Increased Circulating IL-32 Is Associated With Placenta Macrophage-derived IL-32 and Gestational Diabetes Mellitus.

OBJECTIVE: Placenta-derived inflammation plays a vital role in the pathophysiology of gestational diabetes mellitus (GDM). IL-32 is a novel pro-inflammatory cytokine and metabolic regulator involved in the development of metabolic disease. We investigated the effect of IL-32 in GDM. MATERIALS AND METHODS: First-trimester C-reactive protein (CRP) level was monitored in a case-control study of 186 women with GDM and 186 women without. Placental tissue was lysed and analyzed by high-resolution liquid chromatography-tandem mass spectrometry. Circulating level of inflammatory cytokines IL-32, IL-6, and TNF-α were measured by ELISA kits. The expression of placenta-derived macrophages, inflammatory cytokines, and related pathway proteins were assessed by reverse transcriptase-quantitative PCR, western blot, immunohistochemistry, or immunofluorescence. RESULTS: First-trimester CRP level in peripheral blood was closely associated with glucose and insulin resistance index and was an independent correlation with the development of GDM. High-resolution liquid chromatography-tandem mass spectrometry revealed that placenta-derived CRP expression was dramatically elevated in women with GDM. Interestingly, the expression of placenta-derived IL-32 was also increased and located in the macrophages of placental tissue. Meanwhile, the expression of IL-6, TNF-α, and p-p38 were up-regulated in the placental tissues with GDM. Either IL-6 or TNF-α was colocated with IL-32 in the placental tissue. Importantly, circulating IL-32 throughout pregnancy was increased in GDM and was related to placental-derived IL-32 expression, circulating IL-6, and TNF-α, glucose and insulin resistance index. CONCLUSION: Increased circulating IL-32 throughout pregnancy was closely associated with placenta macrophage-derived IL-32 expression and GDM. First trimester IL-32 level in peripheral blood may serve to predict the development of GDM.

Perilipin5 protects against non-alcoholic steatohepatitis by increasing 11-Dodecenoic acid and inhibiting the occurrence of ferroptosis.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a major contributor to liver cirrhosis and hepatocellular carcinoma. There remains no effective pharmacological therapy. The hepatic lipid metabolism and fatty acid ß-oxidation are regulated by Perilipin5 (Plin5). However, it is yet unknown how Plin5 affects NASH and the molecular process. METHODS: High-fat, high-cholesterol and high-fructose (HFHC) diets were used to mimic the progression of NASH in wild type (WT) mice and Plin5 knockout (Plin5 KO) mice. The degree of ferroptosis was measured by detecting the expression of key genes of ferroptosis and the level of lipid peroxide. The degree of NASH was judged by observing the morphology of the liver, detecting the expression of inflammation and fibrosis related genes of liver damage. Plin5 was overexpressed in the liver of mice by tail vein injection of adenovirus, and the process of NASH was simulated by methionine choline deficiency (MCD) diet. The occurrence of ferroptosis and NASH was detected by the same detection method. Targeted lipidomics sequencing was used to detect the difference in free fatty acid expression in the WT Plin5 KO group. Finally, it was verified in cell experiments to further study the effect of free fatty acids on ferroptosis of hepatocytes. RESULTS: In various NASH models, hepatic Plin5 was dramatically reduced. Plin5 knockout (KO) worsened NASH-associated characteristics in mice given a high-fat/high-cholesterol (HFHC) diet, such as lipid accumulation, inflammation and hepatic fibrosis. It has been shown that ferroptosis is involved in NASH progression. We revealed that Plin5 KO in mice aggravated the degree of ferroptosis in NASH models. Conversely, overexpression of Plin5 significantly alleviated ferroptosis and further ameliorated progression of MCD-induced NASH. Analysis of livers obtained from HFHC diet-fed mice by targeted lipidomics revealed that 11-Dodecenoic acid was significantly decreased in Plin5 KO mice. Addition of 11-Dodecenoia acid to Plin5 knockdown hepatocytes effectively prevented ferroptosis. CONCLUSION: Our study demonstrates that Plin5 protects against NASH progression by increasing 11-Dodecenoic acid level and further inhibiting ferroptosis, suggesting that Plin5 has therapeutic potential as a target for the management of NASH.

