FTO: a critical role in obesity and obesity-related diseases.

In recent years, obesity is a growing pandemic in the world and has likely contributed to increasing the incidence of obesity-related diseases. Fat mass and obesity-associated gene (FTO) is the first gene discovered which has a close connection with fat. Recent studies suggested that FTO gene has played an important role in the molecular mechanisms of many diseases. Obesity is considered to be a hereditary disease and can evoke many kinds of diseases, including polycystic ovary syndrome (PCOS), type 2 diabetes mellitus (T2DM), cancer, etc., whose exact possible molecular mechanisms responsible for the effect of FTO on obesity and obesity-related diseases remain largely unknown. In this review, we comprehensively discuss the correlation between FTO gene and obesity, cancer, PCOS, T2DM, as well as the molecular mechanism involved in these diseases.

Aortic Regurgitation Requiring Unplanned Surgery following Transcatheter Closure of Ventricular Septal Defect in Children: Incidence and Risk Factors.

INTRODUCTION: Our aim was to investigate the incidence and risk factors for aortic regurgitation (AR) requiring unplanned surgery after transcatheter closure of ventricular septal defect (VSD) in children. METHODS: Medical records of 876 children with VSD who underwent transcatheter closure from July 2009 to September 2018 in our hospital were retrospectively reviewed. Groups with and without new-onset or increasing AR requiring unplanned surgery were compared. Univariate and multivariate analyses were used to identify the possible risk factors. Smoothing plot and threshold effect analysis were carried out to find the relationship between possible factors and risk of new-onset or increasing AR. RESULTS: A total of 29 children (3.3%) underwent unplanned surgery after transcatheter closure owing to new-onset or increasing AR, including 6 children with new-onset AR and 23 children with increasing AR. Multivariate regression analysis revealed that preoperative mild AR (OR: 60.39, 95% CI: 11.53-316.30, p < 0.001), larger ratio between diameter to body surface area (OR: 1.25, 95% CI: 1.01-1.55, p = 0.039), intracristal VSD (OR: 34.09, 95% CI: 4.07-285.65, p < 0.001), and shorter distance from the upper edge of defect to the aortic valve (or the sub-aortic rim) (OR: 0.12, 95% CI: 0.05-0.27, p < 0.001) were risk factors for new-onset or increasing AR requiring unplanned surgery. And, low risk of AR after muscular VSD transcatheter closure was found. An L-shaped nonlinear relationship between the sub-aortic rim and the risk of new-onset or increasing AR was observed, and the risk of new-onset or increasing AR with the sub-aortic rim up to the turning point (2 mm) (adjusted OR: 0.00, 95% CI: 0.00-0.08; p =0.001). With a median time of 7.3 years' follow-up, no new-onset or increasing AR has been found for children who initially did not have unplanned surgery. CONCLUSION: Preoperative mild AR, larger ratio between diameter to body surface area, intracristal VSD, and shorter distance of the sub-aortic rim (especially <2 mm) could increase the risk of new-onset or increasing AR requiring unplanned surgery after transcatheter closure of VSD.

The role of zinc in follicular development.

Follicles consist of specialized somatic cells that encase a single oocyte. Follicle development is a process regulated by a variety of endocrine, paracrine, and secretory factors that work together to select follicles for ovulation. Zinc is an essential nutrient for the human body and is involved in many physiological processes, such as follicle development, immune response, homeostasis, oxidative stress, cell cycle progression, DNA replication, DNA damage repair, apoptosis, and aging. Zinc deficiency can lead to blocked oocyte meiotic process, cumulus expansion, and follicle ovulation. In this mini-review, we summarize the the role of zinc in follicular development.

