Short-chain fatty acids: bridges between diet, gut microbiota, and health.

In recent years, gut microbiota has become a hot topic in the fields of medicine and life sciences. Short-chain fatty acids (SCFAs), the main metabolites of gut microbiota produced by microbial fermentation of dietary fiber, play a vital role in healthy and ill hosts. SCFAs regulate the process of metabolism, immune, and inflammation and have therapeutic effects on gastrointestinal and neurological disorders, as well as antitumor properties. This review summarized the production, distribution, and molecular mechanism of SCFAs, as well as their mechanisms of action in healthy and ill hosts. In addition, we also emphasized the negative effects of SCFAs, aiming to provide the public with a more comprehensive understanding of SCFAs.

Incidence of Cement Leakage and Potential Risk Factors in Surgery for Spinal Metastasis: A Systematic Review and Meta-Analysis.

OBJECTIVES: The current meta-analysis was performed to gather available evidence regarding the incidence and risk factors of cement leakage (CL) in patients undergoing surgical procedures for spinal metastasis. METHODS: Two authors independently searched the PubMed, Embase, and CENTRAL databases. Clinical studies reporting the incidence or risk factors of CL were included for analysis. The primary outcome analyzed was the incidence of various types of CL. Random-effects or fixed-effects single-proportion meta-analyses were conducted to pool the available evidence, based on the heterogeneity test. Subgroup analyses were conducted based on surgical procedures (percutaneous vertebroplasty, percutaneous kyphoplasty, and others). Risk factors of CL were synthesized narratively to identify the most commonly accepted factors. RESULTS: A total of 26 studies, involving 2551 patients, were included. The number of operated spine segments was reported in 23 studies, accounting for 4101 vertebrae. The pooled incidences of general, intradiscal, paravertebral, spinal canal, and intravascular CLs were 0.18 (95% confidence interval [CI], 0.11-0.28), 0.14 (95% CI, 0.08-0.21), 0.13 (95% CI, 0.06-0.21), 0.11 (95% CI, 0.05-0.19), and 0.12 (95% CI, 0.08-0.17), respectively. Subgroup analyses revealed significantly different incidences of general CL (0.37 vs. 0.06 vs. 0.09, P < 0.01), intradiscal CL (0.22 vs. 0.06 vs. 0.12, P < 0.01), paravertebral CL (0.25 vs. 0.03 vs. 0.06, P < 0.01), and vascular CL (0.14 vs. 0.03 vs. 0.15, P < 0.01) among the three groups. Posterior wall disruption, pathologic fracture, and the number of treated vertebral levels were the most commonly identified independent risk factors for general CL. Posterior wall disruption was determined as a common significant risk factor for spinal canal CL. CONCLUSIONS: This review provides insights into the incidence and risk factors associated with CL in surgical procedures for spinal metastasis. Understanding these risk factors can contribute to the development of tailored strategies aimed at minimizing CL occurrence and optimizing surgical outcomes for patients undergoing spinal metastatic surgery.

[Effects of Methionine Restriction on Proliferation, Cell Cycle, and Apoptosis of Human Acute Leukemia Cells].

OBJECTIVE: To investigate the effects of methionine restriction on proliferation, cell cycle and apoptosis of human acute leukemia cells. METHODS: Cell Counting Kit-8 (CCK-8) assay was used to detect the effect of methionine restriction on HL-60 and Jurkat cells proliferation. The effect of methionine restriction on cell cycle of HL-60 and Jurkat cells was examined by PI staining. Annexin V-FITC / PI double staining was applied to detect apoptosis of HL-60 and Jurkat cells following methionine restriction. The expression of cell cycle-related proteins cyclin B1, CDC2 and apoptosis-related protein Bcl-2 was evaluated by Western blot assay. RESULTS: Methionine restriction significantly inhibited the proliferation of HL-60 and Jurkat cells in a time-dependent manner (HL-60: r =0.7773, Jurkat: r =0.8725), arrested the cells at G2/M phase (P < 0.001), and significantly induced apoptosis of HL-60 and Jurkat cells (HL-60: P < 0.001; Jurkat: P < 0.05). Furthermore, Western blot analysis demonstrated that methionine restriction significantly reduced the proteins expression of Cyclin B1 (P < 0.05), CDC2 (P < 0.01) and Bcl-2 (P < 0.001) in HL-60 and Jurkat cells. CONCLUSION: Acute leukemia cells HL-60 and Jurkat exhibit methionine dependence. Methionine restriction can significantly inhibit the proliferation, promote cell cycle arrest and induce apoptosis of HL-60 and Jurkat cells, which suggests that methionine restriction may be a potential therapeutic strategy for acute leukemia.

