples (p = 0.002) and supralabial area (p = 0.009). DiscussionThis study confirms a strong clinical inflammatory response after p-PDT. Severity of inflammation is positively associated with AK tumor burden, suggesting that post-treatment inflammation may be a pre-requisite for p-PDT efficacy. Interestingly, the results also identify certain gender-related differences in the severity of side effects experienced by patients post-PDT.

Protection of lipopolysaccharide-induced otic injury by a single dose administration of a novel dexamethasone formulation

BackgroundThe blood-labyrinth barrier (BLB) separates the inner ear from the circulation and is critical for maintaining ionic homeostasis and limiting the entry of deleterious agents. BLB integrity is disrupted by bacterial lipopolysaccharide (LPS), which elicits a strong inflammatory response in the inner ear leading to irreversible otic damage. Prolonged administration of systemic corticosteroids is the available treatment, but it shows both limited efficacy and major adverse effects. SPT-2101 is a novel in situ-forming gel formulation of dexamethasone allowing slow and sustained drug release after single intratympanic administration.MethodsWe used a rat model of LPS-induced injury to define the functional, cellular and molecular mechanisms associated to BLB dysfunction and the protection by SPT-2101. Hearing was assessed by auditory brainstem response (ABR) recording, BLB permeability by gadolinium dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and Evans blue extravasation. Gross cochlear histology and cellular alterations were studied by hematoxylin-eosin staining and immunofluorescence. RT-qPCR, PCR array and western blotting were used to assess transcriptional and protein changes.ResultsLPS-challenged rats showed BLB breakdown and altered permeability as shown by the progressive increase in cochlear gadolinium uptake and Evans blue incorporation. LPS administration increased the cochlear expression of the LPS toll-like receptors Tlr2 and co-receptor Cd14, pro-inflammatory cytokines and receptors such as Il1b and ll1r1, and also the oxidative stress and inflammasome mediators NRF2 and NLRP3. LPS also increased IBA1-positive macrophage infiltration in the lateral wall and spiral ganglion. A single intratympanic injection of SPT-2101 protected BLB integrity and prevented otic injury. Comparable effects were obtained by repeated administration of systemic dexamethasone, but not by a single dose. SPT-2101 administration normalized molecular inflammatory mediators and suppressed macrophage infiltration.ConclusionsOur data indicate that single local administration of dexamethasone formulated as SPT-2101 protects BLB functional integrity during endotoxemia, providing a novel therapeutic opportunity to treat diseases related to BLB dysfunction.

In-depth biological characterization of two black soldier fly anti-Pseudomonas peptides reveals LPS-binding and immunomodulating effects.

As effector molecules of the innate immune system, antimicrobial peptides (AMPs) have gathered substantial interest as a potential future generation of antibiotics. Here, we demonstrate the anti-Pseudomonas activity and lipopolysaccharide (LPS)-binding ability of HC1 and HC10, two cecropin peptides from the black soldier fly (Hermetia Illucens). Both peptides are active against a wide range of Pseudomonas aeruginosa strains, including drug-resistant clinical isolates. Moreover, HC1 and HC10 can bind to lipid A, the toxic center of LPS and reduce the LPS-induced nitric oxide and cytokine production in murine macrophage cells. This suggests that the peptide-LPS binding can also lower the strong inflammatory response associated with P. aeruginosa infections. As the activity of AMPs is often influenced by the presence of salts, we studied the LPS-binding activity of HC1 and HC10 in physiological salt concentrations, revealing a strong decrease in activity. Our research confirmed the early potential of HC1 and HC10 as starting points for anti-Pseudomonas drugs, as well as the need for structural or formulation optimization before further preclinical development can be considered. IMPORTANCE The high mortality and morbidity associated with Pseudomonas aeruginosa infections remain an ongoing challenge in clinical practice that requires urgent action. P. aeruginosa mostly infects immunocompromised individuals, and its prevalence is especially high in urgent care hospital settings. Lipopolysaccharides (LPSs) are outer membrane structures that are responsible for inducing the innate immune cascade upon infection. P. aeruginosa LPS can cause local excessive inflammation, or spread systemically throughout the body, leading to multi-organ failure and septic shock. As antimicrobial resistance rates in P. aeruginosa infections are rising, the research and development of new antimicrobial agents remain indispensable. Especially, antimicrobials that can both kill the bacteria themselves and neutralize their toxins are of great interest in P. aeruginosa research to develop as the next generation of drugs.

