Paeoniflorin alleviates lipopolysaccharide-induced disseminated intravascular coagulation by inhibiting inflammation and coagulation activation.

Lipopolysaccharide (LPS) is a toxic component of the outer membrane of gram-negative bacteria that can activate the blood coagulation system, leading to disseminated intravascular coagulation (DIC). DIC is a syndrome characterized by thromboembolism and multiple organ failure. Herein, the beneficial effect of paeoniflorin (PF) on the alleviation of LPS-induced DIC was investigated with an experimental DIC mouse model. Briefly, mice were randomly divided into the following six groups: (1) control; (2) LPS; (3) heparin; (4) low-PF treatment; (5) medium-PF treatment; and (6) high-PF treatment. The histological morphology of the liver and kidney was observed, and the coagulation indicators (such as prothrombin time), function indicators (such as alanine transferase), and inflammatory factors (such as TNF-α) were detected. Additionally, an in vitro cell inflammation model using RAW 264.7 murine macrophages was established. Activation of the nuclear factor kappa B (NF-κB) signaling pathway and tumor necrosis factor-α (TNF-α) were determined by western blotting. Based on our findings, PF could significantly improve the histological morphology of the liver and kidney, indicating that PF protects the liver and kidney against damage induced by LPS. Additionally, PF improved the function and coagulation indicators and reduced the production of inflammatory factors. In vitro, PF inhibited the expression of TNF-α by suppressing NF-κB signaling pathway activation. Collectively, our findings support the hypothesis that PF has anti-inflammatory and anticoagulation effects for the alleviation of LPS-induced DIC. PF is thus a potential co-treatment option for DIC.

Comprehensive assessment of the association between genes on JAK-STAT pathway (IFIH1, TYK2, IL-10) and systemic lupus erythematosus: a meta-analysis.

Previous studies have reported that genes relating to JAK-STAT pathway (IFIH1, TYK2 and IL-10) conferred the susceptibility to SLE. In this study, we performed a meta-analysis (including 43 studies) to evaluate the association between IFIH1 (9288 patients and 24,040 controls), TYK2 (4928 patients and 11,536 controls), IL-10 (3623 patients and 4907 controls) polymorphisms and systemic lupus erythematosus (SLE) in a comprehensive way. We found that IFIH1 rs1990760_T allele was associated with risk of SLE in overall population under three models (allelic: P = 2.56 × 10-11, OR 1.135, 95% CI 1.094-1.179, dominant: P = 1.8 × 10-8, OR 1.203, 95% CI 1.128-1.284, recessive: P = 2.6 × 10-7, OR 1.163, 95% CI 1.098-1.231). A strong association had been observed between TYK2 polymorphism rs2304256_C allele and SLE in Europeans (P = 5.82 × 10-5, OR 1.434, 95% CI 1.203-1.710). When coming to overall population, TYK2 rs2304256_C showed a significant association with SLE under recessive model (P = 8.05 × 10-3, OR 1.314, 95% CI 1.074-1.608). However, the other two SNPs (rs12720270, rs280519) of TYK2 were not significant. The results also indicated an association between IL-10 rs1800896_G allele and SLE in Asians under recessive model (P = 4.65 × 10-3, OR 2.623, 95% CI 1.346-5.115), while, IL-10 rs1800896_G had a trend of association with SLE in European population in dominant model (P = 1.21 × 10-2, OR 1.375, 95% CI 1.072-1.764). In addition, we found IL-10 rs1800896 GG homozygote might be associated with increased susceptibility to SLE (GG vs AA, P = 4.65 × 10-3, OR 1.539, 95% CI 1.142-2.072). We concluded that IFIH1 rs1990760_T and TYK2 rs2304256_C alleles were significantly associated with SLE, and IL-10 rs1800896 GG homozygote might have an enhancement effect on SLE risk.

Genistein has the function of alleviating and treating disseminated intravascular coagulation caused by lipopolysaccharide.