Decreased Monocyte Count Is Associated With Gestational Diabetes Mellitus Development, Macrosomia, and Inflammation.

CONTEXT: The immune system plays a central role in the pathophysiology of gestational diabetes mellitus (GDM). Monocytes, the main innate immune cells, are especially important in the maintenance of a normal pregnancy. OBJECTIVE: Here, we investigated the potential effect of monocytes in GDM. METHODS: Monocyte count was monitored throughout pregnancy in 214 women with GDM and 926 women without in a case-control and cohort study. Circulating levels of inflammatory cytokines, placenta-derived macrophages, and their products were measured. RESULTS: Throughout pregnancy, monocyte count was significantly decreased in women with GDM, and was closely associated with glucose level, insulin resistance, and newborn weight. First-trimester monocyte count outperformed that of the second and third trimester as a risk factor and diagnostic predictor of GDM and macrosomia both in the case-control and cohort study. In addition, our cohort study showed that as first-trimester monocyte count decreased, GDM and macrosomia incidence, glucose level, and newborn weight increased in a stepwise manner. Risk of GDM started to decrease rapidly when first-trimester monocyte count exceeded 0.48 × 109/L. Notably, CD206 and interleukin 10 (IL-10) were significantly lower, whereas CD80, CD86, tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) were higher both in GDM placental tissue and peripheral blood. First-trimester monocyte count was positively related to IL-10 and CD206, but negatively related to CD80, CD86, TNF-α, and IL-6. CONCLUSION: Decreased monocyte count throughout pregnancy was closely associated with the development of GDM, macrosomia, and the chronic inflammatory state of GDM. First-trimester monocyte count has great potential as an early diagnostic marker of GDM.

Alterations in CD8+ Tregs, CD56+ Natural Killer Cells and IL-10 Are Associated With Invasiveness of Nonfunctioning Pituitary Adenomas (NFPAs).

Invasive nonfunctioning pituitary adenomas (NFPAs) grow rapidly and the mechanisms are unclear. Among many complex mechanisms, the role of immunity in the development of NFPAs has not been fully explored. Here, we analyzed the clinical features 146 NFPA patients who underwent trans-sphenoidal surgery or craniotomy and examined the effects of immune tolerance in invasiveness of NFPA patients using fluorescence-activated cell sorting and immunohistochemical methods. We found patients with invasive NFPAs had more visual deficits and defective fields, higher tumor size, and lower white blood cell count compared with patients with noninvasive NFPAs. Additionally, compared with patients with noninvasive NFPAs, patients with invasive NFPAs had conspicuously lower CD3-CD56+ natural killer (NK) cells and significantly higher levels of CD3+CD8+CD28-T cells (CD8+ Tregs) and interleukin-10 (IL-10) in peripheral blood. Moreover, patients with invasive NFPAs had lower infiltrated CD56+ cells, less infiltrated CD28+ cells, and significantly greater IL-10 expression. These results demonstrated that low CD56+ cells infiltration and CD28+ cells infiltration, as well as high IL-10 expression in pituitary tumor tissues, were related with increased invasiveness of NFPAs. Levels of CD3-CD56+ NK cells, CD8+ Tregs and IL-10 in the peripheral blood could be feasible diagnostic markers for invasive NFPAs.

Berberine prevents non-alcoholic steatohepatitis-derived hepatocellular carcinoma by inhibiting inflammation and angiogenesis in mice.

