Phytotherapy-Induced Hepatocytotoxicity: A Case Report.

Herbal and complementary medicine are frequently integrated with conventional medicine. We aim to report a case of severe herbal-induced liver injury (HILI) due to chronic use of green tea and protein shake. We present both clinical and laboratory evidence implicating mitochondrial toxicity and an immune response leading to a hypersensitivity reaction to the products. We have recently treated a 39-year-old man with hepatotoxicity resulting from a combination of a green tea-containing powder and a branched-chain amino acid supplement that was commenced 2 months previously. The hepatotoxicity resolved by stopping the consumption of these products and no other cause was detected. We decided to perform a lymphocyte toxicity assay (LTA) to determine if there was laboratory support for this diagnosis. LTA (% toxicity) represents the response of the mitochondria to toxic injury. To determine the role of the proinflammatory and anti-inflammatory cytokines and chemokines in the patient's reaction, we measured the level of cytokines and chemokine in the media of growing cells, exposed to each product or to a combination of products. The increased cytokines and chemokines are presented as the x-fold elevations from the upper limit of normal (ULN) for matrix metalloproteinase (MMP) (pg/mL × 1.5 ULN) and interleukin (IL)-1ß (pg/mL × 1.8 ULN). Higher elevations were found for interferon (IFN)-ß, IFN-γ, IL-8, IL 13, IL-15 (pg/mL × 2 ULN), regulated upon activation, normal T cell expressed and presumably secreted (RANTES) (pg/mL × 2 ULN), and nuclear factor (NFκB) (pg/mL × 3 ULN). The highest increases were for vascular endothelial factor (VEGF) (pg/mL × 10 ULN), tumor necrosis factor (TNF)-α, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (pg/mL × 13 ULN). An examination of cellular markers showed the difference between programmed cell death (apoptosis) and cell death due to necrosis. In our case, cytokeratin-ccK18 (M-30) U/L was within the normal limits, suggesting that apoptosis was normal, while ccK8(M65) U/L was elevated at 1.5 × ULN. This result implies that upon the treatment of the patient's lymphocytes with the products, the mechanism of toxicity is necrosis. In susceptible individuals, the combination of protein and herbal tea produces mitochondrial toxicity and a strong T-lymphocyte-1 response, leading to HILI. There is a need of international reporting of adverse drug reactions by clinicians, laboratories, and pharmaceutical manufacturers to drug regulatory authorities. This requires internationally accepted standard definitions of reactions, as well as criteria for assessment.

Evaluation of some proinflammatory cytokines and biochemical parameters in pre and postmenopausal breast cancer women.

The study was planned to evaluate the differences in certain proinflammatory cytokines(IL-6, TNF-α) with CRP and biochemical parameters (E2, D3, LDH, GGT, TSB, Ca, Ph, uric acid), between women with pre- and postmenopausal breast cancer and seemingly healthy women in Iraqi women as controls; at medical city in teaching Oncology hospital,70 breast cancer patients women their ages ranged (47.51 ± 1.18) and 20 healthy women with age (44.45 ± 2.66) begun from September (2020) to February (2021). The aims of this study to investigate the evaluation of chemotherapy effects especially doxorubicin and cyclophosphamide only use in this study in pre and postmenopausal breast cancer women on proinflammatory cytokines(IL-6, TNF-α) with CRP and on biochemical parameters(E2, D3, LDH, GGT, TSB, Ca, Ph, uric acid) in pre and postmenapausal breast cancer women. The patients were divided into five groups and each group contains 14 patients women with breast cancer during pre and postmenopausal periods. The control groups were divided into 10 pre and 10 postmenopausal women(Fig. 1). The results of proinflammatory cytokines of and biochemical parameters in premenopausal groups were as the levels of IL-6 (pg/ml),TNF-α(pg/ml) and CRP (ng/ml) showed significant increase differences (P < 0.01)among breast cancer treated (BCT) groups in comparison with control groups,While the Liver enzymes GGT,LDH and TSB showed highly significant increase (P < 0.01) in BCT groups, Estrogen levels (pg/ml) and D3(ng/ml) increased significantly (P < 0.01)among BCT groups. Blood serum calcium and phosphorus with uric acid levels (mg/dl) showed significant difference (P < 0.01); While the result in postmenopausal of IL-6(pg/ml), TNF-α (pg/ml) and CRP (ng/ml) showed highly significant differences (P < 0.01)among BCT groups.While GGT(IU/L), LDH(IU/L) and TSB (mg/dl) enzymes were increased significantly (p < 0.01), Estrogen (pg/ml) and D3(ng/ml) levels showed significant increase (P < 0.01) among BCT groups.Blood calcium and phosphorus showed significant increase (P < 0.01) while uric acid was non-significant increase (P > 0.05).