Berberine retarded the growth of gastric cancer xenograft tumors by targeting hepatocyte nuclear factor 4α.

BACKGROUND: Gastric cancer is the third deadliest cancer in the world and ranks second in incidence and mortality of cancers in China. Despite advances in prevention, diagnosis, and therapy, the absolute number of cases is increasing every year due to aging and the growth of high-risk populations, and gastric cancer is still a leading cause of cancer-related death. Gastric cancer is a consequence of the complex interaction of microbial agents, with environmental and host factors, resulting in the dysregulation of multiple oncogenic and tumor-suppressing signaling pathways. Global efforts have been made to investigate in detail the genomic and epigenomic heterogeneity of this disease, resulting in the identification of new specific and sensitive predictive and prognostic biomarkers. Trastuzumab, a monoclonal antibody against the HER2 receptor, is approved in the first-line treatment of patients with HER2+ tumors, which accounts for 13%-23% of the gastric cancer population. Ramucirumab, a monoclonal antibody against VEGFR2, is currently recommended in patients progressing after first-line treatment. Several clinical trials have also tested novel agents for advanced gastric cancer but mostly with disappointing results, such as anti-EGFR and anti-MET monoclonal antibodies. Therefore, it is still of great significance to screen specific molecular targets for gastric cancer and drugs directed against the molecular targets. AIM: To investigate the effect and mechanism of berberine against tumor growth in gastric cancer xenograft models and to explore the role of hepatocyte nuclear factor 4α (HNF4α)-WNT5a/ß-catenin pathways played in the antitumor effects of berberine. METHODS: MGC803 and SGC7901 subcutaneous xenograft models were established. The control group was intragastrically administrated with normal saline, and the berberine group was administrated intragastrically with 100 mg/kg/d berberine. The body weight of nude mice during the experiment was measured to assess whether berberine has any adverse reaction. The volume of subcutaneous tumors during this experiment was recorded to evaluate the inhibitory effect of berberine on the growth of MGC803 and SGC7901 subcutaneous transplantation tumors. Polymerase chain reaction assays were conducted to evaluate the alteration of transcriptional expression of HNF4α, WNT5a and ß-catenin in tumor tissues and liver tissues from the MGC803 and SGC7901 xenograft models. Western blotting and IHC were performed to assess the protein expression of HNF4α, WNT5a and ß-catenin in tumor tissues and liver tissues from the MGC803 and SGC7901 xenograft models. RESULTS: In the both MGC803 and SGC7901 xenograft tumor models, berberine significantly reduced tumor volume and weight and thus retarded the growth rate of tumors. In the SGC7901 and MGC803 subcutaneously transplanted tumor models, berberine down-regulated the expression of HNF4α, WNT5a and ß-catenin in tumor tissues from both transcription and protein levels. Besides, berberine also suppressed the protein expression of HNF4α, WNT5a and ß-catenin in liver tissues. CONCLUSION: Berberine retarded the growth of MGC803 and SGC7901 xenograft model tumors, and the mechanism behind these anti-growth effects might be the downregulation of the expression of HNF4α-WNT5a/ß-catenin signaling pathways both in tumor tissues and liver tissues of the xenograft models.

A case report of acute testicular pain secondary to segmental testicular infarction.

