Overexpression Of Cytokines Research Articles

Коронавирусная инфекция и дислипидемия — есть ли связь?

Dyslipidemia is one of the most common comorbidities in patients infected with the SARS-CoV-2 coronavirus. In this review based on the up- to-date publications the authors assess the potential impact of dyslipidemia on the clinical course and prognosis in COVID-19 infected patients, as well as the viral infection effects on the lipid profile in patients with dyslipidemia. The COVID-19 driven inflammatory response leads to an increase in high-density lipoprotein (HDL) levels, modulation of apolipoproteins, increase in serum amyloid protein A concentration, and a decrease in apolipoprotein A-I, M and E levels, thus affecting the antioxidant, anti-inflammatory and immunomodulatory properties of HDL. The use of statins in patients with COVID-19 may mitigate the risk of lipid disorders. By inhibiting endogenous cholesterol synthesis, statins reduce its amount in lipid rafts and therefore may limit the entry of the SARS-CoV-2 virus into host cells. Moreover, statins, by reducing the overexpression of proinflammatory cytokines, can counteract COVID-19-associated cytokine storm. KEYWORDS: COVID-19, dyslipidemia, obesity, treatment, lipoproteins, statins, fibrates. FOR CITATION: Akhmedov V.A. Coronavirus disease and dyslipidemia — is there an association? Russian Medical Inquiry. 2023;7(1):36– 40 (in Russ.). DOI: 10.32364/2587-6821-2023-7-1-36-40.

Surface-decorated nanoliposomal leonurine targets activated fibroblast-like synoviocytes for efficient rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes progressive joint destruction, leading to impaired life quality, disability, and even premature mortality. However, current medications suffer from limited clinical outcomes and severe side effects due to low bioavailability and non-specific distribution after administration. Herein, a targeting nanosystem (HAP-Lipo@Leo) was constructed for efficient RA treatment, which can precisely deliver a natural anti-arthritic drug leonurine (Leo) to the inflamed joint by HAP-1 peptide-mediated recognition of activated fibroblast-like synoviocytes (FLS). More specifically, HAP-Lipo@Leo was prepared by a combination of thin film hydration and high-pressure microfluidization and surface-decorated with HAP-1 peptide and PEG before encapsulating Leo by the ammonium sulfate gradient method. The as-obtained HAP-Lipo@Leo can be selectively internalized by activated FLS and impairs the lamellipodia formation and overexpression of inflammatory cytokines, both of which play detrimental roles in joint damage. Furthermore, HAP-Lipo@Leo demonstrated arthritic joint-specific distribution, significant inhibition of synovial inflammation, and reversal of cartilage and bone destruction in adjuvant-induced arthritis rats as evidenced by comprehensive investigations including ELISA tests, histopathology examinations, and micro-CT analysis. In addition, HAP-Lipo@Leo exhibited good biocompatibility and safety both in vitro and in vivo. Taken together, HAP-Lipo@Leo holds great potential for clinical RA management by integrating activated FLS targeting, long circulation, multifaceted therapeutic effects, and excellent biocompatibility.

Cationic phosphorus dendron nanomicelles deliver microRNA mimics and microRNA inhibitors for enhanced anti-inflammatory therapy of acute lung injury.

The development of efficient nanomedicines to repress the repolarization of M1 phenotype macrophages and therefore inhibit pro-inflammatory cytokine overexpression for anti-inflammatory therapy is still a challenging task. We report here an original gene delivery nanoplatform based on pyrrolidinium-modified amphiphilic generation 1 phosphorus dendron (C12G1) nanomicelles with a rigid phosphorous dendron structure. The nanomicelles display higher gene delivery efficiency than the counterpart materials of pyrrolidinium-modified G1 phosphorus dendrimers, and meanwhile exhibit excellent cytocompatibility. The C12G1 nanomicelles can be employed to co-deliver the miRNA-146a mimic (miR-146a mimic) and miRNA-429 inhibitor (miR-429i) to inhibit the Toll-like receptor-4 signaling pathway and p38 mitogen-activated protein kinase signaling pathway, respectively, thus causing repression of M1 phenotype alveolar macrophage polarization. The developed C12G1/miR-mixture polyplexes enable efficient therapy of lipopolysaccharide-activated alveolar macrophages in vitro and an acute lung injury mouse model in vivo. The generated cationic phosphorus dendron nanomicelles may hold promising potential for anti-inflammatory gene therapy of other inflammatory diseases.