The roles of SFKs in the regulation of proinflammatory cytokines and NLRP3 in familial mediterranean fever patients.

Familial Mediterranean Fever (FMF) is caused by mutations in pyrin, a protein produced in innate immune cells that regulates the development of interleukin (IL)-1ß by interacting with caspase-1 and other components of inflammasomes. Although overexpression of proinflammatory cytokines have been observed in FMF patients, no studies have been conducted on the role of Src family kinases (SFKs). The purpose of this study was to examine the impact of SFKs on the modulation of IL-1ß, IL-6, IL-8, TNF-α, and NLRP3 inflammasome in patients with FMF. The study included 20 FMF patients and 20 controls. Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation. Protein expression levels of SFKs members were measured by western blot. The effect of lipopolysaccharide-induced (LPS) activation and PP2- induced inhibition of SFKs on NLRP3 and IL-1ß, IL 6, IL-8, TNF-α were examined by western blot and flow cytometry respectively. Patients with FMF have considerably greater levels of Lck expression. In addition, patients had a substantially greater basal level of NLRP3 than the control group (*p = 0.016). Most importantly, the levels of IL-1 ß were elevated with LPS stimulation and reduced with PP2 inhibition in FMF patients. These results suggest that SFKs are effective in regulation of IL-1 ß in FMF patients.

Mucosal-associated invariant T cells modulate innate immune cells and inhibit colon cancer growth.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can be activated by microbial antigens and cytokines and are abundant in mucosal tissues including the colon. MAIT cells have cytotoxic and pro-inflammatory functions and have potentials for use as adoptive cell therapy. However, studies into their anti-cancer activity, including their role in colon cancer, are limited. Using an animal model of colon cancer, we showed that peritumoral injection of in vivo-expanded MAIT cells into RAG1-/- mice with MC38-derived tumours inhibits tumour growth compared to control. Multiplex cytokine analyses showed that tumours from the MAIT cell-treated group have higher expression of markers for eosinophil-activating cytokines, suggesting a potential association between eosinophil recruitment and tumour inhibition. In a human peripheral leukocyte co-culture model, we showed that leukocytes stimulated with MAIT ligand showed an increase in eotaxin-1 production and activation of eosinophils, associated with increased cancer cell killing. In conclusion, we showed that MAIT cells have a protective role in a murine colon cancer model, associated with modulation of the immune response to cancer, potentially involving eosinophil-associated mechanisms. Our results highlight the potential of MAIT cells for non-donor restricted colon cancer immunotherapy.

TLR2 immunotherapy suppresses neuroinflammation, tau spread, and memory loss in rTg4510 mice.