Hepatocellular carcinoma (HCC) is one of the most malignant and poor prognosis tumors, which was increasingly caused by nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) in western countries. In this study, we aimed to investigate the mechanism and therapeutic prospect of berberine in the treatment of NASH-HCC mice. Combination of STZ injection and high fat and high-cholesterol diet (HFHC) was used to establish NASH-HCC model. The effect of berberine intervention is studied from histology, biochemistry and molecular level. Our results showed that administration of berberine to NASH-HCC mice reduced the incidence of tumors and mitigated NASH. Berberine significantly reduced the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), glucose (GLU), high-density lipoprotein (HDL), low-density lipoprotein (LDL) and total cholesterol (TC). Transcriptome sequencing and bioinformatics analysis identified numberous genes and various pathways may participate in the favorite effect of berberine. Specifically, berberine suppressed the expressions of genes related to lipogenesis, inflammation, fibrosis and angiogenesis. Moreover, our results showed that berberine suppressed phosphorylation of p38MAPK and ERK as well as COX2 expression significantly. This suggested berberine achieved its biological functions mainly by regulating inflammation and angiogenesis genes involving p38MAPK/ERK-COX2 pathways. This study demonstrated the anti-tumor effects of berberine and its possible mechanism, providing a potential drug for treating NASH-HCC.

Haptoglobin 2-2 Genotype is Associated with More Advanced Disease in Subjects with Non-Alcoholic Steatohepatitis: A Retrospective Study.

INTRODUCTION: Haptoglobin (Hp) genotypes were reported as an independent risk factor for metabolic diseases. This study aimed to investigate the association between Hp gene polymorphism and the severity of nonalcoholic fatty liver disease (NAFLD). METHODS: A total of 441 subjects (NAFLD group, n = 272; healthy control, n = 169) were recruited, and their clinical biochemical parameters were measured in all subjects. Haptoglobin genotyping was performed using genomic DNA extracted from peripheral blood leukocytes. Among the NAFLD group, 107 patients underwent liver biopsy, and histology was evaluated by a pathologist on the basis of the CRN scoring system. RESULTS: NAFLD patients had much lower frequency of Hp 1-1 genotype and higher frequency of Hp 2-2 than healthy controls (0.4% vs 9.5%, 55.8% vs 47.9%, P < 0.001). NAFLD patients with Hp 2-2 genotype had much higher levels of body mass index (BMI), total cholesterol (TC), liver enzymes, ferritin, and controlled attenuation parameter (CAP) values than non-Hp 2-2 genotype (P < 0.05). In histology, patients with nonalcoholic steatohepatitis (NASH) had higher frequency of Hp 2-2 genotype than non-NASH patients (71.3% vs 22.2%, P < 0.001); patients with significant fibrosis had higher frequency of Hp 2-2 genotype (78.3% vs 54.8%, P < 0.05) than no/mild fibrosis patients. NAFLD patients with Hp 2-2 genotype had higher proportion with higher steatosis scores, lobular inflammation scores, ballooning scores, NAFLD activity scores (NAS), and fibrosis stages (P < 0.05 for all) than Hp 2-2 groups. Furthermore, Hp 2-2 genotype was independently associated with NASH (OR = 5.985, P < 0.05) and significant fibrosis (OR = 6.584, P < 0.05). CONCLUSIONS: Hp 2-2 genotype is closely associated with the severity of NAFLD.

The association between nonalcoholic fatty liver disease and risk of colorectal adenoma and cancer incident and recurrence: a meta-analysis of observational studies.

BACKGROUND & AIM: Lifestyle modification plays a key role in nonalcoholic fatty liver disease (NAFLD) and colorectal adenoma and/or cancer (CRA/CRC) development. However, the association between NAFLD and the risk of CRA/CRC has not been carefully evaluated. METHODS: In this meta-analysis, we assessed 21 eligible studies including 124,206 participants to determine the association between NAFLD and the risk of incident and recurrent CRA/CRC. RESULTS: NAFLD presence was associated with an increased risk of any incident CRA (aOR: 1.30, 95% CI: 1.19-1.43) and advanced incident CRA/CRC (aOR: 1.57, 95% CI: 1.21-2.04). The severity of NAFLD affected this correlation: compared to mild and/or moderate NAFLD, severe NAFLD was associated with an increased risk of incident CRA/CRC (aOR: 2.19, 95% CI: 1.33-3.60). Although pooled cOR revealed that NAFLD was associated with an increased risk of recurrent CRA/CRC (cOR = 1.73; 95% CI: 1.12-2.68), after adjustment for confounding factors, NAFLD had less correlation with the risk of recurrent CRA/CRC (aOR: 1.81, 95% CI: 0.70-4.65). CONCLUSIONS: The presence and severity of NAFLD are associated with an increased risk of incident CRA/CRC. However, there is insufficient evidence to indicate that NAFLD is associated with an increased risk of recurrent CRA/CRC.