Thrombotic thrombocytopenic purpura in a patient on long-term alpha-interferon therapy for essential thrombocythemia: a case report.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is rare and severe thrombotic microangiopathy characterized by thrombocytopenia, hemolytic anemia, and renal dysfunction. In contrast, essential thrombocythemia (ET) is a myeloproliferative disease associated with an abnormal increase in platelet numbers. Previous studies reported several cases of the development of ET in patients with TTP. However, the case of an ET patient complicated with TTP has not been previously reported. In this case study, we present a patient with TTP who was previously diagnosed with ET. Therefore, to the best of our knowledge, this is the first report of TTP in ET. CASE PRESENTATION: A 31-year-old Chinese female who was previously diagnosed with ET presented with anemia and renal dysfunction. The patient had been on long-term treatment with hydroxyurea, aspirin, and alpha interferon (INF-α) for ten years. The diagnosis of TTP was confirmed by clinical features, schistocytes noted on the peripheral blood smear, and lower ADAMTS13 activity (8.5%), together with the renal biopsy results. INF-α was discontinued, and the patient was then treated with plasma exchange and corticosteroids. After one year of follow-up, the patient had a normal hemoglobin level and platelet numbers, and her ADAMTS13 activity had improved. However, the patient's renal function remains impaired. CONCLUSIONS: We report a case of an ET patient complicated with TTP that was possibly due to INF-α, highlighting the potential complications associated with long-term ET therapy. The case also highlights the importance of considering TTP in patients with pre-existing ET who present with anemia and renal dysfunction, extending the spectrum of known studies.

Contamination profiles and potential health risks of environmentally persistent free radicals in PM2.5 over typical central Chinese megacity.

As one of the most important transportation hubs and industrial bases in China, Zhengzhou has suffered from serious PM2.5 pollution for a long time. However, the investigation of contamination status and possible exposure risks of environmentally persistent free radicals (EPFRs) in PM2.5 from Zhengzhou is rare. In this work, a comprehensive study of pollution levels, seasonal variations, sources, and potential health risks of PM2.5-bound EPFRs in Zhengzhou was conducted for the first time. The atmospheric concentrations of EPFRs in PM2.5 from Zhengzhou ranged from 1.732 × 1012 spin m-3 to 7.182 × 1014 spin m-3 between 2019 and 2020. Relatively serious contamination was noticed in winter and spring. Primary fossil fuel combustion and Fe-mediated secondary formation were apportioned as possible sources of PM2.5-bound EPFRs in Zhengzhou. Moreover, to avert the bias of the toxicity assessment induced by utilization of incompletely extracted EPFRs from sample filter, simulatively generated EPFRs were applied to toxicological evaluations (cell viability and reactive oxygen species assays). Corresponding experimental dosages were based on the estimated adults' annual exposure amounts of EPFRs in real PM2.5 samples. The results elucidated that EPFRs might cause growth inhibition and oxidative stress of human lung cells, suggesting the possible exposure-induced health concerns for local people in Zhengzhou. This study provides practical information of real contamination status of PM2.5-bound EPFRs in Zhengzhou, which is favorable to local air pollution control and reduction of exposure risks on public health in central China.

Pathophysiological Effects of Various Interleukins on Primary Cell Types in Common Heart Disease.

Myocardial infarction (MI), heart failure, cardiomyopathy, myocarditis, and myocardial ischemia-reperfusion injury (I/R) are the most common heart diseases, yet there is currently no effective therapy due to their complex pathogenesis. Cardiomyocytes (CMs), fibroblasts (FBs), endothelial cells (ECs), and immune cells are the primary cell types involved in heart disorders, and, thus, targeting a specific cell type for the treatment of heart disease may be more effective. The same interleukin may have various effects on different kinds of cell types in heart disease, yet the exact role of interleukins and their pathophysiological pathways on primary cell types remain largely unexplored. This review will focus on the pathophysiological effects of various interleukins including the IL-1 family (IL-1, IL-18, IL-33, IL-37), IL-2, IL-4, the IL-6 family (IL-6 and IL-11), IL-8, IL-10, IL-17 on primary cell types in common heart disease, which may contribute to the more precise and effective treatment of heart disease.

Enzymatic basis for stepwise C-glycosylation in the formation of flavonoid di-C-glycosides in sacred lotus (Nelumbo nucifera Gaertn.).