In Alzheimer's disease, chronic neuroinflammation is accompanied by amyloid and tau pathologies. Especially, aberrant microglial activation is known to precede the regional tau pathology development, but the mechanisms how microglia affect tau spread remain largely unknown. Here, we found that toll-like receptor 2 (TLR2) in microglia recognizes oligomeric tau as a pathogenic ligand and induces inflammatory responses. Knockout of TLR2 reduced tau pathology and microglial activation in rTg4510 tau transgenic mice. Treatment of oligomeric tau induced TLR2 activation and increased inflammatory responses in microglial cells. TLR2 further mediated the tau-induced microglial activation and promoted tau uptake into neurons in neuron-microglia co-culture system and in mouse hippocampus after intracranial tau injection. Importantly, treatment with anti-TLR2 monoclonal antibody Tomaralimab blocked TLR2 activation and inflammatory responses in a dose-dependent manner, and significantly reduced tau spread and memory loss in rTg4510 mice. These results suggest that TLR2 plays a crucial role in tau spread by causing aberrant microglial activation in response to pathological tau, and blocking TLR2 with immunotherapy may ameliorate tau pathogenesis in Alzheimer's disease.

Loss of interleukin 1 signaling causes impairment of microglia- mediated synapse elimination and autistic-like behaviour in mice.

In the last years, the hypothesis that elevated levels of proinflammatory cytokines contribute to the pathogenesis of neurodevelopmental diseases has gained popularity. IL-1 is one of the main cytokines found to be elevated in Autism spectrum disorder (ASD), a complex neurodevelopmental condition characterized by defects in social communication and cognitive impairments. In this study, we demonstrate that mice lacking IL-1 signaling display autistic-like defects associated with an excessive number of synapses. We also show that microglia lacking IL-1 signaling at early neurodevelopmental stages are unable to properly perform the process of synapse engulfment and display excessive activation of mammalian target of rapamycin (mTOR) signaling. Notably, even the acute inhibition of IL-1R1 by IL-1Ra is sufficient to enhance mTOR signaling and reduce synaptosome phagocytosis in WT microglia. Finally, we demonstrate that rapamycin treatment rescues the defects in IL-1R deficient mice. These data unveil an exclusive role of microglial IL-1 in synapse refinement via mTOR signaling and indicate a novel mechanism possibly involved in neurodevelopmental disorders associated with defects in the IL-1 pathway.

miR-206-3p Targets Brain-Derived Neurotrophic Factor and Affects Postoperative Cognitive Function in Aged Mice.

Postoperative cognitive dysfunction (POCD) occurs after surgery and severely impairs patients' quality of life. Finding POCD-associated variables can aid in its diagnosis and prognostication. POCD is associated with noncoding RNAs, such as microRNAs (miRNAs), involved in metabolic function, immune response alteration, and cognitive ability impairment; however, the underlying mechanisms remain unclear. The aim of this study was to investigate hub miRNAs (i.e., miRNAs that have an important regulatory role in diseases) regulating postoperative cognitive function and the associated mechanisms. Hub miRNAs were identified by bioinformatics, and their expression in mouse hippocampus tissues was determined using real-time quantitative polymerase chain reaction. Hub miRNAs were overexpressed or knocked down in cell and animal models to test their effects on neuroinflammation and postoperative cognitive function. Six differentially expressed hub miRNAs were identified. miR-206-3p was the only broadly conserved miRNA, and it was used in follow-up studies and animal experiments. Its inhibitors reduced the release of proinflammatory cytokines in BV-2 microglia by regulating its target gene, brain-derived neurotrophic factor (BDNF), and the downstream signaling pathways. miR-206-3p inhibition suppressed microglial activation in the hippocampi of mice and improved learning and cognitive decline. Therefore, miR-206-3p significantly affects POCD, implying its potential as a therapeutic target.

Dysregulated inflammatory response to urogynecologic meshes in women with diabetes and its implications.