Haptoglobin Genotype and Vitamin E Versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis in China: A Multicenter, Randomized, Placebo-Controlled Trial Design.

INTRODUCTION: Vitamin E is one of the most promising agents for nonalcoholic steatohepatitis (NASH) treatment, and its drug responsiveness may be closely associated with haptoglobin (Hp) genotype. However, its efficacy and safety remain unknown in China. This clinical trial of vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis (VENS) is conducted to evaluate (a) the efficacy and safety of treatment with vitamin E softgel (300 mg/day) determined from standardized histologic scoring of liver biopsies, (b) whether treatment with vitamin E improves biochemical parameters, cytokines, anthropometric parameters, controlled attenuation parameter (CAP), and transient elastography (TE) values determined by Fibroscan and health-related quality of life (SF-36), (c) whether the efficacy of vitamin E treatment is associated with the Hp genotype in nondiabetic adults with NASH. METHODS: VENS is a multicenter, randomized, double-masked, placebo parallel controlled trial to evaluate the efficacy and safety of treatment with vitamin E softgel in nondiabetic adults with NASH versus treatment with placebo in China. Liver biopsies are read by a pathological evaluation committee independently according to the NASH Clinical Research Network (CRN) scoring system. The NAFLD activity score (NAS) represents the sum of scores for steatosis, lobular inflammation, and hepatocyte ballooning. The definition of histologic improvement requires all three of the following criteria to be met: (a) either improvement in NAS by at least 2 points or post-treatment NAS score no higher than 3, (b) at least 1-point improvement in the score for ballooning, and (c) no worsening of fibrosis stages. We plan to recruit 120 biopsy-proven NASH patients from13 centers in China. Participants will be randomly assigned to groups treated with either with vitamin E (100 mg, tid) or placebo for 96 weeks then followed by 24 weeks of post-treatment observation. Biochemical parameters, cytokines, anthropometric parameters, CAP and TE values, Hp genotype, and several questionnaires will be collected as per the schedule. This protocol was approved by the Ethics Committee of Hangzhou Normal University Affiliated Hospital to ensure patients safety, and R&G Pharmastudies Co., Ltd. was established for monitoring the accumulated interim data to review efficacy and quality of data collection and overall study management. RESULTS: As a preliminary study, a mobile phone application (app) for lifestyle modification and database recording ( http://laiyivens.365hy.com ) was exploited for every participant. The percentage of NAFLD patients with Hp 2-2 allele is much higher than that of Western patients (65.71% vs 36%, respectively), which suggests that the Chinese benefit more from vitamin E treatment. CONCLUSION: VENS is the first randomized controlled trial (RCT) to evaluate the efficacy of Vitamin E in treating nondiabetic NASH patients in China. TRIAL REGISTRATION: This study registered at https://clinicaltrials.gov (registration number: NCT02962297). FUNDING: Zhejiang Medicine Co., Ltd.

Relationship of serum uric acid level with non-alcoholic fatty liver disease and its inflammation progression in non-obese adults.

AIM: This study aimed to evaluate the relationship between serum uric acid (SUA) level and non-alcoholic fatty liver disease (NAFLD) in non-obese adults. METHODS: A cross-sectional study was carried out among 4098 adults, including 1936 non-obese and 2162 obese individuals. An additional 93 non-obese adults with biopsy-proven NAFLD were also included. RESULTS: The overall prevalence of NAFLD was 39.51% in the study group, and 14.88% in non-obese adults. The NAFLD patients had significantly higher SUA levels than controls in both men and women. The non-obese group had a higher NAFLD risk with increased SUA levels than the obese group, with odd ratios (95% confidence interval) of 2.559 (1.870-3.503) and 1.692 (1.371-2.087), respectively. In 93 non-obese adults with biopsy-proven NAFLD, SUA levels were significantly higher in those with non-alcoholic steatohepatitis. The prevalence of non-alcoholic steatohepatitis and lobule inflammation tended to increase to 57.58% and 66.67% as the SUA level increased to the fourth quartile. Subjects with hyperuricemia had significantly higher NAFLD activity scores and more serious lobule inflammation than the normal group. CONCLUSION: Non-obese adults have higher NAFLD risk with increased SUA levels than obese individuals, and the inflammation progression of NAFLD is associated with increased SUA level in non-obese subjects.