Assessment of Micronuclei Frequency in the Peripheral Blood of Adult and Pediatric Patients Receiving Fractionated Total Body Irradiation

The cytokinesis-block micronucleus (CBMN) assay is an established method for assessing chromosome damage in human peripheral blood lymphocytes resulting from exposure to genotoxic agents such as ionizing radiation. The objective of this study was to measure cytogenetic DNA damage and hematology parameters in vivo based on MN frequency in peripheral blood lymphocytes (PBLs) from adult and pediatric leukemia patients undergoing hematopoietic stem cell transplantation preceded by total body irradiation (TBI) as part of the conditioning regimen. CBMN assay cultures were prepared from fresh blood samples collected before and at 4 and 24 h after the start of TBI, corresponding to doses of 1.25 Gy and 3.75 Gy, respectively. For both age groups, there was a significant increase in MN yields with increasing dose (p < 0.05) and dose-dependent decrease in the nuclear division index (NDI; p < 0.0001). In the pre-radiotherapy samples, there was a significantly higher NDI measured in the pediatric cohort compared to the adult due to an increase in the percentage of tri- and quadri-nucleated cells scored. Complete blood counts with differential recorded before and after TBI at the 24-h time point showed a rapid increase in neutrophil (p = 0.0001) and decrease in lymphocyte (p = 0.0006) counts, resulting in a highly elevated neutrophil-to-lymphocyte ratio (NLR) of 14.45 ± 1.85 after 3.75 Gy TBI (pre-exposure = 4.62 ± 0.49), indicating a strong systemic inflammatory response. Correlation of the hematological cell subset counts with cytogenetic damage, indicated that only the lymphocyte subset survival fraction (after TBI compared with before TBI) showed a negative correlation with increasing MN frequency from 0 to 1.25 Gy (r = −0.931; p = 0.007). Further, the data presented here indicate that the combination of CBMN assay endpoints (MN frequency and NDI values) and hematology parameters could be used to assess cytogenetic damage and early hematopoietic injury in the peripheral blood of leukemia patients, 24 h after TBI exposure.

Two synthetic steroid analogs reduce human respiratory syncytial virus replication and the immune response to infection both in vitro and in vivo

HRSV is responsible for many acute lower airway infections and hospitalizations in infants, the elderly and those with weakened immune systems around the world. The strong inflammatory response that mediates viral clearance contributes to pathogenesis, and is positively correlated with disease severity. There is no specific effective therapy on hand. Antiviral synthetic stigmastanes (22S, 23S)-22,23-dihydroxystigmast-4-en-3-one (Compound 1) and 22,23-dihydroxystigmasta-1,4-dien-3-one (Compound 2) have shown to be active inhibiting unrelated virus like Herpes Simplex type 1 virus (HSV-1) and Adenovirus, without cytotoxicity. We have also shown that Compound 1 modulates the activation of cell signaling pathways and cytokine secretion in infected epithelial cells as well as in inflammatory cells activated by nonviral stimuli. In the present work, we investigated the inhibitory effect of both compounds on HRSV replication and their modulatory effect on infected epithelial and inflammatory cells. We show that compounds 1 and 2 inhibit in vitro HRSV replication and propagation and reduce cytokine secretion triggered by HRSV infection in epithelial and inflammatory cells. The compounds reduce viral loads and inflammatory infiltration in the lungs of mice infected with HRSV.

Morphometric and microbiological features of ventilator associated tracheobronchitis