BACKGROUND: Diabetes is an independent risk factor for mesh complications in women undergoing mesh-augmented surgical repairs of stress urinary incontinence and/or pelvic organ prolapse. The underlying mechanism remains unclear. OBJECTIVE: This study aimed to define the diabetes-associated alterations in the host inflammatory response to mesh and correlate them with perioperative glucose management. STUDY DESIGN: Deidentified demographics and medical records of patients who underwent mesh removal and participated in a mesh biorepository study were reviewed (n=200). In patients with diagnosed diabetes (n=25), blood glucose management before initial mesh implantation and before and after mesh removal was assessed by blood glucose and hemoglobin A1c levels. Age- and body mass index-matched tissue samples excised from patients with and without diabetes were examined. Transcriptomic profiles of immune cell markers, immune mediators, key inflammatory regulators, cell senescence, and epigenetic enzymes were determined by multiplex transcriptomic assays (NanoString). Ratios of apoptotic cells to CD68+ macrophages were examined with immunofluorescence. Protein profiles of 12 molecules involved in apoptotic cell clearance were examined with a multiplex protein assay (Luminex). RESULTS: Demographic and clinical characteristics, including duration between mesh implantation and removal, reason for removal, and type of mesh, etc., were comparable between patients with and without diabetes, except for 11.6% higher body mass index in the former (P=.005). In patients with diabetes, suboptimal management of blood glucose following mesh implantation was observed, with 59% of the patients having loosely or poorly controlled glucose before and after the mesh removal. Ongoing chronic inflammatory response was observed in the excised mesh-tissue complexes in both groups, whereas markers for M2 macrophages (Mrc1 [mannose receptor C-type 1]) and helper T cells (Cd4 [CD4 molecule]) were increasingly expressed in the diabetic vs nondiabetic group (P=.023 and .047, respectively). Furthermore, the gene expressions of proinflammatory Ccl24 (C-C motif chemokine ligand 24) and Ccl13 (C-C motif chemokine ligand 13) were upregulated by 1.5- and 1.8-fold (P=.035 and .027, respectively), whereas that of Il1a (interleukin 1 alpha) was paradoxically downregulated by 2.2-fold (P=.037) in the diabetic vs nondiabetic group. Interestingly, strong positive correlations were found between the expression of Ccl13, Setdb2 (SET domain bifurcated histone lysine methyltransferase 2), and M2 macrophage markers, and between the expression of Il1a, Fosl1 (activator protein-1 transcription factor subunit), and dendritic cell markers, suggesting the involvement of macrophages and dendritic cells in the diabetes-dysregulated proinflammatory response. Supportively, apoptotic cell clearance, which is an important function of macrophages, appeared to be impaired in the diabetic group, with a significantly increased protein level of CALR (calreticulin), an "eat-me" signal on the surface of apoptotic cells (P=.031), along with an increase of AXL (AXL receptor tyrosine kinase) (P=.030), which mediates apoptotic cell clearance. CONCLUSION: Diabetes was associated with altered long-term inflammatory response in complicated mesh implantation, particularly involving innate immune cell dysfunction. Suboptimal blood glycemic control following mesh implantation may contribute to this immune dysregulation, necessitating further mechanistic studies.

HbpA from Glaesserella parasuis induces an inflammatory response in 3D4/21 cells by activating the MAPK and NF-κB signalling pathways and protects mice against G. parasuis when used as an immunogen.

Glaesserella parasuis is usually a benign swine commensal in the upper respiratory tract, but virulent strains can cause systemic infection characterized by pneumonia, meningitis, and fibrinous polyserositis. The intensive pulmonary inflammatory response following G. parasuis infection is the main cause of lung injury and death in pigs. Vaccination has failed to control the disease due to the lack of extended cross-protection. Accumulating evidence indicates that the heme-binding protein A (HbpA) is a potential virulence determinant and a promising antigen candidate for the development of a broader range of vaccines. However, it is not yet known whether HbpA contributes to G. parasuis virulence or has any potential immune protective effects against G. parasuis. Here, we show that HbpA can induce the transcription and secretion of proinflammatory cytokines (IL-6, TNF-α, and MCP-1) in porcine alveolar macrophages (PAM, 3D4/31). The HbpA protein is recognized by Toll-like receptors 2 and 4 on 3D4/21 macrophages, resulting in the activation of MAP kinase and NF-κB signalling cascades and the transcription and secretion of proinflammatory cytokines. HbpA contributes to virulence and bacterial pulmonary colonization in C57BL/6 mice and plays a role in adhesion to host cells and evasion of the bactericidal effect of pulmonary macrophages. In addition, mice immunized with HbpA were partially protected against challenge by G. parasuis SC1401. The results suggest that HbpA plays an important role in the pathogenesis of disease caused by G. parasuis and lay a foundation for the development of a subunit or chimeric anti-G. parasuis vaccine.