BACKGROUND: Segmental testicular infarction is a rare condition that often occurs in the upper pole of the left testicle and usually presents with acute onset of scrotal pain. Contrast-enhanced ultrasound and MR are essential for diagnosing and differentiating segmental testicular infarction in clinical practice, and conservative treatment can only be adopted after a definitive diagnosis. In the present case, after conservative treatment, the infarct volume was reduced, the blood flow around the infarct was increased, and blood flow signals appeared in the infarct. We performed a correlation analysis to investigate the causes of these changes. CASE PRESENTATION: A 33-year-old male, without any specific disease history, was admitted to the hospital with a 5-day history of left testicular pain, and the imaging showed focal necrosis of the left testicle with hemorrhage. He was diagnosed with segmental testicular infarction after differentiating and excluding it from malignant tumors. Conservative medical treatment was given, and the symptoms of testicular pain were relieved after treatment. After discharge, regular reexamination at follow-ups showed that the infarct's size was reduced, the blood flow around the infarct was increased, and blood flow signals appeared in the infarct. CONCLUSION: Conservative treatment has become the standard treatment currently adopted after confirming the diagnosis of segmental testicular infarction through contrast-enhanced ultrasound and MR. The blood flow changes in and around the focus of testicular infarction can be related to various factors. At present, relevant conclusions of the underlying mechanisms were mainly deduced from infarction studies of other related organs such as the heart and brain; thus, the specific pathological mechanism needs further experimental verification.

Therapeutic lumbar puncture and lumbar drainage: which is more effective for the management of intracranial hypertension in HIV patients with cryptococcal meningitis? Results of a prospective non-randomized interventional study in China.

OBJECTIVE: This study aimed to evaluate the effectiveness of therapeutic lumbar drainage (LD) compared to therapeutic lumbar puncture (LP) for the management of intracranial hypertension (ICH) among HIV-positive patients with cryptococcal meningitis (CM). METHODS: The study was a multicenter prospective non-randomized interventional clinical trial. One hundred and sixteen HIV-associated CM patients were identified who presented with ICH (≥250 mmH2O). The LP group comprised 76 cases, while the LD group consisted of 40 cases. We compared mortality, intracranial pressure (ICP) normalization rate, and clinical symptom remission at 10 weeks, between the two groups. RESULTS: The cumulative mortality at week 10 was 22.4% in the LP group and 20% in the LD group (p = .927), without any significant difference in mortality between the two groups. Improvement after treatment at 2-weeks, ICP normalization, and headache reversal event occurrence in the two groups showed no significant difference (p > .05). The incidence of CSF Cryptococcus clearance at two weeks in the LD group was significantly higher than in the LP group (p < .05). The frequency of invasive lumbar therapeutic procedures in the LP group during the first week was higher than that of the LD group (p < .05). Localized infection at the puncture site occurred more frequently in the LD group than in the LP group (p < .05). CONCLUSION: For HIV-positive CM patients with an elevated ICP, LD and LP are comparably effective and safe options to normalize ICP. LP increases the frequency of invasive lumbar therapeutic procedures but does not incur more risk of infection events at the puncture site, while LD may accelerate CSF Cryptococcus clearance but may induce more frequent localized infection. TRIAL REGISTRATION: This study was registered as one of 12 trials under a general project at the Chinese Clinical Trial Registry (ChiCTR1900021195).

Effect of natural garlic essential oil on chickens with artificially infected Eimeria tenella.

Chicken coccidiosis is a kind of parasitic protozoosis caused by Eimeria parasitizing in the chicken intestinal epithelial cells. Eimeria tenella is considered as a significantly virulent and harmful parasite. At present, drug resistance remains a major problem and a large number of drug residues have been found to be produced in the treatment of the disease. Hence, novel strategies are needed to avoid the harmful effects caused by the generation of various chemical drug residues to the human body and also reduce the economic loss caused by coccidiosis to the chicken industry. In this study, natural garlic essential oil was used to control Eimeria tenella infection. The anticoccidial index (ACI) was calculated according to the clinical symptoms, body weight gain, oocyst excretion and cecal lesions. The immune organ index and serum biochemical indexes were measured to verify the possible anticoccidial effects. The results showed that: compared with the infected group, continuous feeding of different doses of natural garlic essential oil could significantly reduce the clinical symptoms, cecal lesions, the number of oocysts, but increase the weight of sick chickens, and effectively improve the intestinal functions. Moreover, compared with diclazuril control group, 0.06 mL/L garlic essential oil exhibited similar anticoccidial index. The content of immune organ index, serum biochemical index IgM, IgG and IgA in 0.06 mL/L garlic essential oil group was the highest, which indicated that garlic essential oil had a significant tendency to improve the immune function of the chickens. This study also showed that the natural garlic essential oil exhibited the same beneficial effects as that of diclazuril on chicken coccidiosis, and the anti-coccidiosis index of 0.06 mL/L garlic essential oil was favorable. Thus based on the above evidences and its relatively low cost, garlic essential oil can be potentially be used as an efficient anti parasitic drug.