Changes in the composition of the microbiota of the tracheobronchial tree in patients on prolonged mechanical ventilation can contribute to various disorders of the immune defense of the respiratory tract, damaging mucociliary clearance, and cause a strong inflammatory response, including the formation of ventilator-associated tracheobronchitis (VAT). The aim was to study the specifics of changes in the microflora and histopathology of the tracheobronchial tree in VAT. Over a 10 year period 975 bacteriological analyzes were carried out in 355 patients who were on extended mechanical ventilation for more than 48 hours. VAT is accompanied by a pronounced lymphoid-neutrophilic infiltration of the mucosa of the trachea and bronchi, and in a complicated course with the presence of a purulent-inflammatory and erosive-hemorrhagic component leads to a violation of the integrity of tissues due to destruction and necrosis. The leading pathogens were representatives of gram-negative flora of 65.8% (47-76%), gram-positive flora was detected in 17.5% (10-30%) of cases, fungi of the genus Candida in 16.5 (4-42%) cases. Analysis of the antibiograms of isolated cultures in patients on prolonged mechanical ventilation shows high resistance to a wide range of antibiotics, namely: acinetobacter spp. - high resistance to all antibiotics, except for imipenem (0% resistant strains), polymyxin (0%) and tetracyclines (7-15.4%). Imipenem (10.5%), polymyxin (10.5%), amikacin (31.5%) and cefoperazone/sulbactam (31.5%) are active against Esherichia coli. Klebsiella pneumoniae was susceptible to imipenem, amikacin, ofloxacin and inhibitor-protected antibiotics-cefoperazone/sulbactam, piperacillin/tazobactam. Staphylococcus aureus was susceptible to III generation cephalosporins (cefotaxime, ceftriaxone, cefoperazone) and tetracyclines - 36.3% of resistant strains. Microbiological monitoring in patients with VAT over a 10-year period revealed a trend towards the prevalence of gram-negative microflora inoculation, and over the past two years, the range of isolated multi-resistant flora has been expanding.

Morphometric and microbiological features of ventilator associated tracheobronchitis

Changes in the composition of the microbiota of the tracheobronchial tree in patients on prolonged mechanical ventilation can contribute to various disorders of the immune defense of the respiratory tract, damaging mucociliary clearance, and cause a strong inflammatory response, including the formation of ventilator-associated tracheobronchitis (VAT). The aim was to study the specifics of changes in the microflora and histopathology of the tracheobronchial tree in VAT. Over a 10 year period 975 bacteriological analyzes were carried out in 355 patients who were on extended mechanical ventilation for more than 48 hours. VAT is accompanied by a pronounced lymphoid-neutrophilic infiltration of the mucosa of the trachea and bronchi, and in a complicated course with the presence of a purulent-inflammatory and erosive-hemorrhagic component leads to a violation of the integrity of tissues due to destruction and necrosis. The leading pathogens were representatives of gram-negative flora of 65.8% (47-76%), gram-positive flora was detected in 17.5% (10-30%) of cases, fungi of the genus Candida in 16.5 (4-42%) cases. Analysis of the antibiograms of isolated cultures in patients on prolonged mechanical ventilation shows high resistance to a wide range of antibiotics, namely: acinetobacter spp. - high resistance to all antibiotics, except for imipenem (0% resistant strains), polymyxin (0%) and tetracyclines (7-15.4%). Imipenem (10.5%), polymyxin (10.5%), amikacin (31.5%) and cefoperazone/sulbactam (31.5%) are active against Esherichia coli. Klebsiella pneumoniae was susceptible to imipenem, amikacin, ofloxacin and inhibitor-protected antibiotics-cefoperazone/sulbactam, piperacillin/tazobactam. Staphylococcus aureus was susceptible to III generation cephalosporins (cefotaxime, ceftriaxone, cefoperazone) and tetracyclines - 36.3% of resistant strains. Microbiological monitoring in patients with VAT over a 10-year period revealed a trend towards the prevalence of gram-negative microflora inoculation, and over the past two years, the range of isolated multi-resistant flora has been expanding.

Retention of Human iPSC-Derived or Primary Cells Following Xenotransplantation into Rat Immune-Privileged Sites.

In regenerative medicine, experimental animal models are commonly used to study potential effects of human cells as therapeutic candidates. Although some studies describe certain cells, such as mesenchymal stromal cells (MSC) or human primary cells, as hypoimmunogenic and therefore unable to trigger strong inflammatory host responses, other studies report antibody formation and immune rejection following xenotransplantation. Accordingly, the goal of our study was to test the cellular retention and survival of human-induced pluripotent stem cell (iPSCs)-derived MSCs (iMSCs) and primary nucleus pulposus cells (NPCs) following their xenotransplantation into immune-privileged knee joints (14 days) and intervertebral discs (IVD; 7 days) of immunocompromised Nude and immunocompetent Sprague Dawley (SD) rats. At the end of both experiments, we could demonstrate that both rat types revealed comparably low levels of systemic IL-6 and IgM inflammation markers, as assessed via ELISA. Furthermore, the number of recovered cells was with no significant difference between both rat types. Conclusively, our results show that xenogeneic injection of human iMSC and NPC into immunoprivileged knee and IVD sites did not lead to an elevated inflammatory response in immunocompetent rats when compared to immunocompromised rats. Hence, immunocompetent rats represent suitable animals for xenotransplantation studies targeting immunoprivileged sites.