The Role of Obesity in the Development of Preeclampsia.

PURPOSE OF REVIEW: This comprehensive review provides an in-depth exploration of the complex relationship between obesity and preeclampsia (PE) and emphasizes the clinical implications of this association. It highlights the crucial role of screening tools in assessing individual risk and determining the need for additional antenatal care among women with obesity. The review investigates various markers for identifying the risk of developing PE, while emphasizing the significance of interventions such as exercise, weight management, and a balanced diet in reducing the incidence of preeclampsia and improving outcomes for both mother and fetus. RECENT FINDINGS: Actually, there is a global pandemic of obesity, particularly among women of childbearing age and pregnant women. PE, which is characterized by maternal hypertension, proteinuria, and complications, affects 2-4% of pregnancies worldwide, posing significant risks to maternal and perinatal health. Women with obesity face an elevated risk of developing PE due to the systemic inflammation resulting from excess adiposity, which can adversely affect placental development. Adipose tissue, rich in proinflammatory cytokines and complement proteins, contributes to the pathogenesis of PE by promoting the expression of antiangiogenic factors in the mother. This review emphasizes the need for appropriate screening, interventions, and a holistic approach to reduce the incidence of preeclampsia and enhance maternal-fetal well-being, thus providing valuable insights into the multifaceted association between obesity and PE.

Identification and functional characterization of interleukin-22 (IL-22) in orange-spotted grouper (Epinephelus coioides).

In mammals, IL-22 is considered as a critical cytokine regulating of immunity and homeostasis at barrier surfaces. Although IL-22 have been functional characterization in different species of fish, the studies about distinct responses of IL-22 in different organs/tissues/cell types is rather limited. Here, we identified and cloned IL-22 gene (named as Ec-IL-22) from grouper (Epinephelus coioides). Ec-IL-22 gene was detected in all orangs/tissues examined, and was induced in intestine, gill, spleen, head kidney, and primary head kidney/intestine leukocytes following the stimulation of LPS and poly (I:C), as well as Vibrio harveyi and Singapore grouper iridovirus infection (SGIV). In addition, the stimulation of DSS could induce the expression of Ec-IL-22 in intestine and primary leukocytes from intestine. Importantly, the treatment of recombinant Ec-IL-22 induced the mRNA level of proinflammatory cytokines in primary intestine/head kidney leukocytes. The present results improve the understanding of expression patterns and functional characteristics of fish IL-22 in different organs/tissues/cell types.

LPS priming-induced immune tolerance mitigates LPS-stimulated microglial activation and social avoidance behaviors in mice.

In this study, we investigated the regulatory mechanisms underlying the effects of LPS tolerance on the inflammatory homeostasis of immune cells. LPS priming-induced immune tolerance downregulated cyclooxygenase-2, and lowered the production of prostaglandin-E2 in microglial cells. In addition, LPS tolerance downregulated the expression of suppressor of cytokine signaling 3, and inducible nitric oxide synthase/nitric oxide; suppressed the LPS-mediated induction of tumor necrosis factor-α, interleukin (IL)-6, and IL-1; and reduced reactive oxygen species production in microglial cells. LPS stimulation increased the levels of the adaptive response-related proteins heme oxygenase-1 and superoxide dismutase 2, and the levels of heme oxygenase-1 (HO-1) enhanced after LPS priming. Systemic administration of low-dose LPS (0.5 mg/kg) to mice for 4 consecutive days attenuated high-dose LPS (5 mg/kg)-induced inflammatory response, microglial activation, and proinflammatory cytokine expression. Moreover, repeated exposure to low-dose LPS suppressed the recruitment of peripheral monocytes or macrophages to brain regions and downregulated the expression of proinflammatory cytokines. Notably, LPS-induced social avoidance behaviors in mice were mitigated by immune tolerance. In conclusion, immune tolerance may reduce proinflammatory cytokine expression and reactive oxygen species production. Our findings provide insights into the effects of endotoxin tolerance on innate immune cells and social behaviors.

