Coronavirus disease 2019 (COVID-19) is a multi-system disease that can lead to various severe complications. Acute limb ischemia (ALI) has been increasingly recognized as a COVID-19-associated complication that often predicts a poor prognosis. However, the pathophysiology and molecular mechanisms underlying COVID-19-associated ALI remain poorly understood. Hypercoagulability and thrombosis are considered important mechanisms, but we also emphasize the roles of vasospasm, hypoxia, and acidosis in the pathogenesis of the disease. The angiotensin-converting enzyme 2 (ACE2) pathway, inflammation, and platelet activation may be important molecular mechanisms underlying these pathological changes induced by COVID-19. Furthermore, we discuss the hypotheses of risk factors for COVID-19-associated ALI from genetic, age, and gender perspectives based on our analysis of molecular mechanisms. Additionally, we summarize therapeutic approaches such as use of the interleukin-6 (IL-6) blocker tocilizumab, calcium channel blockers, and angiotensin-converting enzyme inhibitors, providing insights for the future treatment of coronavirus-associated limb ischemic diseases.
Humans ; COVID-19/physiopathology* ; Ischemia/etiology* ; SARS-CoV-2 ; Extremities/blood supply* ; Risk Factors ; Interleukin-6/antagonists & inhibitors* ; Acute Disease ; Angiotensin-Converting Enzyme 2

OBJECTIVE: To study the diagnostic value of P2X7 receptor for rheumatoid arthritis (RA) and its role in the inflammatory response. METHODS: With the synovial tissues from 25 patients with bone and joint replacement as the control,the synovial tissues of 25 RA patients were examined for the relative expression of P2X7 receptor mRNA using qRT-PCR.In an immortalized RA synovial cell line (MH7A),the effect of P2X7 receptor knockdown via a small interfering RNA were examined on the productions of the inflammatory cytokines including interleukin-1β(IL-1β),IL-6,and IL-8 using ELISA. RESULTS: The RA patients showed significantly higher levels of P2X7 receptor mRNA expression in the synovial tissue than the control patients.P2X7 receptor had a good diagnostic value for RA.The expression levels of IL-1β,IL-6,and IL-8 were positively correlated with the levels of P2X7 receptor in the synovial tissues of RA patients (<0.001).In MH7A cells,P2X7 receptor knockdown obviously reduced the secretion of IL-1β and IL-6. CONCLUSIONS RA patients show elevated P2X7 receptor level in the synovial tissue, which has a good diagnostic value for RA.Blocking P2X7 receptor can inhibit inflammatory factor secretion and suppress inflammatory reactions.
Arthritis, Rheumatoid ; diagnosis ; physiopathology ; Case-Control Studies ; Cell Line ; Gene Knockdown Techniques ; Humans ; Inflammation ; metabolism ; Interleukin-1beta ; metabolism ; Interleukin-6 ; metabolism ; Interleukin-8 ; metabolism ; Purinergic P2X Receptor Antagonists ; RNA, Messenger ; metabolism ; Receptors, Purinergic P2X7 ; physiology ; Synovial Membrane ; metabolism

Emerging evidence indicates that aldosterone and mineralocorticoid receptors (MRs) are associated with the pathogenesis of erectile dysfunction. However, the molecular mechanisms remain largely unknown. In this study, freshly isolated penile corpus cavernosum tissue from rats was treated with aldosterone, with or without MRs inhibitors. Nuclear factor (NF)-kappa B (NF-κB) activity was evaluated by real-time quantitative PCR, luciferase assay, and immunoblot. The results demonstrated that mRNA levels of the NF-κB target genes, including inhibitor of NF-κB alpha (IκB-α), NF-κB1, tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6), were higher after aldosterone treatment. Accordingly, phosphorylation of p65/RelA, IκB-α, and inhibitor of NF-κB kinase-β was markedly increased by aldosterone. Furthermore, knockdown of MRs prevented activation of the NF-κB canonical pathway by aldosterone. Consistent with this finding, ectopic overexpression of MRs enhanced the transcriptional activation of NF-κB by aldosterone. More importantly, the MRs antagonist, spironolactone blocked aldosterone-mediated activation of the canonical NF-κB pathway. In conclusion, aldosterone has an inflammatory effect in the corpus cavernosum penis, inducing NF-κB activation via an MRs-dependent pathway, which may be prevented by selective MRs antagonists. These data reveal the possible role of aldosterone in erectile dysfunction as well as its potential as a novel pharmacologic target for treatment.
Aldosterone/pharmacology* ; Animals ; Cytokines/biosynthesis* ; Gene Knockdown Techniques ; I-kappa B Kinase/antagonists & inhibitors* ; Interleukin-6/genetics* ; Male ; Mineralocorticoid Receptor Antagonists/pharmacology* ; NF-kappa B/genetics* ; Penis/metabolism* ; Protein Serine-Threonine Kinases/antagonists & inhibitors* ; RNA, Messenger/biosynthesis* ; Rats ; Rats, Inbred WKY ; Receptors, Mineralocorticoid/genetics* ; Signal Transduction/drug effects* ; Spironolactone/pharmacology* ; Transcriptional Activation ; Tumor Necrosis Factor-alpha/biosynthesis* ; NF-kappaB-Inducing Kinase