Secretion of mitochondrial DNA via exosomes promotes inflammation in Behçet's syndrome.

Mitochondrial DNA (mtDNA) leakage into the cytoplasm can occur when cells are exposed to noxious stimuli. Specific sensors recognize cytoplasmic mtDNA to promote cytokine production. Cytoplasmic mtDNA can also be secreted extracellularly, leading to sterile inflammation. However, the mode of secretion of mtDNA out of cells upon noxious stimuli and its relevance to human disease remain unclear. Here, we show that pyroptotic cells secrete mtDNA encapsulated within exosomes. Activation of caspase-1 leads to mtDNA leakage from the mitochondria into the cytoplasm via gasdermin-D. Caspase-1 also induces intraluminal membrane vesicle formation, allowing for cellular mtDNA to be taken up and secreted as exosomes. Encapsulation of mtDNA within exosomes promotes a strong inflammatory response that is ameliorated upon exosome biosynthesis inhibition in vivo. We further show that monocytes derived from patients with Behçet's syndrome (BS), a chronic systemic inflammatory disorder, show enhanced caspase-1 activation, leading to exosome-mediated mtDNA secretion and similar inflammation pathology as seen in BS patients. Collectively, our findings support that mtDNA-containing exosomes promote inflammation, providing new insights into the propagation and exacerbation of inflammation in human inflammatory diseases.

Experimental investigation of biostimulatory effects after polydioxanone thread insertion in a pig model.

Polydioxanone (PDO) threads have been widely used to tighten and lift the facial soft tissue. This research aims to determine the collagenation and inflammation changes that occur in the adipose tissue over time when different types of threads are implanted. Three threads types, PDO, poly glycolic-co-lactic acid (PGLA), and nylon, were inserted in the subcutaneous fat of 12-month-old Bama miniature pigs. Collagen production and inflammatory response were evaluated by hematoxylin and eosin and Masson trichrome staining at 1, 4, 12, 24, and 48 weeks. The integrity of the PDO thread lasted up to 24 weeks with mild inflammation and collagen production. The PGLA thread integrity lasted until 12 weeks and had a strong inflammatory response. The nylon thread's integrity was maintained for 48 weeks and showed minor inflammation and collagen production. Our data suggest that PDO thread is the best choice for clinicians, as it has a mild action process with minimal irritation, moderate collagen production, a reasonable explanation time, with obvious bridging fibrous tissue, and thickening action for the superficial fascia.

Platelet P2Y12 signalling pathway in the dysregulated immune response during sepsis.

Sepsis is a complicated pathological condition in response to severe infection. It is characterized by a strong systemic inflammatory response, where multiple components of the immune system are involved. Currently, there is no treatment for sepsis. Blood platelets are known for their role in haemostasis, but they also participate in inflammation through cell-cell interaction and the secretion of inflammatory mediators. Interestingly, an increase in platelet activation, secretion, and aggregation with other immune cells (such as monocytes, T-lymphocytes and neutrophils) has been detected in septic patients. Therefore, antiplatelet therapy in terms of P2Y12 antagonists has been evaluated as a possible treatment for sepis. It was found that blocking P2Y12 receptors decreased platelet marker expression and limited attachment to immune cells in some studies, but not in others. This review addresses the role of platelets in sepsis and discusses whether antagonizing P2Y12 signalling pathways can alter the disease outcome. Challenges in studying P2Y12 antagonists in sepsis also are discussed. LINKED ARTICLES: This article is part of a themed issue on Platelet purinergic receptor and non-thrombotic disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.4/issuetoc.

Identification of two pIgR-like molecules in teleost fish with opposite roles in mucosal immunity against bacterial infection