Phage cocktail alleviated type 2 diabetes by reshaping gut microbiota and decreasing proinflammatory cytokines.

Type 2 diabetes (T2D), a global health concern, is closely associated with the gut microbiota. Restoration of a balanced microbiota and intestinal homeostasis benefit therapy of T2D. Some special phages may selectively alter the gut microbiota without causing dysbiosis, such as MS2 and P22. However, scarcely systematic analysis of cascading effects triggered by MS2 and P22 phages on the microbiota, as well as interactions between specific gut bacteria and systemic metabolism, seriously inhibit the development of positive interventions of phages. Based on multi-omic analysis, we analyzed the intrinsic correlations among specific microbiota, their bioactive metabolites, and key indicators of T2D. We found that gavage of the MS2-P22 phage cocktail could significantly alter the gut microbiome to attenuate dysbiosis of diabetic C57BL/6 mice caused by high-fat diets (HFDs) and streptozotocin (STZ), by affecting microbial compositions as well as their metabolic pathways and metabolites, especially increasing amounts of short-chain fatty acid-producing (SCFA-producing) bacteria (e.g., Blautia and Romboutsia) and short-chain fatty acids (SCFAs). Correspondingly, a noteworthy reduction in the number of several opportunistic pathogens occurred, e.g., Candidatus Saccharimonas, Aerococcus, Oscillibacter, Desulfovibrio, and Clostridium sensu stricto 1. Synchronously, the levels of proinflammatory cytokines and lipopolysaccharide (LPS) were reduced to recover gut barrier function in T2D mice. These findings might benefit the development of a new dietary intervention for T2D based on phage cocktails. KEY POINTS: • Intestinal barrier integrity of T2D mice is improved by a phage cocktail • Negative relationship between Muribaculaceae and Corynebacterium reshaped gut microbiota • Acetate, propionate, and butyrate decreased the level of proinflammatory factors.

The elasticity of silicone-stabilized liposomes has no impact on their in vivo behavior.

BACKGROUND: The elastomechanical properties of nanocarriers have recently been discussed as important for the efficient delivery of various therapeutics. Some data indicate that optimal nanocarriers' elasticity can modulate in vivo nanocarrier stability, interaction with phagocytes, and uptake by target cells. Here, we presented a study to extensively analyze the in vivo behavior of LIP-SS liposomes that were modified by forming the silicone network within the lipid bilayers to improve their elastomechanical properties. We verified liposome pharmacokinetic profiles and biodistribution, including retention in tumors on a mouse model of breast cancer, while biocompatibility was analyzed on healthy mice. RESULTS: We showed that fluorescently labeled LIP-SS and control LIP-CAT liposomes had similar pharmacokinetic profiles, biodistribution, and retention in tumors, indicating that modified elasticity did not improve nanocarrier in vivo performance. Interestingly, biocompatibility studies revealed no changes in blood morphology, liver, spleen, and kidney function but indicated prolonged activation of immune response manifesting in increased concentration of proinflammatory cytokines in sera of animals exposed to all tested liposomes. CONCLUSION: Incorporating the silicone layer into the liposome structure did not change nanocarriers' characteristics in vivo. Further modification of the LIP-SS surface, including decoration with hydrophilic stealth polymers, should be performed to improve their pharmacokinetics and retention in tumors significantly. Activation of the immune response by LIP-SS and LIP-CAT, resulting in elevated inflammatory cytokine production, requires detailed studies to elucidate its mechanism.

Metabolic Adaptations and Functional Activity of Macrophages in Homeostasis and Inflammation.