Symptoms of disseminated intravascular coagulation (DIC) include thromboembolism, acute attrition bleeding and multiple organ failure. Genistein isolated from leguminous plants has been shown to be effective in oxidation resistance and tumor inhibition. The present study was designed to evaluate the therapeutic effects of genistein in DIC and preliminarily discuss the mechanisms regarding the anti-inflammatory and anticoagulant effect of genistein. Swiss mice were randomly divided into the following groups-(1) lipopolysaccharide (LPS), (2) genistein, (3) dimethyl sulfoxide (DMSO, the non-major solvent component of genistein), (4) DMSO + LPS, (5) saline control group, and (6) heparin control group. LPS was injected intraperitoneally in all the groups except the DMSO group and saline control group. Our results significantly showed that the morphological structure of the liver and kidneys was improved and the fiber protein deposition was decreased, with remarkable improvement of coagulation indicators, function indicators and inflammatory factors in the genistein treatment group compared with the LPS group. In vitro phosphorylated-nuclear factor kappa-light-chain-enhancer of activated B cells and interleukin-6 were obviously reduced in the genistein treatment group compared with the LPS group in RAW 264.7 murine macrophage cells. All the results suggested that genistein has the function of alleviating and treating LPS-induced DIC by anti-inflammatory and anticoagulation effects. We tentatively propose that genistein is a potential drug for auxiliary treatment of DIC.

Factors Associated with Development of Vitiligo in Patients with Halo Nevus.

BACKGROUND: Halo nevus (HN) has been shown to be associated with vitiligo, but no standard signs are currently available to identify HN patients at risk of vitiligo, and the relevant data obtained in previous studies are somewhat conflicting. This study aimed to identify factors affecting the presence of vitiligo in HN patients. METHODS: We performed a retrospective study on consecutive patients with HN at the First Affiliated Hospital of Sun Yat-sen University between January 2011 and December 2016. Detailed demographic and clinical data were collected to identify the factors associated with the presence of vitiligo in this cohort of patients using uni- and multi-variate logistic regression analyses. RESULTS: A total of 212 HN patients were included, 101 of whom had vitiligo-associated HN (HNV). Univariate analysis indicated that a personal history of thyroid diseases was positively associated with HNV (odds ratio [OR] = 10.761, P = 0.025), while the onset age of HN was negatively associated with HNV (OR = 0.537, P = 0.026). Multivariate analysis demonstrated that the Koebner phenomenon (KP; OR = 10.632, P < 0.0001), multiple HN (OR = 3.918, P < 0.0001), and a familial history of vitiligo (OR = 3.222, P = 0.014) were independent factors associated with HNV. CONCLUSIONS: HN without vitiligo has clinical features distinct from HN associated with vitiligo. HN patients with KP, multiple lesions, or familial history of vitiligo are more likely to develop vitiligo and therefore should be monitored for clinical signs of such accompanied conditions.

Comprehensive analysis of circRNA expression profiles in humans by RAISE.

Circular RNAs (circRNAs) are pervasively expressed circles of non­coding RNAs. Even though many circRNAs have been reported in humans, their expression patterns and functions remain poorly understood. In this study, we employed a pipeline named RAISE to detect circRNAs in RNA­seq data. RAISE can fully characterize circRNA structure and abundance. We evaluated inter-individual variations in circRNA expression in humans by applying this pipeline to numerous non­poly(A)-selected RNA­seq data. We identified 59,128 circRNA candidates in 61 human liver samples, with almost no overlap in the circRNA of the recruited samples. Approximately 89% of the circRNAs were detected in one or two samples. In comparison, 10% of the linear mRNAs and non­coding RNAs were detected in each sample. We estimated the variation in other tissues, especially the circRNA high-abundance tissues, in advance. Only 0.5% of the 50,631 brain circRNA candidates were shared among the 30 recruited brain samples, which is similar to the proportion in liver. Moreover, we found inter- and intra-individual diversity in circRNAs expression in the granulocyte RNA­seq data from seven individuals sampled 3 times at one-month intervals. Our findings suggest that careful consideration of inter-individual diversity is required when extensively identifying human circRNAs or proposing their use as potential biomarkers and therapeutic targets in disease.

Atractylenolide â protects against lipopolysaccharide-induced disseminated intravascular coagulation by anti-inflammatory and anticoagulation effect.