The immunoregulatory role of fish specific type II SOCS via inhibiting metaflammation in the gut-liver axis

SOCS8, also known as CISHb, is a fish-specific type II SOCS. Because CISH binds to cytokine receptors and may inhibit STAT5 activation (a substrate of the insulin receptor), SOCS8 may be involved in the control of metaflammation. The socs8−/− zebrafish were created, and both longer trunks and intestinal villi were observed in 1-month-old (mo) fish. Altered mucosal immunity and gut-liver metabolism were also found in socs8−/− fish. Increased intestinal neutrophils and macrophages, together with overexpression of cytokines and T cell markers in this mutant fish, suggested SOCS8's immunoregulating role. During modeling of soybean-induced enteritis using the 3 ​mo zebrafish, lower expression levels of inflammatory genes but more mucosa barrier disruption were discovered in socs8−/− zebrafish, compared with wide type counterparts. Furthermore, the shrunk villi at 6 ​mo in socs8−/− fish suggested that the mucosa might have been protected by SOCS8. This is also consistent with the assertion that metaflammation eventually leads to tissue degeneration and premature death. The fact that socs8−/− fish had more hepatic oil droplets compared to their wild-type counterparts suggested SOCS8's role in inhibiting hepatic metaflammation. Transcriptomic analysis as well as 16S rRNA gene sequencing were done on 3 ​mo socs8−/− fish to methodically reveal the altered immunity and metabolic reprogramming in the gut and liver caused by socs8−/−. The enriched GO terms for the intestinal tract, such as "cytokine-mediated signaling pathway" and "response to external biotic stimulus", as well as KEGG pathways in both gut and liver like "carbon metabolism" and "glycolysis/gluconeogenesis", were consistent with previously revealed pathological clues and improved growth performance at early age, respectively. In addition, the microbiota in the socs8−/− strain had adapted to the host's increased carbohydrate metabolism, as evidenced by higher levels of Bacteroidota. Furthermore, Verrucomicrobiota associated with immunoregulation were found in lower abundance in socs8−/− fish. As a result, current findings indicate that SOCS8 plays immunoregulatory and mucosa-protective roles in the fish gut and liver by inhibiting carbohydrate metabolism.

What Are the Roles of Proprotein Convertases in the Immune Escape of Tumors?

Protein convertases (PCs) play a significant role in post-translational procedures by transforming inactive precursor proteins into their active forms. The role of PCs is crucial for cellular homeostasis because they are involved in cell signaling. They have also been described in many diseases such as Alzheimer's and cancer. Cancer cells are secretory cells that send signals to the tumor microenvironment (TME), remodeling the surrounding space for their own benefits. One of the most important components of the TME is the immune system of the tumor. In this review, we describe recent discoveries that link PCs to the immune escape of tumors. Among PCs, many findings have determined the role of Furin (PC3) as a paramount enzyme causing the TME to induce tumor immune evasion. The overexpression of various cytokines and proteins, for instance, IL10 and TGF-B, moves the TME towards the presence of Tregs and, consequently, immune tolerance. Furthermore, Furin is implicated in the regulation of macrophage activity that contributes to the increased impairment of DCs (dendritic cells) and T effector cells. Moreover, Furin interferes in the MHC Class_1 proteolytic cleavage in the trans-Golgi network. In tumors, the T cytotoxic lymphocytes (CTLs) response is impeded by the PD1 receptor (PD1-R) located on CTLs and its ligand, PDL1, located on cancer cells. The inhibition of Furin is a subtle means of enhancing the antitumor response by repressing PD-1 expression in tumors or macrophage cells. The impacts of other PCs in tumor immune escape have not yet been clarified to the extent that Furin has. Accordingly, the influence of other types of PCs in tumor immune escape is a promising topic for further consideration.

Drug Repurposing Using Gene Co-Expression and Module Preservation Analysis in Acute Respiratory Distress Syndrome (ARDS), Systemic Inflammatory Response Syndrome (SIRS), Sepsis, and COVID-19.