[Effect of Compound Zhajin Granule on Toll-like Receptor 4 Signaling Pathway in Nonalcoholic Steatohepatitis Mice].

OBJECTIVE: To observe the effect of Compound Zhajin Granule (CZG) on Toll-like re-ceptor 4 (TLR4) signaling pathway in high-fructose corn syrup induced NASH mice. METHODS: Thirty 6-week-old male C3H mice were divided into the high fat and high fructose (HFHFr) group (n = 20) and the control group (n = 10) according to body weight. Mice in the HFHFr group ate high fat diet and drank 20% fructose water, while those in the control group ate common diet and drank common water. After 8 weeks mice in the HFHFr group were divided into two group according to body weight, the HFHFr group and the CZG group, 10 in each group. Mice in the CZG group were fed with high fat forage and 20% fructose water, and administered with 50 mL/kg 12. 8% CZG (prepared by hawthorn, Radix Curcumae, Alisma Orientale, Fritillaria Thunbergii, Silybum Marianum, peach seed in the ratio of 3:1.5:1.5:2:1.5:2:1) by gastrogavage. Mice in the HFHFr group were fed in the same way and daily administered with equal volume of distilled water by gastrogavage. Sixteen weeks later all mice were sacrificed. Body weight, liver wet weight, liver function, and lipid metabolism were detected. Pathological changes of liver tissues were assessed by HE staining, oil red O staining, and Masson staining. Expressions of TLR4, myeloid differentiation factor 88 (MyD88), tumor necrosis factor-alpha (TNF-α) were detected using immunohistochemical staining and real-time fluorescent quantitative PCR. RESULTS: Body weight, alanine aminotransferase (ALT), aspartate aminotransferase (AST) were obviously lower in the CZG group than in the HFHFr group (P < 0.05); oil red O stained area and density were decreased more in the CZG group than in the control group. HE staining showed ballooning inflammation was reduced more in the CZG group than in the HFHFr group. Masson staining was negative. Positive rates of TLR4 and MyD88 and mRNA expressions were significantly lower in the CZG group than in the HFHFr group (all P < 0.05). CONCLUSION: CZG could significantly inhibit TLR4 signaling pathway of liver in NASH mice.

Lipocalin-2 mediates non-alcoholic steatohepatitis by promoting neutrophil-macrophage crosstalk via the induction of CXCR2.