Polymeric immunoglobulin (Ig) receptor-like (pIgRL) molecules have been identified in teleost fish. However, compared to functional studies of their related genes (e.g., mammalian CD300 family) in eliminating pathogen invasion while preserving homeostasis, the roles of pIgRL in teleost fish remain unclear. In this study, we demonstrated that a pair of pIgRL molecules in zebrafish, pIgRL3.5 and pIgRL4.2, were highly expressed in the intestine and immune cells. Moreover, we constructed an Edwardsiella piscicida infection model, which induced strong inflammatory responses in the zebrafish intestine. Interestingly, pIgRL3.5 and pIgRL4.2 exhibited opposite inducible expression patterns in response to bacterial infection, suggesting that they perform different roles. More importantly, by conducting overexpression and knockdown experiments, our findings demonstrated that zebrafish pIgRL3.5 played a protective role in host defense against E. piscicida infection by inhibiting excessive inflammatory responses. In contrast, pIgRL4.2 facilitated pathogen growth and dissemination in zebrafish intestine. Collectively, our findings are the first to demonstrate that a pair of pIgRL molecules in teleost fish play opposite roles in mucosal immune response to bacterial infection. Therefore, our results provide crucial insights into the conserved role of pIgRL molecules in immune regulatory functions throughout vertebrate evolution.

Construction and validation of an immune infiltration-related risk model for predicting prognosis and immunotherapy response in low grade glioma

BackgroundLow grade glioma (LGG) is considered a heterogeneous tumor with highly variable survival and limited efficacy of immunotherapy. To identify high-risk subsets and apply immunotherapy effectively in LGG, the status and function of immune infiltration in the glioma microenvironment must be explored.MethodsFour independent glioma cohorts comprising 1,853 patients were enrolled for bioinformatics analysis. We used ConsensusClusterPlus to cluster patients into four different immune subtypes based on immune infiltration. The immune-infiltration signature (IIS) was constructed by LASSO regression analysis. Somatic mutation and copy number variation (CNV) analyses were performed to explore genomic and transcriptomic traits in the high- and low- risk groups. The correlation between response to programmed cell death 1 (PD-1) blockade and the IIS risk score was confirmed in an in vivo glioma model.ResultsPatients were clustered into four different immune subtypes based on immune infiltration, and the high immune infiltration subtype was associated with worse survival in LGG. The high immune infiltration subtype had stronger inflammatory response, immune response and immune cell chemotaxis. The IIS, consisting of EMP3, IQGAP2, METTL7B, SLC1A6 and TNFRSF11B, could predict LGG malignant progression, which was validated with internal clinical samples. M2 macrophage infiltration positively correlated with the IIS risk score. The high-risk group had significantly more somatic mutations and CNVs. The IIS risk score was related to immunomodulatory molecules and could predict immunotherapy clinical benefit. In vivo, immunotherapy-sensitive glioma model exhibited higher IIS risk score and more infiltration of immune cells, especially M2 macrophages. The IIS risk score was decreased in an immunotherapy-sensitive glioma model after anti-PD1 immunotherapy.ConclusionDifferent immune subtypes of LGG had unique immune cell infiltration characteristics, and the high immune infiltration subtype was associated with immunosuppressive signaling pathways. A novel IIS prognostic model based on immune infiltration status was constructed for immunophenotypic classification, risk stratification, prognostication and immunotherapy response prediction in LGG.

Celastrol relieves myocardial infarction-induced cardiac fibrosis by inhibiting NLRP3 inflammasomes in rats.

Myocardial infarction (MI) triggers a strong inflammatory response mediating by NLRP3 inflammasome which is associated with cardiac fibrosis. The key players in this response are Interleukin (IL)-1 and IL-18, which are regulated by NLRP3 inflammasomes. Celastrol, a traditional Chinese medicine with strong anti-inflammatory activity, has recently reported as a cardioprotective agent. However, the mechanisms by which celastrol is cardioprotective in MI remain elusive. We hypothesized that Celastrol could reduce IL-1β and IL-18 expression and ameliorate myocardial fibrosis after myocardial infarction in rats, improve poor heart remodeling, and preserve heart function. Myocardial infarction (MI) was caused by ligating the left anterior descending of male SD rats. Celastrol (1mg/kg) or saline was administered every other day for 4weeks. Heart function and fibrosis were assessed. Inflammatory and fibrotic markers in the myocardia were evaluated with immunohistochemistry, western blot, and ELISA. Molecular docking was employed to predict Celastrol's binding to NLRP3 protein. The effects of Celastrol on the expression of NLRP3 inflammasome and myocardial fibrosis genes were then examined in vitro. Celastrol maintained the left ventricular fractional shortening (FS) and ejection fraction (EF). Fibrosis was significantly reduced in animals treated with 1mg/kg Celastrol (15.17±1.82%) relative to controls (29.88±4.28%). Celastrol also significantly reduced the NLRP3, IL-18, and IL-1β levels, together with macrophage and neutrophil infiltration in the myocardium. Molecular docking predicted that NLRP3 would bind tightly to Celastrol [Docking energy: -8.9 (kcal/mol)]. In vitro experiments showed reduced NLRP3 inflammasome and myocardial fibrosis-associated proteins expression in neonatal rat cardiac fibroblasts treated with Celastrol. In post-MI rats, Celastrol, a naturally occurring active ingredient, was able to reduce myocardial fibrosis and improve cardiac function, according to our study. These effects may result from inhibiting the NLRP3 inflammasome and attenuating the early inflammatory storm after MI, suggesting that Celastrol may be useful in treating acute MI.