SARS-CoV-2 infections are highly correlated with the overexpression of pro-inflammatory cytokines in what is known as a cytokine storm, leading to high fatality rates. Such infections are accompanied by SIRS, ARDS, and sepsis, suggesting a potential link between the three phenotypes. Currently, little is known about the transcriptional similarity between these conditions. Herein, weighted gene co-expression network analysis (WGCNA) clustering was applied to RNA-seq datasets (GSE147902, GSE66890, GSE74224, GSE177477) to identify modules of highly co-expressed and correlated genes, cross referenced with dataset GSE160163, across the samples. To assess the transcriptome similarities between the conditions, module preservation analysis was performed and functional enrichment was analyzed in DAVID webserver. The hub genes of significantly preserved modules were identified, classified into upregulated or downregulated, and used to screen candidate drugs using Connectivity Map (CMap) to identify repurposed drugs. Results show that several immune pathways (chemokine signaling, NOD-like signaling, and Th1 and Th2 cell differentiation) are conserved across the four diseases. Hub genes screened using intramodular connectivity show significant relevance with the pathogenesis of cytokine storms. Transcriptomic-driven drug repurposing identified seven candidate drugs (SB-202190, eicosatetraenoic-acid, loratadine, TPCA-1, pinocembrin, mepacrine, and CAY-10470) that targeted several immune-related processes. These identified drugs warrant further study into their efficacy for treating cytokine storms, and in vitro and in vivo experiments are recommended to confirm the findings of this study.

The Educational Program of Macrophages toward a Hyperprogressive Disease-Related Phenotype Is Orchestrated by Tumor-Derived Extracellular Vesicles

Hyperprogressive disease (HPD), an aggressive acceleration of tumor growth, was observed in a group of cancer patients treated with anti-PD1/PDL1 antibodies. The presence of a peculiar macrophage subset in the tumor microenvironment is reported to be a sort of "immunological prerequisite" for HPD development. These macrophages possess a unique phenotype that it is not clear how they acquire. We hypothesized that certain malignant cells may promote the induction of an "HPD-related" phenotype in macrophages. Bone-marrow-derived macrophages were exposed to the conditioned medium of five non-small cell lung cancer cell lines. Macrophage phenotype was analyzed by microarray gene expression profile and real-time PCR. We found that human NSCLC cell lines, reported as undergoing HPD-like tumor growth in immunodeficient mice, polarized macrophages towards a peculiar pro-inflammatory phenotype sharing both M1 and M2 features. Lipid-based factors contained in cancer cell-conditioned medium induced the over-expression of several pro-inflammatory cytokines and the activation of innate immune receptor signaling pathways. We also determined that tumor-derived Extracellular Vesicles represent the main components involved in the observed macrophage re-education program. The present study might represent the starting point for the future development of diagnostic tools to identify potential hyperprogressors.

Overexpression of proinflammatory cytokines in dental pulp tissue and distinct bacterial microbiota in carious teeth of Mexican Individuals.

The prevalence of dental caries in the Mexican adult population aged 20 to 85 years is around 93.3%, and 50% in Mexican children and adolescents. Worldwide, it is the most common non-communicable disease. One of the main etiological factors for dental caries is the oral microbiome and changes in its structure and function, with an expansion of pathogenic bacteria like Streptococcus mutans. The exposed dental pulp tissue triggers an innate immune response to counteract this bacterial invasion. The relation between oral dysbiosis and innate immune responses remains unclear. We aimed to understand the relationship between innate immune response and the oral microbiota by quantifying the expression of Toll-like receptors (TLRs) and proinflammatory markers (cytokines and a chemokine) in dental pulp tissue, either exposed or not to carious dentin, and to correlate this information with the oral microbiome found in healthy teeth and those with moderate caries. RNA was purified from pulp tissue, subjected to RT-qPCR and analysed with the ΔΔCt method. Supragingival dental plaque of non-carious teeth and dentin of carious teeth were subjected to 16S targeted sequencing. Principal coordinate analysis, permutational multivariate ANOVA, and linear discriminant analysis were used to assess differences between non-carious and carious teeth. Correlations were assessed with Spearman´s test and corrected for multiple comparisons using the FDR method. The relative abundance (RA) of Lactobacillus, Actinomyces, Prevotella, and Mitsuokella was increased in carious teeth; while the RA of Haemophilus and Porphyromonas decreased. Olsenella and Parascardovia were only detected in carious teeth. Significant overexpression of interleukin 1 beta (IL1 β), IL6, and CXCL8 was detected in pulp tissue exposed to carious dentin. IL1β correlated positively with TLR2 and Actinomyces; yet negatively with Porphyromonas. These findings suggest that immune response of pulp tissue chronically exposed to cariogenic microbiome is triggered by proinflammatory cytokines IL1β and IL6 and the chemokine CXCL8.