New role for ceramide in hypoxia and insulin resistance.

Ceramides are significant metabolic products of sphingolipids in lipid metabolism and are associated with insulin resistance and hepatic steatosis. In chronic inflammatory pathological conditions, hypoxia occurs, the metabolism of ceramide changes, and insulin resistance arises. Hypoxia-inducible factors (HIFs) are a family of transcription factors activated by hypoxia. In hypoxic adipocytes, HIF-1α upregulates pla2g16 (a novel HIF-1α target gene) gene expression to activate the NLRP3 inflammasome pathway and stimulate insulin resistance, and adipocyte-specific Hif1a knockout can ameliorate homocysteine-induced insulin resistance in mice. The study on the HIF-2α-NEU3-ceramide pathway also reveals the role of ceramide in hypoxia and insulin resistance in obese mice. Under obesity-induced intestinal hypoxia, HIF-2α increases the production of ceramide by promoting the expression of the gene Neu3 encoding sialidase 3, which is a key enzyme in ceramide synthesis, resulting in insulin resistance in high-fat diet-induced obese mice. Moreover, genetic and pathophysiologic inhibition of the HIF-2α-NEU3-ceramide pathway can alleviate insulin resistance, suggesting that these could be potential drug targets for the treatment of metabolic diseases. Herein, the effects of hypoxia and ceramide, especially in the intestine, on metabolic diseases are summarized.

The therapeutic value of SC66 in human renal cell carcinoma cells.

The PI3K-AKT-mTOR cascade is required for renal cell carcinoma (RCC) progression. SC66 is novel AKT inhibitor. We found that SC66 inhibited viability, proliferation, migration and invasion of RCC cell lines (786-O and A498) and patient-derived primary RCC cells. Although SC66blocked AKT-mTORC1/2 activation in RCC cells, it remained cytotoxic in AKT-inhibited/-silenced RCC cells. In RCC cells, SC66 cytotoxicity appears to occur via reactive oxygen species (ROS) production, sphingosine kinase 1inhibition, ceramide accumulation and JNK activation, independent of AKT inhibition. The ROS scavenger N-acetylcysteine, the JNK inhibitor (JNKi) and the anti-ceramide sphingolipid sphingosine-1-phosphate all attenuated SC66-induced cytotoxicity in 786-O cells. In vivo, oral administration of SC66 potently inhibited subcutaneous 786-O xenograft growth in SCID mice. AKT-mTOR inhibition, SphK1 inhibition, ceramide accumulation and JNK activation were detected in SC66-treated 786-O xenograft tumors, indicating that SC66 inhibits RCC cell progression through AKT-dependent and AKT-independent mechanisms.

Jiao-tai-wan Up-regulates Hypothalamic and Peripheral Circadian Clock Gene Cryptochrome and Activates PI3K/AKT Signaling in Partially Sleep-deprived Rats.

This study aims to explore the effect and mechanism of Jiao-tai-wan (JTW) on systemic and tissue-specific inflammation and insulin resistance in obesity-resistant (OR) rats with chronic partial sleep deprivation (PSD). OR rats with PSD were orally given JTW and Estazolam for 4 weeks. The amount of food intake and metabolic parameters such as body weight increase rate, fasting plasma glucose (FPG), fasting insulin (FINS), homeostasis model assessment-insulin resistance (HOMA-IR) and plasma inflammatory markers were measured. The expression levels of circadian proteins cryptochrome 1 (Cryl) and cryptochrome 2 (Cry2) in hypothalamus, adipose and liver tissues were also determined. Meanwhile, the mRNA expression of inflammatory markers, activity of nuclear factor kappa B (NF-κB) p65 protein, as well as the expression levels of insulin signaling pathway proteins in hypothalamus, adipose and liver tissues were measured. Additionally, cyclic adenosine 3', 5'-monophosphate (cAMP) and activity of vasodilator-stimulated phosphoprotein (VASP) in hypothalamus tissue were measured. JTW significantly decreased the body weight increase rate and food intake, ameliorated systemic inflammation and insulin resistance. JTW effectively ameliorated inflammation and increased PI3K/AKT signaling activation in hypothalamus, adipose and liver. Interestingly, all these changes were associated with the up-regulation of circadian gene Cryl and Cry2 protein expression. We also found that in hypothalamus tissue of PSD rats, down-regulation of Cryl and Cry2 activated cAMP/PKA signaling and then led to inflammation, while JTW inhibited this signaling. These results suggested that JTW has the beneficial effect on ameliorating inflammation and insulin resistance in partially sleep-deprived rats by up-regulating Cry expression.