Are persons living with diagnosed HIV capable of mounting a strong inflammatory response to the new coronavirus?

The impact of COVID-19 on persons living with diagnosed HIV (PLWDH) remains incompletely understood. It's unclear whether an impaired immune system offers protection against mounting cytokine storm. Retrospective matched cohort study of COVID-19 hospitalized individuals in New York State (NYS). Medical records were abstracted and analyzed for 853 PLWDH hospitalized with COVID-19 in NYS and 1621 HIV-negative controls. Preexisting comorbidities and inflammatory markers measured within 24h of hospital admission were abstracted. PLWDH were significantly less likely to have elevated inflammatory markers compared to matched controls. Elevated WBC occurred in 23.3% of PLWDH vs 30.1% of controls (p = .0002), elevated CRP in 37.4% of PLWDH vs 43.2% of controls (p = .03), elevated ferritin in 73.4% of PLWDH vs 78.9% of controls (p = .004). There was an inverse but not statistically significant relationship between the frequency of elevated inflammatory markers and HIV disease stage, with greatest percent of PLWDH with elevated WBC, LDH, CRP, and ferritin among PLWDH with HIV disease stage 1. PLWDH had lower inflammatory marker elevation during COVID-19 infection compared to matched controls. PLWDH with low CD4 were less likely to mount a cytokine storm in the setting of impaired immune function.

Vagus nerve inflammation contributes to dysautonomia in COVID-19.

Dysautonomia has substantially impacted acute COVID-19 severity as well as symptom burden after recovery from COVID-19 (long COVID), yet the underlying causes remain unknown. Here, we hypothesized that vagus nerves are affected in COVID-19 which might contribute to autonomic dysfunction. We performed a histopathological characterization of postmortem vagus nerves from COVID-19 patients and controls, and detected SARS-CoV-2 RNA together with inflammatory cell infiltration composed primarily of monocytes. Furthermore, we performed RNA sequencing which revealed a strong inflammatory response of neurons, endothelial cells, and Schwann cells which correlated with SARS-CoV-2 RNA load. Lastly, we screened a clinical cohort of 323 patients to detect a clinical phenotype of vagus nerve affection and found a decreased respiratory rate in non-survivors of critical COVID-19. Our data suggest that SARS-CoV-2 induces vagus nerve inflammation followed by autonomic dysfunction which contributes to critical disease courses and might contribute to dysautonomia observed in long COVID.

Systemic host inflammation induces stage-specific transcriptomic modification and slower maturation in malaria parasites.

Maturation rates of malaria parasites within red blood cells (RBCs) can be influenced by host nutrient status and circadian rhythm; whether host inflammatory responses can also influence maturation remains less clear. Here, we observed that systemic host inflammation induced in mice by an innate immune stimulus, lipopolysaccharide (LPS), or by ongoing acute Plasmodium infection, slowed the progression of a single cohort of parasites from one generation of RBC to the next. Importantly, plasma from LPS-conditioned or acutely infected mice directly inhibited parasite maturation during in vitro culture, which was not rescued by supplementation, suggesting the emergence of inhibitory factors in plasma. Metabolomic assessments confirmed substantial alterations to the plasma of LPS-conditioned and acutely infected mice, and identified a small number of candidate inhibitory metabolites. Finally, we confirmed rapid parasite responses to systemic host inflammation in vivo using parasite scRNA-seq, noting broad impairment in transcriptional activity and translational capacity specifically in trophozoites but not rings or schizonts. Thus, we provide evidence that systemic host inflammation rapidly triggered transcriptional alterations in circulating blood-stage Plasmodium trophozoites and predict candidate inhibitory metabolites in the plasma that may impair parasite maturation in vivo. IMPORTANCE Malaria parasites cyclically invade, multiply, and burst out of red blood cells. We found that a strong inflammatory response can cause changes to the composition of host plasma, which directly slows down parasite maturation. Thus, our work highlights a new mechanism that limits malaria parasite growth in the bloodstream.