Airway epithelial cell-specific delivery of lipid nanoparticles loading siRNA for asthma treatment.

With specific and inherent mRNA cleaving activity, small interfering RNA (siRNA) has been deemed promising therapeutics to reduce the exacerbation rate of asthma by inhibiting the expression and release of proinflammatory cytokines from airway epithelial cells (AECs). To exert the therapeutic effects of siRNA drugs, nano-formulations with high efficiency and safety are required to deliver these nucleic acids to the target cells. Herein, we exploited novel inhaled lipid nanoparticles (LNPs) targeting intercellular adhesion molecule-1 (ICAM-1) receptors on the apical side of AECs. This delivery system is meant to enhance the specific delivery efficiency of siRNA in AECs to prevent the expression of proinflammatory cytokines in AECs and the concomitant symptoms in parallel. A cyclic peptide that resembles part of the capsid protein of rhinovirus and binds to ICAM-1 receptors was initially conjugated with cholesterol and subsequently assembled with ionizable cationic lipids to form the LNPs (Pep-LNPs) loaded with siRNA against thymic stromal lymphopoietin (TSLP siRNA). The obtained Pep-LNPs were subjected to thorough characterization and evaluations in vitro and in vivo. Pep-LNPs significantly enhanced cellular uptake and gene silencing efficiency in human epithelial cells expressing ICAM-1 in vitro, exhibited AEC-specific delivery and improved the gene silencing effect in ovalbumin-challenged asthmatic mice after pulmonary administration. More importantly, Pep-LNPs remarkably downregulated the expression of TSLP in AECs, effectively alleviated inflammatory cell infiltration, and reduced the secretion of other proinflammatory cytokines, including IL-4 and IL-13, as well as mucus production in asthmatic mice. This study demonstrates that Pep-LNPs are safe and efficient to deliver siRNA drugs to asthmatic AECs and could potentially alleviate allergic asthma by inhibiting the overexpression of proinflammatory cytokines in the airway.

The use of carbon monoxide breath test to detect the effect of iron overload on erythrocyte lifespan in MDS.

To investigate the effect of iron overload (IO) on red blood cell (RBC) lifespan in MDS patients with the use of carbon monoxide breath test. The red blood cell lifespan of 93 patients with myelodysplastic syndrome (MDS) and 22 healthy volunteers in the control group were measured by alveolar gas carbon monoxide (CO) assay, with the detection of liver iron concentration, iron metabolism index, erythropoietin (EPO) concentration, peripheral blood inflammatory cytokines, etc. The MDS patients were divided into the severe IO group, mild IO group and non IO group according to liver iron concentration. The effect of IO on RBC lifespan was analyzed in MDS patients. The RBC lifespan of MDS patients in the severe IO group was significantly lower than that in the mild IO group (p<0.05), while the RBC life span in the mild IO group was significantly lower than that in the non IO group (p<0.05). The expression of inflammatory cytokines in the severe IO group was significantly higher than that of the mild and non IO groups. After receiving iron removal treatment(ICT), the expression of inflammatory cytokines was decreased significantly, and the RBC lifespan was significantly prolonged (p<0.05).Besides, liver iron concentration was significantly positively correlated with EPO concentration, while EPO concentration was significantly negatively correlated with RBC lifespan, especially in the MDS-RS subgroup. The RBC lifespan in the EPO>1000 group was significantly lower than that in the EPO<1000 group. IO can shorten RBC lifespan in MDS patients, which may be result from the increase of endogenous EPO and the over-expression of inflammatory cytokines. After ICT, the ineffective hematopoiesis caused by increased EPO may reduced and the decrease of inflammatory cytokine may significantly prolong the RBC lifespan in MDS patients.