Combined inhibition of JAK1,2/Stat3­PD­L1 signaling pathway suppresses the immune escape of castration­resistant prostate cancer to NK cells in hypoxia.

Castration­resistant prostate cancer (CRPC) is difficult to treat in current clinical practice. Hypoxia is an important feature of the CRPC microenvironment and is closely associated with the progress of CRPC invasion. However, no research has been performed on the immune escape of CRPC from NK cells. The present study focused on this subject. Firstly, when the CRPC cell lines C4­2 and CWR22Rv1 were induced by hypoxia, the expression of the UL16 binding protein (ULBP) ligand family of natural killer (NK) group 2D (NKG2D; ULBP­1, ULBP­2 and ULBP­3) and MHC class I chain­related proteins A and B (MICA/MICB) decreased. NKG2D is the main activating receptor of NK cells. Tumor cells were then co­cultured with NK cells to conduct NK cell­mediated cytotoxicity experiments, which revealed the decreased immune cytolytic activity of NK cells on hypoxia­induced CRPC cells. In exploring the mechanism behind this observation, an increase in programmed death­ligand 1 (PD­L1) expression in CRPC cells induced by hypoxia was observed, while the addition of PD­L1 antibody effectively reversed the expression of NKG2D ligand and enhanced the cytotoxic effect of NK cells on CRPC cells. In the process of exploring the upstream regulatory factors of PD­L1, inhibition of the Janus kinase (JAK)1,2/signal transducer and activator of transcription 3 (Stat3) signaling pathway decreased the expression of PD­L1 in CRPC cells. Finally, it was observed that combined inhibition of JAK1,2/PD­L1 or Stat3/PD­L1 was more effective than inhibition of a single pathway in enhancing the immune cytolytic activity of NK cells. Taking these results together, it is thought that combined inhibition of the JAK1,2/PD­L1 and Stat3/PD­L1 signaling pathways may enhance the immune cytolytic activity of NK cells toward hypoxia­induced CRPC cells, which is expected to provide novel ideas and targets for the immunotherapy of CRPC.

ATM­JAK­PD­L1 signaling pathway inhibition decreases EMT and metastasis of androgen­independent prostate cancer.

Castration-resistant prostate cancer (CRPC), also known as androgen-independent prostate cancer, frequently develops local and distant metastases, the underlying mechanisms of which remain undetermined. In the present study, surgical specimens obtained from patients with clinical prostate cancer were investigated, and it was revealed that the expression levels of ataxia telangiectasia mutated kinase (ATM) were significantly enhanced in prostate cancer tissues isolated from patients with CRPC compared with from patients with hormone­dependent prostate cancer. CRPC C4­2 and CWR22Rv1 cells lines were subsequently selected to establish prostate cancer models, and ATM knockout cells were established via lentivirus infection. The results of the present study demonstrated that the migration and epithelial­mesenchymal transition (EMT) of ATM knockout cells were significantly decreased, which suggested that ATM is closely associated with CRPC cell migration and EMT. To further investigate the mechanisms underlying this process, programmed cell death 1 ligand 1 (PD­L1) expression was investigated in ATM knockout cells. In addition, inhibitors of Janus kinase (JAK) and signal transducer and activator of transcription 3 (STAT3; Stattic) were added to C4­2­Sc and CWR22Rv1­Sc cells, and the results demonstrated that PD­L1 expression was significantly decreased following the addition of JAK inhibitor 1; however, no significant change was observed following the addition of Stattic. Furthermore, a PD­L1 antibody and JAK inhibitor 1 were added to C4­2­Sc and CWR22Rv1­Sc cells, and it was revealed that cell migration ability was significantly decreased and the expression of EMT­associated markers was effectively reversed. The results of the present study suggested that via inhibition of the ATM­JAK­PD­L1 signaling pathway, EMT, metastasis and progression of CRPC may be effectively suppressed, which may represent a novel therapeutic approach for targeted therapy for patients with CRPC.