OBJECTIVE: To investigate whether atractylenolide Ⅰ (ATL-Ⅰ) has protective effect on lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC) in vivo and in vitro, and explore whether NF-κB signaling pathway is involved in ATL-Ⅰ treatment. METHODS: New Zealand white rabbits were injected with LPS through marginal ear vein over a period of 6 h at a rate of 600 µg/kg (10 mL/h). Similarly, in the treatment groups, 1.0, 2.0, or 5.0 mg/kg ATL-Ⅰ were given. Both survival rate and organ function were tested, including the level of alanine aminotransferase (ALT), blood urine nitrogen (BUN), and TNF-α were examined by ELISA. Also hemostatic and fibrinolytic parameters in serum were measured. RAW 264.7 macrophage cells were administered with control, LPS, LPS + ATL-Ⅰ and ATL-Ⅰ alone, and TNF-α, phosphorylation (P)-IκBα, phosphorylation (P)-NF-κB (P65) and NF-κB (P65) were determined by Western blot. RESULTS: The administration of LPS resulted in 73.3% mortality rate, and the increase of serum TNF-α, BUN and ALT levels. When ATL-Ⅰ treatment significantly increased the survival rate of LPS-induced DIC model, also improved the function of blood coagulation. And protein analysis indicated that ATL-I remarkably protected liver and renal as decreasing TNF-α expression. In vitro, ATL-I obviously decreased LPS-induced TNF-α production and the expression of P-NF-κB (P65), with the decrease of P-IκBα. CONCLUSIONS: ATL-Ⅰ has protective effect on LPS-induced DIC, which can elevate the survival rate, reduce organ damage, improve the function of blood coagulation and suppress TNF-α expression by inhibiting the activation of NF-κB signaling pathway.

Combined hepatocellular cholangiocarcinoma: Controversies to be addressed.

Combined hepatocellular cholangiocarcinoma (CHC) accounts for 0.4%-14.2% of primary liver cancer cases and possesses pathological features of both hepatocellular carcinoma and cholangiocarcinoma. Since this disease was first described and classified in 1949, the classification of CHC has continuously evolved. The latest definition and classification of CHC by the World Health Organization is based on the speculation that CHC arises from hepatic progenitor cells. However, there is no evidence demonstrating the common origin of different components of CHC. Furthermore, the definition of CHC subtypes is still ambiguous and the identification of CHC subtype when a single tumor contains many components has remained unresolved. In addition, there is no summary on the newly recognized histopathology features or the contribution of CHC components to prognosis and outcome of this disease. Here we provide a review of the current literature to address these questions.

NADPH oxidase-2 is a key regulator of human dermal fibroblasts: a potential therapeutic strategy for the treatment of skin fibrosis.

The proliferation of human skin dermal fibroblasts (HDFs) is a critical step in skin fibrosis, and transforming growth factor-beta1 (TGF-ß1) exerts pro-oxidant and fibrogenic effects on HDFs. In addition, the oxidative stress system has been implicated in the pathogenesis of skin disease. However, the role of NADPH oxidase as a mediator of TGF-ß1-induced effects in HDFs remains unknown. Thus, our aim was to investigate the role of NADPH in human skin dermal fibroblasts. Primary fibroblasts were cultured and pretreated with various stimulants. Real-time Q-PCR and Western blotting analyses were used for mRNA and protein detection. In addition, siRNA technology was applied for gene knock-down analysis. Hydrogen peroxide production and 2',7'-dichlorofluorescein diacetate (DCFDA) measurement assay were performed. Here, our findings demonstrated that HDFs express key components of non-phagocytic NADPH oxidase mRNA. TGF-ß1 induced NOX2 and reactive oxygen species formation via NADPH oxidase activity. In contrast, NOX3 was barely detectable, and other NOXs did not display significant changes. In addition, TGF-ß1 phosphorylated MAPKs and increased activator protein-1 (AP-1) in a redox-sensitive manner, and NOX2 suppression inhibited baseline and TGF-ß1-mediated stimulation of Smad2 phosphorylation. Moreover, TGF-ß1 stimulated cell proliferation, migration, collagen I and fibronectin expression, and bFGF and PAI-1 secretion: these effects were attenuated by diphenylene iodonium (DPI), an NADPH oxidase inhibitor, and NOX2 siRNA. Importantly, NOX2 siRNA suppresses collagen production in primary keloid dermal fibroblasts. These findings provide the proof of concept for NADPH oxidase as a potential target for the treatment of skin fibrosis.

Recurrent facial erythema with burning sensation and increased temperature: a variant of erythromelalgia or a new entity?