Cryptotanshinone-Doped Photothermal Synergistic MXene@PDA Nanosheets with Antibacterial and Anti-Inflammatory Properties for Wound Healing.

Humans are threatened by bacteria and other microorganisms, resulting in countless pathogen-related infections and illnesses. Accumulation of reactive oxygen species (ROS) in infected wounds activates strong inflammatory responses. The overuse of antibiotics has led to increasing bacterial resistance. Therefore, effective ROS scavenging and bactericidal capacity are essential and the advanced development of collaborative therapeutic techniques to combat bacterial infections is needed. Here, this work developes an MXene@polydopamine-cryptotanshinone (MXene@PDA-CPT) antibacterial nanosystem with excellent reactive oxygen and nitrogen species scavenging ability, which effectively inactivates drug-resistant bacteria and biofilms, thereby promoting wound healing. In this system, the adhesion of polydopamine nanoparticles to MXene produced a photothermal synergistic effect and free radical scavenging activity, presenting a promising antibacterial and anti-inflammatory strategy. This nanosystem causes fatal damage to bacterial membranes. The loading of cryptotanshinone further expanded the advantages of the system, causing a stronger bacterial killing effect and inflammation mitigatory effect with desired biosafety and biocompatibility. In addition, combining nanomaterials and active ingredients of traditional Chinese medicine, this work provides a new rationale for the future development of wound dressings, which contributes to eliminating bacterial resistance, delaying disease deterioration, and alleviating the pain of patients.

Sex differences in innate and adaptive immunity impact fetal, placental, and maternal health.

The differences between males and females begin shortly after birth, continue throughout prenatal development, and eventually extend into childhood and adult life. Male embryos and fetuses prioritize proliferation and growth, often at the expense of the fetoplacental energy reserves. This singular focus on growth over adaptability leaves male fetuses and neonates vulnerable to adverse outcomes during pregnancy and birth and can have lasting impacts throughout life. Beyond this prioritization of growth, male placentas and fetuses also respond to infection and inflammation differently than female counterparts. Pregnancies carrying female fetuses have a more regulatory immune response whereas pregnancies carrying male fetuses have a stronger inflammatory response. These differences can be seen as early as the innate immune response with differences in cytokine and chemokine signaling. The sexual dimorphism in immunity then continues into the adaptive immune response with differences in T cell biology and antibody production and transfer. As it appears that these sex-specific differences are amplified in pathologic pregnancies, it stands to reason that differences in the placental, fetal, and maternal immune responses in pregnancy contribute to increased male perinatal morbidity and mortality. In this review, we will describe the genetic and hormonal contributions to the sexual dimorphism of fetal and placental immunity. We will also discuss current research efforts to describe the sex-specific differences of the maternal-fetal interface and how it impacts fetal and maternal health.

Molecular docking analysis of selected bioactive components of Glycyrrhiza glabra against bronchial asthma

Bronchial asthma is a chronic inflammatory disease of the lung by the combined action of various cytokines. As a result of the strong inflammatory response increased infiltration of cytokines result, damages respiratory epithelium, Hyperplasia of the trachealis muscle, and increased mucous production. Athimathura choornam is a promising drug used in all inflammatory conditions. Objective: To explore the efficacy of the Siddha formulation Athimathura choornam, an anti asthmatic drug using computational molecular docking analysis. Method: Based on the phytochemical study the active principles present in the plant Athimathuram were retrieved. 3D structure of the targets were retrieved from the repository and purified before the initiation of docking using the software. The potency of the drug was screened based on the binding of the ligands Asparagine, Liquiritin, and Glabridin with targets mentioned. These results were compared with the standard drugs such as Cetirizine, Salicylic acid, Diclofenac, Ibuprofen, and Celecoxib. Results and Conclusion: Liquiritin has 9 interactions (90%) similar to that of Ibuprofen, 14 interactions (90%) similar to that of Citrazinehence , 5 interactions (100%) similar to that of salicylic acid hence it has promising COX 1 inhibition ,Histamine 1 blocking activity and Prostaglandin Synthase inhibition activity. Asparagine has 3 interactions (60%) similar to Celecoxib, has promising COX 2 inhibition activity. Glabridin has 2 interactions (50%) similar to that of Diclofenac hence it has promising IL6 inhibition activity.