Radiation alters PD-L1/NKG2D ligand levels in lung cancer cells and leads to immune escape from NK cell cytotoxicity via IL-6-MEK/Erk signaling pathway.

We investigated whether radiation influences the susceptibility of non-small cell lung cancer (NSCLC) cells to NK cell mediated cytotoxicity. We found radiation treatment increased expression of programmed cell death ligand 1 (PD-L1), but decreased NK group 2, member D (NKG2D) ligand expressions in A549 and H157 NSCLC cells. Both types of changes would have protected tumor cells from the cytotoxic action of NK cells. Consistently, we detected similar alteration in these molecules in radioresistant A549R26-1 and H157R24-1 subline cells. Higher PD-L1 level was also observed in tumors of A549R26-1 cell-derived xenografts than tumors of parental A549 (A549P) cell-derived xenografts. Accordingly, we found radioresistant cells were more resistant to the cytotoxic action of NK cells than parental cells, and such resistance was decreased when neutralizing antibody (Ab) of PD-L1 was added to the radioresistant cell/NK cell co-cultures. In mechanism studies, we found that IL-6-MEK/Erk signaling contributed most significantly to the up-regulation of PD-L1/down-regulation of NKG2D ligands in radioresistant cells. The addition of the MEK/Erk inhibitor increased the susceptibility of A549R26-1 and H157R24-1 cells to NK-cell cytotoxicity while no significant effect was observed in parental cells. Moreover, we detected enhanced NK-cell cytotoxicity to radioresistant cells when PD-L1 Ab and MEK/Erk inhibitor were added together to co-cultures of tumor/NK cells compared to when PD-L1 Ab was used alone. We suggest that combined use of PD-L1 Ab and MEK/Erk inhibitor may offer better therapeutic benefits than PD-L1 Ab alone to treat NSCLC patients who are receiving radiotherapy or who are at the radioresistant stage.

Enhancing NK cell-mediated cytotoxicity to cisplatin-resistant lung cancer cells via MEK/Erk signaling inhibition.

Major progress has been made clinically in inhibiting the programmed death receptor 1 (PD-1)/PD-L1 interaction to enhance T cell-mediated immune function, yet the effectiveness of anti-PD-L1/PD-1 agents in enhancing natural killer (NK) cell's function remains largely unknown. Susceptibilities of cisplatin-resistant A549CisR and H157CisR cells vs. parental cells to the cytotoxic action of NK cells were examined. We found cisplatin-resistant cells more resistant to NK cell cytotoxicity than parental cells. There were constitutively higher expressions of PD-L1 in A549CisR and H157CisR cells than in parental cells in vitro, as well as in H157CisR cell-derived tumors than H157P cell-derived tumors. In contrast, we observed that the expression of PD-1 in NK cells was induced after co-culture with cisplatin-resistant cells. We also observed increased susceptibility of cisplatin-resistant cells to NK cell cytotoxicity when neutralizing antibody of PD-1 or PD-L1 was added. Further, we found that the NK group 2, member D (NKG2D) ligand levels were lower in A549CisR and H157CisR cells than in parental cells. Meanwhile, we discovered that the MEK/Erk signaling pathway played a significant role in this regulation, and the addition of a MEK/Erk pathway inhibitor significantly enhanced the PD-L1 Ab effect in enhancing NK cell cytotoxicity to cisplatin-resistant cells.

Grb2-associated binder-2 gene promotes migration of non-small cell lung cancer cells via Akt signaling pathway.