The Role of Nuclear Factor-Kappa B in Fibrinogen-Induced Inflammatory Responses in Cultured Primary Neurons.

Traumatic brain injury (TBI) is an inflammatory disease associated with a compromised blood-brain barrier (BBB) and neurodegeneration. One of the consequences of inflammation is an elevated blood level of fibrinogen (Fg), a protein that is mainly produced in the liver. The inflammation-induced changes in the BBB result in Fg extravasation into the brain parenchyma, creating the possibility of its contact with neurons. We have previously shown that interactions of Fg with the neuronal intercellular adhesion molecule-1 and cellular prion protein induced the upregulation of pro-inflammatory cytokines, oxidative damage, increased apoptosis, and cell death. However, the transcription pathway involved in this process was not defined. The association of Fg with the activation of the nuclear factor-κB (NF-κB) and the resultant expression of interleukin-6 (IL-6) and C-C chemokine ligand-2 (CCL2) were studied in cultured primary mouse brain cortex neurons. Fg-induced gene expression of CCL2 and IL-6 and the expression of NF-κB protein were increased in response to a specific interaction of Fg with neurons. These data suggest that TBI-induced neurodegeneration can involve the direct interaction of extravasated Fg with neurons, resulting in the overexpression of pro-inflammatory cytokines through the activation of transcription factor NF-κB. This may be a mechanism involved in vascular cognitive impairment during neuroinflammatory diseases.

Protective effect of cerium oxide on testicular function and oxidative stress after torsion/detorsion in adult male rats.

Testicular torsion (T)/detorsion (D) can cause testicular injury due to the rotation of the spermatic cord and its vessels, therefore it represents an urological emergency that is surgically treated. Oxidative damage occurs in the testis and distant organs because of the overproduction of free radicals and overexpression of proinflammatory cytokines by reperfusion after surgery. Cerium oxide (CeO2) nanoparticles, a material also known as nanoceria, have regenerative antioxidant properties on oxidative stress. The present study aimed to investigate the effects of nanoceria on testis tissues in testicular T/D in rats. A total of 24 rats were equally and randomly divided into four groups: Control, CeO2, T/D and CeO2-T/D groups. Left inguinoscrotal incision was performed in the control group. In the CeO2 group, 0.5 mg/kg CeO2 was given intraperitoneally 30 min before inguinoscrotal incision. In the T/D group, unilateral testicular T/D was performed through an inguinoscrotal incision and rotating the left testis 720˚ clockwise, which was then left ischemic for 120 min, followed by 120 min of reperfusion. In the CeO2-T/D group, 0.5 mg/kg CeO2 was given intraperitoneally 30 min before testicular T/D. At the end of the experiment, testis tissues were removed for histopathological and biochemical examinations. The samples were histologically examined, Glutathione-s transferase (GST), catalase (CAT), paraoxonase (PON) activities and malondialdehyde (MDA) levels were measured via biochemical analysis methods, while the expression levels of p53, Bax and Bcl-2 were detected using immunohistochemistry. The present results revealed statistically significant inter-group differences in PON, CAT and GST activities and MDA levels. GST, CAT and PON activities were significantly higher, whereas MDA levels in the CeO2-T/D group were significantly lower compared with those in the T/D group. The T/D group had increased Bax and decreased Bcl-2 expression levels in their seminiferous tubules compared with the control and CeO2 groups. CeO2 treatment led to downregulation of Bax and upregulation of Bcl-2. The expression of p53 was high in the T/D group compared with that in the control and CeO2 groups, and was upregulated in all germinal cells. However, compared with that in the T/D group, p53 expression was significantly decreased in the CeO2-T/D group. The testicular injury score significantly increased in the CeO2-T/D group compared with the control and CeO2 groups. Rats in the CeO2-T/D group demonstrated significantly milder tissue lesions compared with those in T/D group. The present findings indicated that nanoceria may protect testis in rats against the harmful effects of T/D. Further studies are required to evaluate how CeO2 reduces oxidative stress and cell death in testis tissue that underwent T/D-related injury.