In recent years, the role of cellular metabolism in immunity has come into the focus of many studies. These processes form a basis for the maintenance of tissue integrity and homeostasis, as well as represent an integral part of the immune response, in particular, inflammation. Metabolic adaptations not only ensure energy supply for immune response, but also affect the functions of immune cells by controlling transcriptional and post-transcriptional programs. Studying the immune cell metabolism facilitates the search for new treatment approaches, especially for metabolic disorders. Macrophages, innate immune cells, are characterized by a high functional plasticity and play a key role in homeostasis and inflammation. Depending on the phenotype and origin, they can either perform various regulatory functions or promote inflammation state, thus exacerbating the pathological condition. Furthermore, their adaptations to the tissue-specific microenvironment influence the intensity and type of immune response. The review examines the effect of metabolic reprogramming in macrophages on the functional activity of these cells and their polarization. The role of immunometabolic adaptations of myeloid cells in tissue homeostasis and in various pathological processes in the context of inflammatory and metabolic diseases is specifically discussed. Finally, modulation of the macrophage metabolism-related mechanisms reviewed as a potential therapeutic approach.

Brilaroxazine lipogel displays antipsoriatic activity in imiquimod-induced mouse model.

BACKGROUND: Dopamine (D) and serotonin (5-HT) pathways contribute to psoriasis pathobiology. Disruptions incite increased inflammatory mediators, keratinocyte activation and deterioration, and worsening symptoms. Brilaroxazine (RP5063), which displays potent high binding affinity to D2/3/4 and 5-HT1A/2A/2B/7 receptors and a moderate affinity to serotonin transporter (SERT), may affect the underlying psoriasis pathology. METHODS: An imiquimod-induced psoriatic mouse model (BALB/c) evaluated brilaroxazine's activity in a topical liposomal-aqueous gel (Lipogel) formulation. Two of the three groups (n = 6 per) underwent induction with 5% imiquimod, and one group received topical brilaroxazine Lipogel (Days 1-11). Assessments included (1) Psoriasis Area and Severity Index (PASI) scores (Days 1-12), skin histology for Baker score based on H&E stained tissue (Day 12), and serum blood collection for serum cytokine analysis (Day 12). One-way ANOVA followed by post hoc Dunnett's t-test evaluated significance (p < 0.05). RESULTS: Imiquimod-induced animal Baker scores were higher versus Sham non-induced control's results (p < 0.001). Brilaroxazine Lipogel had significantly (p = 0.003) lower Baker scores versus the induced Psoriasis group. Brilaroxazine PASI scores were lower (p = 0.03) versus the induced Psoriasis group (Days 3-12), with the greatest effect in the last 3 days. The induced Psoriasis group showed higher Ki-67 and TGF-ß levels versus non-induced Sham controls (p = 0.001). The brilaroxazine Lipogel group displayed lower levels of these cytokines versus the induced Psoriasis group, Ki-67 (p = 0.001) and TGF-ß (p = 0.008), and no difference in TNF-α levels versus Sham non-induced controls. CONCLUSION: Brilaroxazine Lipogel displayed significant activity in imiquimod-induced psoriatic animals, offering a novel therapeutic strategy.

Interleukin levels and depressive symptoms in psoriatic arthritis patients: insights from a case-control study on socio-demographic factors and disease perception.

In the course of psoriatic arthritis (PsA), depression occurs much more often than in the general population. Depression can be considered a poor prognostic factor. The aim of the study was to assess the relationships between the occurrence of depression and the levels of proinflammatory cytokines in patients with PsA. The study included 86 (47F/39M) patients with PsA. Only patients with high disease activity (DAPSA > 28) were enrolled in the study. The severity of depressive symptoms was assessed using the Beck Depression Inventory II (BDI-II) for all patients. Additionally, sociodemographic data were collected. All patients were also assessed for the levels of interleukins (IL): IL-1, IL-6, IL-17A, IL-23, and tumor necrosis factor alpha (TNF-α) using the enzyme-linked immunosorbent assay (ELISA) test. In the study group, depression (BDI-II ≥ 14) was diagnosed in 45 patients (52%). Patients with coexisting depression reported higher levels of pain and disease activity on the visual analogue scale compared to patients without depression (8.5 vs. 7.7, p < 0.001 and 9.3 vs. 8.4, p < 0.001, respectively). The mean levels of proinflammatory cytokines [pg/ml], IL-1 and IL-6, were also higher in the group of patients with depression (46.4 vs. 4.7, p < 0.001 and 10.5 vs. 4.9, p < 0.001, respectively). The coexistence of depression in the course of Psoriatic Arthritis (PsA) is associated with higher levels of IL-1 and IL-6. Depression has a negative impact on the perception of the underlying disease and is linked to reduced social and occupational activity.