Early stages of non-small cell lung cancer (NSCLC) can be successfully treated by surgical resection of the tumor, but there is still no effective treatment once it is progressed to metastatic phases. Investigation of NSCLC cancer cell migration, metastasis and development of strategies to block this process is essential to improve the disease prognosis. In the present study, we found that GRB2-associated-binding protein 2 (Gab2) is involved in the migration of NSCLC cells and demonstrated that Gab2 disruption impairs NSCLC cells migration. The requirement of Gab2 in the migration of NSCLC was further confirmed by gene silencing in vitro. In corresponding to this result, over-expression of Gab2 significantly promoted the migratory of NSCLC cells. Finally, we found that Gab2 promotes NSCLC migration through the protein kinase B (Akt) signaling pathway and up-regulation the activity of matrix metallopeptidase (MMP)-2/9. To conclude, our findings suggest a novel mechanism underlying the migration of NSCLC cells which might serve as a new intervention target for the treatment of NSCLC.

A Pharmacogenetic Discovery: Cystamine Protects Against Haloperidol-Induced Toxicity and Ischemic Brain Injury.

Haloperidol is an effective antipsychotic agent, but it causes Parkinsonian-like extrapyramidal symptoms in the majority of treated subjects. To address this treatment-limiting toxicity, we analyzed a murine genetic model of haloperidol-induced toxicity (HIT). Analysis of a panel of consomic strains indicated that a genetic factor on chromosome 10 had a significant effect on susceptibility to HIT. We analyzed a whole-genome SNP database to identify allelic variants that were uniquely present on chromosome 10 in the strain that was previously shown to exhibit the highest level of susceptibility to HIT. This analysis implicated allelic variation within pantetheinase genes (Vnn1 and Vnn3), which we propose impaired the biosynthesis of cysteamine, could affect susceptibility to HIT. We demonstrate that administration of cystamine, which is rapidly metabolized to cysteamine, could completely prevent HIT in the murine model. Many of the haloperidol-induced gene expression changes in the striatum of the susceptible strain were reversed by cystamine coadministration. Since cystamine administration has previously been shown to have other neuroprotective actions, we investigated whether cystamine administration could have a broader neuroprotective effect. Cystamine administration caused a 23% reduction in infarct volume after experimentally induced cerebral ischemia. Characterization of this novel pharmacogenetic factor for HIT has identified a new approach for preventing the treatment-limiting toxicity of an antipsychotic agent, which could also be used to reduce the extent of brain damage after stroke.

Effects of berberine and cinnamic acid on palmitic acid-induced intracellular triglyceride accumulation in NIT-1 pancreatic ß cells.

OBJECTIVE: To investigate the effects of berberine (BBR) and cinnamic acid (CA), the main active components in Jiaotai Pill (, JTP), on palmitic acid (PA)-induced intracellular triglyceride (TG) accumulation in NIT-1 pancreatic ß cells. METHODS: Cells were incubated in culture medium containing PA (0.25 mmol/L) for 24 h. Then treatments with BBR (10 µmol/L), CA (100 µmol/L) and the combination of BBR and CA (BBR+CA) were performed respectively. Intracellular lipid accumulation was assessed by Oil Red O staining and TG content was measured by colorimetric assay. The expression of adenosine monophosphate-activated protein kinase (AMPK) protein and its downstream lipogenic and fatty acid oxidation genes, including fatty acid synthase (FAS), acetyl-coA carboxylase (ACC), phosphorylation acetyl-coA carboxylase (pACC), carnitine acyl transferase 1 (CPT-1) and sterol regulating element binding protein 1c (SREBP-1c) were determined by Western blot or real time polymerase chain reaction. RESULTS: PA induced an obvious lipid accumulation and a significant increase in intracellular TG content in NIT-1 cells. PA also induced a remarkable decrease in AMPK protein expression and its downstream targets such as pACC and CPT-1. Meanwhile, AMPK downstream lipogenic genes including SREBP-1c mRNA, FAS and ACC protein expressions were increased. Treatments with BBR and BBR+CA, superior to CA, significantly reversed the above genes changes in NIT-1 pancreatic ß cells. However, the synergistic effect of BBR and CA on intracellular TG content was not observed in the present study. CONCLUSION: It can be concluded that in vitro, BBR and BBR+CA could inhibit PA-induced lipid accumulation by decreasing lipogenesis and increasing lipid oxidation in NIT-1 pancreatic ß cells.

Photoselective vaporization of the prostate with GreenLight 120-W laser versus transurethral resection of the prostate for benign prostatic hyperplasia: a systematic review with meta-analysis of randomized controlled trials.