OBJECTIVE: Erythromelalgia is a rare clinical syndrome characterized by episodic attacks of burning pain, erythema, and increased temperature, primarily affecting the extremities, and in rare instances, involving the ear, face, neck, and the scrotum. The dermatoscopic features of erythromelalgia in a case with solely facial involvement have never been described previously. OBSERVATIONS: We describe a 14-year-old female who presented with erythema, burning sensation, and warmth on her face only, which mimic the features of erythromelalgia. Physical examination showed higher temperature on the involved cheeks than on axillas during the episode, while the temperature on both areas was the same between episodes. Dermatoscope showed more dilated vessels inside the erythema during the episodes than between the episodes. The symptoms had excellent response to the combination treatment of gabapentin, indomethacin, and topical lidocaine compounds. CONCLUSIONS: The present case is considered to be a variant of erythromelalgia. Its erythema may be resulted from the dilated vessels. Combination of modalities may provide effective management for erythromelalgia. "Erythermalgia" may be better than "erythromelalgia" to describe such conditions.

Effects of quercetin on LPS-induced disseminated intravascular coagulation (DIC) in rabbits.

INTRODUCTION: Quercetin is widely distributed in plants and has been reported to have effects of anti-inflammation and anti-thrombosis. In this study, we evaluated the protective effect of quercetin on LPS-induced experimental DIC in rabbits, and tried to clarify its mechanism against DIC. MATERIALS AND METHODS: LPS-induced DIC model in rabbits was established through continuous infusion of 100 ug · kg(-1) · h(-1) LPS for a period of 6h. Six groups were divided: quercetin-treated groups (0.5, 1.0, and 2.0 mg·kg(-1) · h(-1), respectively), LPS-control group, heparin-control group (100 IU · kg(-1) · h(-1)), and saline-control group. APTT, PT, and plasma FIB level were measured, the plasma levels of ALT, BUN, and TNF-α were detected, and the activity of Protein C and ATIII was recorded. RESULTS: A continuous injection of LPS induced a gradual impairment of hemostatic parameters, a rise in plasma level of TNF-α, and damage in renal and hepatic function. The intravenous administration of quercetin significantly attenuated the increase of APTT, PT, ALT, BUN, and TNF-α, and the decrease of plasma FIB level and activity of Protein C and ATIII. CONCLUSION: Quercetin may have a protective effect against LPS-induced DIC in rabbits through anti-inflammation and anticoagulation.

The glycogen synthase kinase-3ß/nuclear factor-kappa B pathway is involved in cinobufagin-induced apoptosis in cultured osteosarcoma cells.

Cinobufagin, a major component of cinobufacini (huachansu), is an important cardenolidal steroid. Several studies have suggested that cinobufagin has potent anti-cancer effects. The present study examines the apoptosis-inducing activity and the underlying mechanism of action of cinobufagin in osteosarcoma (OS) cells. Our results showed that cinobufagin potently inhibited the proliferation of U2OS, MG63 and SaOS-2 cells. Significant increases in G2/M cell-cycle arrest and apoptosis in OS cells were also observed. The expression levels of several apoptotic proteins were assessed after cinobufagin treatment in U2OS cells. Among them, xIAP, cIAP-1, survivin and Bcl-2 levels decreased remarkably, while the levels of Bax and cleaved-PARP increased. Furthermore, we validated the inhibition of GSK-3ß/NF-κB signaling following cinobufagin treatment. Western blots showed a decrease in nuclear p65 protein expression after exposure to different concentrations of cinobufagin, while the phosphorylation of GSK-3ß was simultaneously increased. Transduction with constitutively active forms of GSK-3ß could protect against the downregulation of p65 and upregulation of cleaved-PARP that are induced by cinobufagin treatment. However, combined treatment with cinobufagin and SB216367 resulted in a significant reduction in p65 and an increase in cleaved-PARP in U2OS cells. Altogether, these results show that cinobufagin is a promising agent for the treatment of OS. These studies are the first to reveal the involvement of the GSK-3ß/NF-κB pathway in cinobufagin-induced apoptosis.

Tanshinone IIA protects rabbits against LPS-induced disseminated intravascular coagulation (DIC).