Osteoarthritis Pain in Old Mice Aggravates Neuroinflammation and Frailty: The Positive Effect of Morphine Treatment.

Knee osteoarthritis is a common cause of pain and disability in old subjects. Pain may predispose to the development of frailty. Studies on mechanisms underlying pain in osteoarthritis models during aging are lacking. In this work, we used the monosodium iodoacetate model of osteoarthritis in adult (11-week-old) and old (20-month-old) C57BL/6J mice to compare hypersensitivity, locomotion, neuroinflammation, and the effects of morphine treatment. After osteoarthritis induction in adult and old mice, weight-bearing asymmetry, mechanical allodynia, and thermal hyperalgesia similarly developed, while locomotion and frailty were more affected in old than in adult animals. When behavioral deficits were present, the animals were treated for 7 days with morphine. This opioid counteracts the behavioral alterations and the frailty index worsening both in adult and old mice. To address the mechanisms that underlie pain, we evaluated neuroinflammatory markers and proinflammatory cytokine expression in the sciatic nerve, DRGs, and spinal cord. Overexpression of cytokines and glia markers were present in osteoarthritis adult and old mice, but the activation was qualitatively and quantitatively more evident in aged mice. Morphine was able to counteract neuroinflammation in both age groups. We demonstrate that old mice are more vulnerable to pain's detrimental effects, but prompt treatment is successful at mitigating these effects.

Discovery of new cinnamic derivatives as anti-inflammatory agents for treating acute lung injury in mice.

The blockade of the overexpression of pro-inflammatory cytokines by anti-inflammatory natural products has been proven therapeutically beneficial in the treatment of acute lung injury (ALI). Given the fact that cinnamic acid has been proven to have significant anti-inflammatory activity, we selected it as a promising lead compound to develop more effective analogs in treating ALI. Learning from the symmetric structure of curcumin, 32 new symmetric cinnamic derivatives were designed, synthesized, and evaluated for their anti-inflammatory activity. Among them, 6h not only displayed a remarkable inhibitory activity in vitro (85.9% and 65.7% forIL-6 and TNF-α, respectively) without cytotoxicity but also possessed chemical structure stability. Furthermore, an in vivo study in mice revealed that the administration of 6h significantly attenuated lipopolysaccharide-induced ALI, providing new lead structures for the development of anti-inflammatory drugs for the treatment of ALI.

Minocycline, a classic antibiotic, exerts psychotropic effects by normalizing microglial neuroinflammation-evoked tryptophan-kynurenine pathway dysregulation in chronically stressed male mice

The dysregulation of tryptophan-kynurenine pathway (TKP) is extensively involved in the pathophysiology of Alzheimer’s disease, depression, and neurodegenerative disorders. Minocycline, a classic antibiotic, may exert psychotropic effects associated with the modulation of TKP. In this study, we examined the effects of minocycline in improving behaviour and modulating TKP components in chronically stressed male mice. Following repeated treatment with 22.5 mg/kg and 45 mg/kg minocycline for 27 days, the stressed mice particularly with higher dose displayed significant improvement on cognitive impairment, depression- and anxiety-like behaviour. Minocycline suppressed stress-induced overexpression of pro-inflammatory cytokines and restored anti-inflammatory cytokines. Chronic stress dramatically suppressed blood and prefrontal cortical levels of the primary substrate tryptophan (TRP), the neuroprotective metabolite kynurenic acid (KYNA), and KYNA/KYN ratio, but increased the intermediate kynurenine (KYN), 3-hydroxykynurenine (3-HK), KYN/TRP ratio, and the neurotoxic metabolite quinolinic acid (QUIN). Minocycline partially or completely reversed changes in these components. Minocycline also inhibited stress-induced overexpression of QUIN-related enzymes, indoleamine 2, 3-dioxygenase 1(iDO-1), kynureninase (KYNU), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilate 3,4-dioxygenase (3-HAO), but rescued the decreased expression of kynurenine aminotransferase (KAT) in brain regions. Behavioral improvements were correlated with multiple TKP metabolites and enzymes. These results suggest that the psychotropic effects of minocycline are mainly associated with the restoration of biodistribution of the primary substrate in the brain and normalization of neuroinflammation-evoked TKP dysregulation.