OBJECTIVETo study the clinical effect and mechanism of action of esmolol in the treatment of severe hand, foot, and mouth disease (HFMD).

METHODSA prospective randomized controlled trial was performed. A total of 102 children with severe HFMD were enrolled in the study and were randomly divided into conventional treatment and esmolol treatment groups (n=51 each). The children in the conventional treatment group were given conventional treatment according to the guidelines for the diagnosis and treatment of HFMD. Those in the esmolol treatment group were given esmolol in addition to the conventional treatment. The heart rate (HR), systolic blood pressure (SBP), and respiratory rate (RR) were continuously monitored for all children. Blood samples were collected from all children before treatment and 1, 3, and 5 days after treatment to measure the levels of norepinephrine (NE), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and nuclear factor-kappa B (NF-κB) p65 in mononuclear cells. Serum levels of myocardial enzymes and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured before treatment and after 5 days of treatment.

RESULTSThere were no significant differences in HR, SBP, RR, NE, TNF-α, IL-6, NF-κB p65, serum myocardial enzymes, and NT-proBNP before treatment between the conventional treatment and esmolol treatment groups. Both groups had significant reductions in these parameters at each time point (P<0.05). Compared with the conventional treatment group, the esmolol treatment group had significant improvements in the above parameters after 1 and 3 days of treatment (P<0.05). After 5 days of treatment, the esmolol treatment group had significant improvements in serum levels of myocardial enzymes and NT-proBNP compared with the conventional treatment group (P<0.05).

CONCLUSIONSEarly application of esmolol can effectively stabilize the vital signs of the children with severe HFMD. Its mechanism of action may be related to reducing serum catecholamine concentration, alleviating myocardial damage, improving cardiac function, and reducing inflammatory response.

Adrenergic beta-1 Receptor Antagonists ; therapeutic use ; Child, Preschool ; Female ; Hand, Foot and Mouth Disease ; blood ; drug therapy ; physiopathology ; Humans ; Infant ; Interleukin-6 ; blood ; Male ; Natriuretic Peptide, Brain ; blood ; Peptide Fragments ; blood ; Propanolamines ; pharmacology ; therapeutic use ; Prospective Studies ; Tumor Necrosis Factor-alpha ; blood

Dendritic Cells ; cytology ; metabolism ; Enzyme-Linked Immunosorbent Assay ; HEK293 Cells ; Humans ; Interferon Regulatory Factor-7 ; metabolism ; Interferon Type I ; metabolism ; Interferon-gamma ; analysis ; Interleukin-6 ; analysis ; Oligonucleotides ; metabolism ; RNA Interference ; RNA, Small Interfering ; metabolism ; Real-Time Polymerase Chain Reaction ; Receptors, Tumor Necrosis Factor ; antagonists & inhibitors ; genetics ; metabolism