Skin innate immune response against fungal infections and the potential role of trained immunity.

Fungal skin infections are distributed worldwide and can be associated with economic and social traits. The immune response related to skin cells is complex and its understanding is essential to the comprehension of each cell's role and the discovery of treatment alternatives. The first studies of trained immunity (TI) described the ability of monocytes, macrophages and natural killer (NK) cells to develop a memory-like response. However, the duration of TI does not reflect the shorter lifespan of these cells. These conclusions supported later studies showing that TI can be observed in stem and haematopoietic cells and, more recently, also in non-immune skin cells such as fibroblasts, highlighting the importance of resident cells in response to skin disorders. Besides, the participation of less studied proinflammatory cytokines in the skin immune response, such as IL-36γ, shed light into a new possibility of inflammatory pathway blockade by drugs. In this review, we will discuss the skin immune response associated with fungal infections, the role of TI in skin and clinical evidence supporting opportunities and challenges of TI and other inflammatory responses in the pathogenesis of fungal skin infections.

RNA Metabolism Governs Immune Function and Response.

Inflammation is a complex process that protects our body from various insults such as infection, injury, and stress. Proper inflammation is beneficial to eliminate the insults and maintain organ homeostasis, however, it can become detrimental if uncontrolled. To tightly regulate inflammation, post-transcriptional mechanisms governing RNA metabolism play a crucial role in monitoring the expression of immune-related genes, such as tumor necrosis factor (TNF) and interleukin-6 (IL-6). These mechanisms involve the coordinated action of various RNA-binding proteins (RBPs), including the Regnase family, Roquin, and RNA methyltransferases, which are responsible for mRNA decay and/or translation regulation. The collaborative efforts of these RBPs are essential in preventing aberrant immune response activation and consequently safeguarding against inflammatory and autoimmune diseases. This review provides an overview of recent advancements in our understanding of post-transcriptional regulation within the immune system and explores the specific roles of individual RBPs in RNA metabolism and regulation.

Puerarin inhibits NHE1 activity by interfering with the p38 pathway and attenuates mitochondrial damage induced by myocardial calcium overload in heart failure rats.

Previous studies have shown that puerarin plays a key role in protecting humans and animals from cardiovascular diseases. The exact mechanism of the therapeutic effect of puerarin on various cardiovascular diseases (protective effect on cardiomyocytes) is still unclear. In the present study, we identify the role of puerarin in an animal model of experimental heart failure (HF) and explore its underlying mechanisms. The HF rat model is induced by intraperitoneal injection of adriamycin (ADR), and puerarin is administered intragastrically at low, medium, and high concentrations. We demonstrate that puerarin significantly improves myocardial fibrosis and inflammatory infiltration and, as a result, improves cardiac function in ADR-induced HF rats. Mechanistically, we find for the first time that puerarin inhibits overactivated Na +/H + exchange isoform 1 (NHE1) in HF, which may improve HF by decreasing Na + and Ca 2+ ion concentrations and attenuating mitochondrial damage caused by calcium overload; on the other hand, puerarin inhibits the activation of the p38 pathway in HF, reduces the expressions of TGF-ß and proinflammatory cytokines, and suppresses myocardial fibrosis. In conclusion, our results suggest that Puerarin is an effective drug against HF and may play a protective role in the myocardium by inhibiting the activation of p38 and its downstream NHE1.