BACKGROUND & AIMS: Inflammatory cell infiltration in the liver is a hallmark of non-alcoholic steatohepatitis (NASH). However, the pathological events which trigger the infiltration of inflammatory cells to mediate NASH pathogenesis remains poorly understood. This study aims to investigate the role of neutrophil-derived lipocalin 2 (LCN2) in mediating the transition from simple steatosis to NASH. METHODS: Animal models of NASH were induced by high fat high cholesterol (HFHC) diet and methionine- and choline-deficient (MCD) diet in LCN2 knockout mice and wild-type controls. RESULTS: Circulating levels of LCN2 and its hepatic expression were markedly increased in both murine models and human subjects with NASH, and these changes were associated with increased infiltration of neutrophils. In diet-induced NASH models, hepatic injury, necroinflammation and infiltration of neutrophils and macrophages were substantially attenuated by genetic depletion of LCN2. In contrast, chronic infusion of recombinant LCN2 exacerbated diet-induced liver injury, inflammation and macrophage accumulation in a neutrophil-dependent manner. Primary mouse neutrophils lacking LCN2 exhibited a defective migration capacity, which can be reversed by replenishment with recombinant LCN2. Mechanistically, LCN2 induced the expression of the chemokine (C-X-C motif) receptor 2 (CXCR2), thereby leading to activation of ERK1/2 and production of proinflammatory chemokines. LCN2-induced inflammation, infiltration of macrophages and liver injury was abrogated in CXCR2-deficient mice. CONCLUSIONS: These findings demonstrated that LCN2 acts as a central mediator to facilitate the crosstalk between neutrophils and hepatic macrophages via induction of the chemokine receptor CXCR2, thereby exacerbating steatohepatitis. LAY SUMMARY: Lipocalin-2 levels in blood and the liver were markedly increased in both mouse models and human subjects with NASH, and these changes were associated with increased infiltration of neutrophils in the liver. In diet-induced NASH models, hepatic injury, necroinflammation and infiltration of neutrophils and macrophages were substantially attenuated by genetic depletion of lipocalin-2, but was augmented by chronic infusion of recombinant lipocalin-2. Lipocalin-2 induced the expression of the chemokine receptor CXCR2, thereby leading to activation of the mitogen-activated protein (MAP) kinase ERK1/2 and production of proinflammatory chemokines. Lipocalin-2-induced inflammation, infiltration of macrophages and liver injury was abrogated in CXCR2-deficient mice.

Increased ratio of neutrophil elastase to α1-antitrypsin is closely associated with liver inflammation in patients with nonalcoholic steatohepatitis.

An imbalance between neutrophil elastase (NE) and its inhibitor α1-antitrypsin (A1 AT) is known to contribute to the development of obesity-related inflammation. This study aimed to investigate the role of the NE-A1 AT system in the histological progression of non-alcoholic fatty liver disease (NAFLD), and to evaluate the ability of it to predict nonalcoholic steatohepatitis (NASH). A total of 252 adults (NAFLD group, n = 202; healthy group, n = 50) were recruited. Clinical biochemical characteristics, NE and A1 AT concentrations were measured in all subjects. Among the NAFLD group, 86 patients had previously undergone liver biopsy and information on histological characteristics was consequently available. The area under the receiver operating characteristic curve (AUC) was used to determine the predictive accuracy of the NE-A1 AT system for NASH. NAFLD patients had an elevated serum NE concentration and a reduced A1 AT level with consequent NE/A1 AT imbalance. NE increased in the early stage of steatosis, preceding the decline in A1 AT, dating from the onset of NASH (NAS 3-4), and subsequently NE/A1 AT increased in the presence of NASH. Nonetheless, this increase began to resolve as the disease state progressed to advanced fibrosis. A1 AT had a sensitivity (SEN) of 83.8% and a specificity (SP) of 83.3% with the optimal cut-off of -1459.43, NE/A1 AT had a SEN of 88.8% and a SP of 83.3% with cut-off of 0.363 to predict NASH. An increased NE: A1 AT ratio is closely associated with liver Inflammation in patients with NASH and could serve as a novel marker to predict NASH in humans.

Isocitrate Dehydrogenase 2 Suppresses the Invasion of Hepatocellular Carcinoma Cells via Matrix Metalloproteinase 9.

BACKGROUND/AIMS: Isocitrate dehydrogenase 2 (IDH2) is a mitochondrial NADP-dependent isocitrate dehydrogenase, and has been found to be a tumor suppressor in several types of tumors. However, the roles of IDH2 in hepatocellular carcinoma (HCC) as well as underlying mechanisms remain unknown. METHODS: The IDH2 and matrix metalloproteinase 9 (MMP9) levels in the specimens from 24 HCC patients were investigated by Western blot and ELISA, respectively. Their relationship was examined by correlation analyses. Patient survival with high IDH2 levels and low IDH2 levels was compared. IDH2 levels and MMP9 levels were modified in a human HCC cell line. The effects of IDH2 or MMP9 modulation on the expression of the other were analyzed. The effects of IDH2 on cell invasion were analyzed in a transwell cell invasion assay. The dependence of nuclear factor x03BA;B (NF-x03BA;B) signaling was examined using a specific inhibitor. RESULTS: The IDH2 levels significantly decreased in HCC, and were lower in HCC with metastases, compared to those without metastases. IDH2 levels inversely correlated with MMP9 levels in HCC. HCC patients with Low IDH2 had lower 5-year survival. MMP9 levels did not regulate IDH2 levels, while IDH2 inhibited MMP9 levels in HCC cells, in a NF-x03BA;B signaling dependent manner, possibly through ix03BA;B, to suppress HCC cell invasion. CONCLUSIONS: Down regulation of IDH2 may promote HCC cell invasion via NF-x03BA;B-dependent increases in MMP9 activity. IDH2 may be a potential therapeutic target for HCC.