OBJECTIVE: To investigate the effect of limb remote ischemic preconditioning (RIPC) on hepatic ischemia/reperfusion (IR) injury and the underlying mechanisms.
 METHODS: Rats were subjected to partial hepatic IR (60 min ischemia followed by 24 hours reperfusion) with or without RIPC, which was achieved by 3 cycles of 10 min-occlusion and 10 min-
reperfusion at the bilateral femoral arteries interval 30 min before ischemia. Some rats were treated with a new PPAR-γ inhibitor, T0070907, before RIPC.
 RESULTS: At the end of reperfusion, liver injury was significantly increased (increases in Suzike's injury score, AST and ALT release), concomitant with elevated oxidative stress (increases in MDA formation, MPO activity, as well as the decrease in SOD activity) and inflammation (increases in TNF-α and IL-6 levels, decrease in IL-10 content). RIPC improved liver function and reduced histologic damage, accompanied by the increased PPAR-γ activation and autophagosome formation as well as the reduced autophagosome clearance. The beneficial effects of RIPC were markedly attenuated by T0070907, an inhibitor of PPAR-γ.
 CONCLUSION RIPC exerts the protective effects on liver by activation of autophagy via PPAR-γ.
Animals ; Autophagy ; drug effects ; genetics ; physiology ; Extremities ; Interleukin-10 ; metabolism ; Interleukin-6 ; metabolism ; Ischemia ; Ischemic Preconditioning ; methods ; Liver ; injuries ; Liver Diseases ; prevention & control ; Oxidative Stress ; drug effects ; PPAR gamma ; antagonists & inhibitors ; Rats ; Reperfusion Injury ; prevention & control ; Tumor Necrosis Factor-alpha ; metabolism

OBJECTIVETo observe the effect of anti-survivin oligonucleotides (ASODN) on the invasion and growth of peritoneally implanted ovarian cancer cell xenografts in nude mice.

METHODSNude mouse models bearing peritoneally implanted ovarian cancer cell (SKOV3) xenografts were established and subjected to intraperitoneal injection of survivin ASODN or saline (control). The number and weight of the intraperitoneal xenografts were compared between the two groups.The expressions of interleukin (IL-6), signal transducer and activator of transcription3 (STAT3), phosphorylated STAT3 (p-STAT3), and survivin protein in the tumor tissues were detected with Western blotting in both groups.

RESULTSCompared with those in the control group, the number and weight of the intraperitoneal xenografts were significantly reduced in ASODN group (P<0.05). ASODN treatment also resulted in significantly lowered protein levels of IL-6, STAT3, p-STAT3, and survivin in the tumor tissues (P<0.05).

CONCLUSIONSurvivin ASODN can suppress the invasion and migration capacity of ovarian cancer cells and inhibit peritoneal metastasis of the tumor in nude mice possibly though down-regulation of IL-6/STAT3 signaling pathway.

Animals ; Cell Line, Tumor ; Down-Regulation ; Female ; Humans ; Inhibitor of Apoptosis Proteins ; antagonists & inhibitors ; metabolism ; Interleukin-6 ; metabolism ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Oligonucleotides ; pharmacology ; Ovarian Neoplasms ; pathology ; therapy ; STAT3 Transcription Factor ; metabolism

To observe the serum samples and the anti-inflammatory effect of Tripterygium wilfordii in treating RA by using the pharmacokinetic-pharmacodynamic model, make a correlation analysis on concentration-time and effect-time curves, and explore RORγt, IL-17, STAT3, IL-6 mRNA transcriptional levels in rats by PCR. Methotrexate, tripterine and high-dose T. wilfordii could down-regulate RORγt, IL-17, STAT3, IL-6 mRNA transcriptional levels in AA rat lymph nodes. The study on PK-PD model showed correlations between inflammatory factors and blood concentration of T. wilfordii. T. wilfordii and its main active constituent tripterine could show the inflammatory effect and treat RA by inhibiting IL-17 cytokine.
Animals ; Arthritis, Rheumatoid ; drug therapy ; immunology ; Biomarkers ; Female ; Interleukin-17 ; antagonists & inhibitors ; genetics ; Interleukin-6 ; genetics ; Phytotherapy ; Rats ; Rats, Sprague-Dawley ; Tripterygium ; Triterpenes ; pharmacokinetics ; pharmacology