The aim of this study is to assess the overall efficacy and safety of photoselective vaporization of the prostate (PVP) with GreenLight 120-W laser versus transurethral resection of the prostate (TURP) for treating patients of benign prostate hyperplasia (BPH) with lower urinary tract symptoms (LUTS). We performed a literature search of The Cochrane Library and the electronic databases, including Embase, Medline, and Web of Science. Manual searches were conducted of the conference proceedings, including European Association of Urology and American Urological Association (2007 to 2012). Outcomes reviewed included clinical baseline characteristics, perioperative data, complications, and postoperative functional results, such as postvoid residual (PVR), international prostate symptom score (IPSS), quality of life (QoL), and maximum flow rate (Qmax). Six randomized controlled trials (RCTs) were enrolled. Three hundred and forty-seven patients undergone 120-W PVP, and 350 patients were treated with TURP in the RCTs. There were no significant differences for clinical characteristics in these trials. In perioperative data, catheterization time and length of hospital stay were shorter in the PVP group. However, the operation time was shorter in the TURP group. Capsular perforation, blood transfusion, clot retention, and macroscopic hematuria were markedly less likely in PVP-treated subjects. The other complications between PVP and TURP did not demonstrate a statistic difference. There were no significant differences in QoL, PVR, IPSS, and Qmax in the 1, 3, 6, 12, and 24 months of postoperative follow-up. There was no significant difference at postoperation follow-up of functional outcomes including IPSS, PVR, Qmax, and QoL between the TURP-treated subjects and PVP-treated subjects. Owing to a shorter catheterization time, reduced hospital duration and less complication, PVP could be used as an alternative and a promising minimal invasive surgical procedure for the treatment of BPH.

CD4(+)CD25(-)Foxp3(+) T cells play a role in tuberculous hydrothorax rather than malignant hydrothorax.

BACKGROUND: Foxp3(+) T cells regulate inflammation and tumorigenesis. However, little is known about the role of different subsets of Foxp3(+) T cells in malignant or tuberculous hydrothorax. METHODS: The numbers of CD4(+)CD25(+)Foxp3(+), CD4(+)CD25(-)Foxp3(+) T cells and the levels of some inflammatory cytokines in patients with tuberculous hydrothorax, malignant hydrothorax, and healthy controls (HCs) were examined by flow cytometry and ELISA. The potential association between the numbers of different subsets of Foxp3 + T cells and the values of clinical measures were analyzed. RESULTS: The numbers of peripheral blood CD4(+)CD25(+)Foxp3(+) T cells were greater in malignant hydrothorax patients than in HCs, but fewer than those of hydrothorax in patients. The percentages of circulating IL-10(+) or LAP(+) CD4(+)CD25(+)Foxp3(+) T cells were higher than in the hydrothorax in patients with malignant hydrothorax. The numbers of circulating CD4(+)CD25(-)Foxp3(+) T cells were significantly fewer in patients with tuberculous hydrothorax than in HCs, and both the numbers of circulating CD4(+)CD25(+)Foxp3(+) and CD4(+)CD25(-)Foxp3(+) T cells were significantly fewer than in the hydrothorax in patients. Significantly higher percentages of circulating IL-10(+) or LAP(+) CD4(+)CD25(+)Foxp3(+) and CD4(+)CD25(-)Foxp3(+) T cells were detected in tuberculous hydrothorax patients. The numbers of CD4(+)CD25(+)Foxp3(+) and CD4(+)CD25(-)Foxp3(+) T cells were associated with hydrothorax adenosine deaminase (ADA) levels in tuberculous hydrothorax patients, while CD4(+)CD25(+)Foxp3(+) T cells were associated with carcino-embryonic antigen (CEA) in malignant hydrothorax patients. The concentrations of serum IL-6 and TGF-ß in the patients were significantly higher than that in the HCs, but lower than that in the corresponding hydrothorax. A similar pattern of IL-10 was observed in different groups, except that there was no significant difference in the levels of serum IL-10 between the tuberculous hydrothorax patients and HCs. CONCLUSIONS: CD4(+)CD25(-)Foxp3(+) T cells, which have lower inhibitory function than CD4(+)CD25(+)Foxp3(+) T cells, may play a role in tuberculous hydrothorax.