Neutrophils Play a Crucial Role in the Early Stage of Nonalcoholic Steatohepatitis via Neutrophil Elastase in Mice.

Neutrophils infiltration in liver is one of the typical histological characteristics of nonalcoholic steatohepatitis (NASH) in both animal models and human subjects. This study was aimed to investigate the role of neutrophils in the process of NASH and its underling mechanisms. C57BL/6J mice were fed with either standard chow (SC) or methionine/choline-deficient (MCD) diet for 1, 2, 4, 8 weeks, respectively. C57BL/6J APOE(-/-) mice were fed with SC or high-fat high-cholesterol (HFHC) diet. Anti-Ly6G antibody was employed to deplete neutrophils and sivelestat was used to inhibit neutrophil elastase (NE). MCD-diet-receiving mice with neutrophil depletion had much lower serum ALT activity, liver inflammation, and mRNA levels of proinflammatory genes in the early stage of NASH (1 and 2 weeks) when compared to non-neutrophil-depleted mice. NE inhibitor sivelestat could recapitulate the effects of neutrophil depletion in APOE(-/-) mice fed with HFHC diet. As the disease progressed (4 and 8 weeks), neutrophil depletion did not lower serum ALT levels and liver lesions due to activation of Kupffer cells. Finally, we found neutrophils also affected anti-inflammation cytokine interleukin-1 receptor antagonist mRNA expression. Neutrophils play a crucial role in the early stage of NASH via NE.

Curcumin: a promising agent targeting cancer stem cells.

Cancer stem cells are a subset of cells that are responsible for cancer initiation and relapse. They are generally resistant to the current anticancer agents. Successful anticancer therapy must consist of approaches that can target not only the differentiated cancer cells, but also cancer stem cells. Emerging evidence suggested that the dietary agent curcumin exerted its anti-cancer activities via targeting cancer stem cells of various origins such as those of colorectal cancer, pancreatic cancer, breast cancer, brain cancer, and head and neck cancer. In order to enhance the therapeutic potential of curcumin, this agent has been modified or used in combination with other agents in the experimental therapy for many cancers. In this mini-review, we discussed the effect of curcumin and its derivatives in eliminating cancer stem cells and the possible underlying mechanisms.

[Effect of alpha-lipoic acid combined with transient intensive insulin therapy on adipokine level in patients with type 2 diabetic perineuropathy].

OBJECTIVE: To evaluate the effect of alpha-lipoic acid (LA) combined with transient intensive insulin therapy on adipokine level in patients with type 2 diabetic perineuropathy (DPN). METHODS: Totally 120 type 2 DPN patients who were receiving transient intensive insulin treatment were equally and randomly divided into LA group and methycobal group (which was set as the control group). The treatment lasted two weeks. The levels of biochemical indicators and adipokine were measured before treament and two weeks after treament. RESULTS: After treatment with insulin, serum blood-fasting glucose(FBG), tumor necrosis factor-Α(TNFΑ), and hypersensitive C-reactive protein (HSCRP)were significantly decreased in both LA group and methycobal group(all P <0.05), while adiponectin (APN) significantly increased (both P <0.05). Compared with the methycobal group,the level of APN was significantly higher and those of TNFΑ and HSCRP were significantly lower in LA group(all P <0.05).Leptin showed no significant change before and after treatment(all P >0.05). CONCLUSION: Transient intensive insulin therapy with LA treatment can regulate adpokine and enhance the anti-inflammatory effect of insulin in type 2 DPN patients.