In this study, the effects of catalase (CAT) inhibitor aminotriazole (ATZ) on alcohol-induced acute liver injury were investigated to explore the potential roles of CAT in alcoholic liver injury. Acute liver injury was induced by intraperitoneal injection of alcohol in Sprague Dawley (SD) rats, and various doses of ATZ (100-400 mg/kg) or vehicle were administered intraperitoneally at 30 min before alcohol exposure. After 24 h of alcohol exposure, the levels of aspartate transaminase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH) in plasma were determined. The degree of hepatic histopathological abnormality was observed by HE staining. The activity of hepatic CAT, hydrogen peroxide (H₂O₂) level and malondialdehyde (MDA) content in liver tissue were measured by corresponding kits. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in plasma were determined by ELISA method. The results showed that treatment with ATZ dose-dependently suppressed the elevation of ALT, AST and LDH levels induced by alcohol exposure, and that ATZ alleviated alcohol-induced histopathological alterations. Furthermore, ATZ inhibited the activity of CAT, reduced hepatic levels of H₂O₂and MDA in alcohol exposed rats. ATZ also decreased the levels of plasma TNF-α and IL-6 in rats with alcohol exposure. These results indicated that ATZ attenuated alcohol-induced acute liver injury in rats, suggesting that CAT might play important pathological roles in the pathogenesis of alcoholic liver injury.
Alanine Transaminase ; metabolism ; Amitrole ; pharmacology ; Animals ; Aspartate Aminotransferases ; metabolism ; Catalase ; antagonists & inhibitors ; Ethanol ; Hydrogen Peroxide ; metabolism ; Interleukin-6 ; blood ; L-Lactate Dehydrogenase ; metabolism ; Liver ; enzymology ; Liver Diseases, Alcoholic ; drug therapy ; Malondialdehyde ; metabolism ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha ; blood

Bacterial biofilms have emerged as potential critical triggers in the pathogenesis of bisphosphonate (BP)-related osteonecrosis of the jaw (ONJ) or BRONJ. BRONJ lesions have shown to be heavily colonized by oral bacteria, most of these difficult to cultivate and presents many clinical challenges. The purpose of this study was to characterize the bacterial diversity in BRONJ lesions and to determine host immune response. We examined tissue specimens from three cohorts (n=30); patients with periodontal disease without a history of BP therapy (Control, n=10), patients with periodontal disease having history of BP therapy but without ONJ (BP, n=5) and patients with BRONJ (BRONJ, n=15). Denaturing gradient gel electrophoresis of polymerase chain reaction (PCR)-amplified 16S rRNA gene fragments revealed less bacterial diversity in BRONJ than BP and Control cohorts. Sequence analysis detected six phyla with predominant affiliation to Firmicutes in BRONJ (71.6%), BP (70.3%) and Control (59.1%). Significant differences (P<0.05) in genera were observed, between Control/BP, Control/BRONJ and BP/BRONJ cohorts. Enzyme-linked immunosorbent assay (ELISA) results indicated that the levels of myeloperoxidase were significantly lower, whereas interleukin-6 and tumor necrosis factor-alpha levels were moderately elevated in BRONJ patients as compared to Controls. PCR array showed significant changes in BRONJ patients with downregulation of host genes, such as nucleotide-binding oligomerization domain containing protein 2, and cathepsin G, the key modulators for antibacterial response and upregulation of secretory leukocyte protease inhibitor, proteinase 3 and conserved helix-loop-helix ubiquitous kinase. The results suggest that colonization of unique bacterial communities coupled with deficient innate immune response is likely to impact the pathogenesis of ONJ.
Actinobacteria ; classification ; Bacteria ; classification ; Bacteroidetes ; classification ; Biofilms ; Bisphosphonate-Associated Osteonecrosis of the Jaw ; immunology ; microbiology ; Bone Density Conservation Agents ; therapeutic use ; Cathepsin G ; analysis ; Cohort Studies ; Down-Regulation ; Female ; Fusobacteria ; classification ; Gram-Negative Bacteria ; classification ; Host-Pathogen Interactions ; immunology ; Humans ; I-kappa B Kinase ; analysis ; Immunity, Innate ; immunology ; Interleukin-6 ; analysis ; Male ; Middle Aged ; Mouth ; immunology ; microbiology ; Myeloblastin ; analysis ; antagonists & inhibitors ; Nod2 Signaling Adaptor Protein ; analysis ; Periodontal Diseases ; microbiology ; Peroxidase ; analysis ; Proteobacteria ; classification ; Tumor Necrosis Factor-alpha ; analysis