Vinpocetine Ameliorates Metabolic-Syndrome-Associated Bladder Overactivity in Fructose-Fed Rats by Restoring Succinate-Modulated cAMP Levels and Exerting Anti-Inflammatory Effects in the Bladder Detrusor Muscle

Succinate and its receptor, the G protein-coupled receptor 91 (GPR91), have pathological implications in metabolic syndrome (MetS) and its associated bladder dysfunction, particularly in decreasing bladder cAMP levels and promoting proinflammation. Using fructose-fed rats (FFRs), a rat model of MetS, we investigate the effects of vinpocetine (a phosphodiesterase-1 inhibitor) and celecoxib (a selective cyclooxygenase-2 inhibitor) on MetS-associated bladder overactivity. Phenotypes of the overactive bladder, including increased micturition frequency and a shortened intercontractile interval in cystometry, were observed in FFRs, together with elevated succinate levels in the liver and serum and the downregulation of GPR91 in the liver and urinary bladder. Treatments with vinpocetine and celecoxib improved tissue fibrosis and ameliorated the overexpression of the inflammatory cytokines, such as IL-1β, in the liver and bladder. In bladder organ bath studies, vinpocetine, but not celecoxib, treatment restored the contraction and relaxation responses of the detrusor muscle strip in response to KCl, carbachol, and forskolin stimulation. At a molecular level, vinpocetine and celecoxib treatments modulated the downstream messengers of GPR91 (i.e., ERK1/2 and JNK), suppressed NF-κB and IL-1β expressions in the bladder, and prevented the fibrogenesis observed in FFRs. The exogenous application of succinate to a bladder organ bath significantly reduced the forskolin-induced cAMP production by the detrusor muscle, which was notably restored in the presence of vinpocetine. Together, these results suggest that vinpocetine may alleviate the MetS-associated bladder overactivity by restoring the succinate-modulated detrusor cAMP production and exerting the anti-inflammatory effects in the bladder detrusor muscle.

Ginsenoside Rh4 remodels the periphery microenvironment by targeting the brain-gut axis to alleviate depression-like behaviors

Depression is a neuropsychiatric disease that threatens the physical and mental health of humans worldwide. This study explored the potential anti-depressant effects of ginsenoside Rh4 and its mechanisms of action. The results showed that Rh4 could significantly inhibit depression-like behavior in the depression mouse model and alleviate neuronal damage and hypothalamic–pituitary–adrenal axis disorder. Concurrently, Rh4 inhibits hippocampal neuronal apoptosis and synaptic structural damage due to the overexpression of proinflammatory cytokines and overactivation of microglia and astrocytes by inhibiting the immune-inflammatory response and signaling molecular interaction pathways. Rh4 can also improve intestinal flora and increase the short-chain fatty-acids content. The correlation analysis indicated that the Rh4-inhibited LPS/NLRP3/caspase-1/IL-1β signaling pathway plays a key role in ameliorating depression. Therefore, this study provides valuable insights into the mode of action of Rh4 on the brain-gut axis in depression, suggesting that Rh4 may be a promising clinical drug for the treatment of depression.

The Influenza-Induced Pulmonary Inflammatory Exudate in Susceptible Tpl2-Deficient Mice Is Dictated by Type I IFN Signaling.