AIM: To evaluate the effects of tanshinone IIA (Tan IIA), a lipophilic diterpene from the Chinese herb Salvia miltiorrhiza, on lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC) in rabbits. METHODS: LPS-induced DIC model was made in adult male New Zealand rabbits by continuous intravenous infusion of LPS (0.5 mg/kg) via marginal ear vein for 6 h. The animals were simultaneously administered with Tan IIA (1, 3 and 10 mg/kg) or heparin (500 000 IU/kg) through continuous infusion via the contralateral marginal ear vein for 6 h. Before and 2 and 6 h after the start of LPS infusion, blood samples were taken for biochemical analyses. RESULTS: Continuous infusion of LPS into the rabbits gradually impaired the hemostatic parameters, damaged renal and liver functions, increased the plasma TNF-α level, and led to a high mortality rate (80%). Treatment of the rabbits with Tan IIA dose-dependently attenuated the increase in activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrin-fibrinogen degradation products (FDP); ameliorated the decrease in plasma levels of fibrinogen and platelets; and reversed the decline in activity of protein C and antithrombin III. Meanwhile, the treatment significantly suppressed the increase in the plasma levels of aminotransferase, creatinine and TNF-α, and led to much lower mortality (46.7% and 26.7% for the medium- and high-dose groups). Treatment of the rabbits with the high dose of heparin also effectively improved the hemostatic parameters, ameliorated liver and renal injuries, and reduced the plasma level of TNF-α, and significantly reduced the mortality (33.3%). CONCLUSION: Tan IIA exerts a protective effect against DIC in rabbits.

Interdigital ulcer: an unusual presentation of Candida infection.

Interdigital ulcer is an exceptionally rare condition while erosio interdigitalis blastomycetica is common for candidiasis. Four Chinese patients with Candida interdigital ulcers were reported. The exudates were examined directly and cultured for fungi. Skin biopsies were stained with haematoxylin-eosin and periodic acid Schiff. There were a man and three women (age range: 34-56 years) who presented with 1- to 3-month history of chronic cutaneous ulcer on the interdigital web of hand or foot. The lesions were located on hand for one woman, and on the left foot for the rest. The patients had poor response to the previous treatment of topical steroids and oral antimicrobials. Candida albicans was isolated from a man and two women, Candida tropicalis from another woman. Biopsy specimens revealed yeast and mycelium as well as inflammatory infiltrate in necrotic tissue in two patients; only inflammatory cells in the other two. The patients had complete remission with oral itraconazole and topical bifonazole cream therapy for 3- to 5-week. Candida species may cause interdigital ulcer on hand or foot. Oral itraconazole and topical bifonazole may be an optional therapy for such an ulcer.

Acral persistent papular mucinosis: a case report and literature review.

Acral persistent papular mucinosis is a rare subtype of localized lichen myxedematosus. It shows symmetric, asymptomatic, chronic, ivory to flesh-colored, 2-5 mm sized papules arranged on the dorsa of the hands and extensor aspects of the distal forearms. Thirty-two cases including two from China, appear to fit the proposed diagnostic criteria. We report a 31-year-old Chinese woman who presented with papules on the extensor aspects of her hands and distal forearms. Histopathology revealed a circumscribed area in the upper and mid reticular dermis with splaying of collagen fibers caused by amorphous deposits. The material was mucin, as it stained positively with alcian blue at pH 2.5. The thyroid profile was normal, and there was no evidence for lupus erythematous. The lesions were treated with electrofulguration and resolved leaving mild scars; there has been no recurrence at follow-up after one year. We also review the literature on this rare form of mucinosis.

Aquagenic acrokeratoderma.

BACKGROUND: Aquagenic acrokeratoderma (AA) is a rare condition with female predilection that occurs after brief water exposure and disappears minutes to an hour after drying. The pathogenesis remains unclear. METHODS: Four Chinese patients with AA were reported and analyzed. RESULTS: There were 2 males and 2 females (age range: 14-33 years) who presented with a 2-week to more than 10-year history of small white papules coalescing into edematous plaques on the hands; lesions appeared within 5-10 minutes of water exposure, began to regress in 3-20 minutes and disappeared within 5 minutes to one hour after drying. Warm water provoked the lesions more rapidly than cold water. Lesions of a female patient could be triggered by detergent. In another female patient, lesions also involved the feet and were associated with palmoplantar erythema and hyperhidrosis. Biopsy from the lesion of one patient after water exposure revealed hyperkeratosis, mild hypergranulosis, and dilatated eccrine ducts. Biopsy from the lesion of another patient after drying showed normal epidermis and dermis. Two patients were treated with topical formalin 3% in alcohol, and two with 3% potassium aluminium sulfate solution with partial relief without any adverse effects. CONCLUSION: AA may occur in both males and females and may involve the feet. Warm water triggers the lesions more rapidly than cold. Topical formalin 3% in alcohol and 3% potassium aluminium sulfate solution may be optional therapy.