The most prominent host response to viral infection is the production of type 1 interferons (T1 IFNs). One host regulator of the T1 IFNs is the serine-threonine kinase, tumor progression locus 2 (TPL2). We have previously demonstrated that Tpl2−/− mice succumb to infection with a low-pathogenicity influenza A strain (x31), in association with with increased pulmonary levels of interferon-β (IFN-β), chemokine CCL2, and excessive monocyte and neutrophil pulmonary infiltration. TPL2-dependent overexpression of IFN-β has been implicated in enhanced susceptibility to Mycobacterium tuberculosis; therefore, we examined the role of T1 IFNs in susceptibility of Tpl2−/− mice to influenza. CCL2 overexpression and monocyte recruitment were normalized in Ifnar1−/−Tpl2−/− mice, confirming that TPL2 constrains inflammatory monocyte recruitment via inhibition of the T1 IFN/CCL2 axis. Unexpectedly, excessive neutrophil recruitment in Ifnar1−/− strains was further exacerbated by simultaneous TPL2 genetic ablation in Ifnar1−/−Tpl2−/− by 7 dpi, accompanied by overexpression of neutrophil-regulating cytokines, CXCL1 and IFN-λ. Collectively, our data suggest that TPL2 and T1 IFNs synergize to inhibit neutrophil recruitment. However, treatment with the neutrophil-depleting anti-Ly6G antibody showed only a modest improvement in disease. Analysis of sorted innate immune populations revealed redundant expression of inflammatory mediators among neutrophils, inflammatory monocytes and alveolar macrophages. These findings suggest that targeting a single cell type or mediator may be inadequate to control severe disease characterized by a mixed inflammatory exudate. Future studies will consider TPL2-regulated pathways as potential predictors of severe influenza progression as well as investigate novel methods to modulate TPL2 function during viral infection.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10753-022-01736-8.

Palmitoleic Acid Acts on Adipose-Derived Stromal Cells and Promotes Anti-Hypertrophic and Anti-Inflammatory Effects in Obese Mice

Adipose tissue (AT) secretes adipokines, modulators of low-grade chronic inflammation in obesity. Molecules that induce the emergence of new and functional adipocytes in AT can alleviate or prevent inflammatory and metabolic disorders. The objective of this study was to investigate the role of palmitoleic acid (n7) in 3T3-L1 and primary pre-adipocyte differentiation and AT inflammation. C57BL/6j mice were submitted to a control or high-fat diet (HFD) for 8 weeks, and treated with n7 for 4 weeks. Mice consuming a HFD presented an increase in body weight, epididymal (Epi) fat mass, and Epi adipocytes size. N7 treatment attenuated the body weight gain and completely prevented the hypertrophy of Epi adipocytes, but not the increment in Epi mass induced by the HFD, suggesting a greater adipocytes hyperplasia in animals treated with n7. It was agreed that n7 increased 3T3-L1 proliferation and differentiation, as well as the expression of genes involved in adipogenesis, such as Cebpa, Pparg, aP2, Perilipin, and Scl2a4. Furthermore, n7 decreased the inflammatory cytokines Mcp1, Tnfa, Il6, Cxcl10, and Nos2 genes in Epi vascular stromal cells, but not in the whole AT. These findings show that n7 exerts anti-hypertrophic effects in adipocytes which influence the surrounding cells by attenuating the overexpression of pro-inflammatory cytokines triggered by a HFD.

Silymarin reduces retinal microvascular damage in streptozotocin-induced diabetic rats

Diabetic retinopathy is a severe microvascular problem in diabetes mellitus. Silymarin is a flavonoid compound, and according to previous studies, it is a bioactive compound with potent antioxidant and anti-inflammatory properties. This investigation aims to peruse the impact of silymarin against diabetic retinopathy in streptozotocin (STZ)-provoked rats. Thirty-two adult male Wistar rats were randomly allocated into the control group, STZ group, STZ + silymarin (50 mg/kg), and STZ + silymarin (100 mg/kg). STZ rats received silymarin every day until 2 months after diabetes induction. The serum and retinal tissues were collected 2 months after silymarin treatment to determine biochemical and molecular analyses. Silymarin markedly lowered the serum glucose concentration in diabetic rats. Silymarin reduced the increased levels of advanced glycosylated end products (AGEs), the receptors for AGEs (RAGE), and reactive oxygen species (ROS) in diabetic rats. Silymarin also attenuated the phosphorylation of p38 MAP kinase and nuclear factor (NF)-κB p65 and diminished diabetes-induced overexpression of inflammatory cytokines, vascular endothelial growth factor (VEGF), adhesion molecules, and extracellular matrix proteins in STZ rats. Our data suggested that silymarin has protective effects against diabetic retinopathy, which might be related to the inhibition of the AGEs/RAGE axis and its antioxidant and anti-inflammatory activities.