Lotus plumule, the embryo of the seed of the sacred lotus (Nelumbo nucifera), contains a high accumulation of secondary metabolites including flavonoids and possesses important pharmaceutical value. Flavonoid C-glycosides, which accumulate exclusively in lotus plumule, have attracted considerable attention in recent decades due to their unique chemical structure and special bioactivities. As well as mono-C-glycosides, lotus plumule also accumulates various kinds of di-C-glycosides by mechanisms which are as yet unclear. In this study we identified two C-glycosyltransferase (CGT) genes by mining sacred lotus genome data and provide in vitro and in planta evidence that these two enzymes (NnCGT1 and NnCGT2, also designated as UGT708N1 and UGT708N2, respectively) exhibit CGT activity. Recombinant UGT708N1 and UGT708N2 can C-glycosylate 2-hydroxyflavanones and 2-hydroxynaringenin C-glucoside, forming flavone mono-C-glycosides and di-C-glycosides, respectively, after dehydration. In addition, the above reactions were successfully catalysed by cell-free extracts from tobacco leaves transiently expressing NnCGT1 or NnCGT2. Finally, enzyme assays using cell-free extracts of lotus plumule suggested that flavone di-C-glycosides (vicenin-1, vicenin-3, schaftoside and isoschaftoside) are biosynthesized through sequentially C-glucosylating and C-arabinosylating/C-xylosylating 2-hydroxynaringenin. Taken together, our results provide novel insights into the biosynthesis of flavonoid di-C-glycosides by proposing a new biosynthetic pathway for flavone C-glycosides in N. nucifera and identifying a novel uridine diphosphate-glycosyltransferase (UGT708N2) that specifically catalyses the second glycsosylation, C-arabinosylating and C-xylosylating 2-hydroxynaringenin C-glucoside.

Development of selective FGFR1 degraders using a Rapid synthesis of proteolysis targeting Chimera (Rapid-TAC) platform.

Proteolysis Targeting Chimera (PROTAC) has emerged as a novel therapeutic strategy. The major bottleneck for the development of PROTACs is the need to screen multiple parameters to create an effective degrader. It often involves the synthesis of dozens to hundreds of compounds one by one through a tedious process. We have developed a two-stage approach that allows for the rapid synthesis of PROTACs (Rapid-TAC) using preassembled building blocks to screen multiple parameters simultaneously. We herein report the application of this method to the development of PROTACs for FGFR, a challenging membrane protein target. In the first stage, we prepared 24 potential PROTACs quickly from a hydrazide-containing FGFR inhibitor and our previously reported VHL and CRBN ligand library bearing various linkers and an aldehyde functional group. These 24 PROTACs were then directly used for screening in cellular assay for protein degradation. Multiple hits were identified from the initial screening. We then prepared the corresponding stable analogues by replacing the hydrolytic labile acylhydrazone motif with an amide in the second stage. Among them, PROTAC LG1188 was identified as a potent and selective FGFR1 degrader.

What is the prognosis of ANCA-associated glomerulonephritis with immune deposition?

OBJECTIVES: This study aimed to analyze histological and clinical characteristics of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) showing renal involvement to investigate the associations between immune complexes (IC) and clinicopathological indicators, and explore the renal outcomes of AAV. METHODS: We retrospectively evaluated the histopathological features and clinical characteristics of 80 renal biopsies of patients with AAV with renal involvement. Renal morphology was classified into two (with and without the presence of IC and complement deposition). Endpoints included end-stage kidney disease (ESKD) and death. RESULTS: Compared with patients without IC, patients with immune deposition had lower complement C3 (0.80 ± 0.27 vs. 0.93 ± 0.20, p = 0.024), more severe hematuria [133 (46-299) vs. 33 (15-115), p = 0.001] but had milder chronic pathology, including chronic tubular atrophy (p = 0.03), chronic interstitial fibrosis (p = 0.049). Patients in the immune deposition group showed a tendency to have more severe crescent formation and less glomerulosclerosis, but the difference was not statistically significant. Endpoints such as death and ESKD were not significantly different between the two groups. CONCLUSIONS: Immune deposition may indicate lower complement C3, more severe hematuria and glomerular lesions, milder tubular atrophy, and interstitial fibrosis, but it cannot predict the renal outcome.

Maleimide-Functionalized Liposomes: Prolonged Retention and Enhanced Efficacy of Doxorubicin in Breast Cancer with Low Systemic Toxicity.

Cell surface thiols can be targeted by thiol-reactive groups of various materials such as peptides, nanoparticles, and polymers. Here, we used the maleimide group, which can rapidly and covalently conjugate with thiol groups, to prepare surface-modified liposomes (M-Lip) that prolong retention of doxorubicin (Dox) at tumor sites, enhancing its efficacy. Surface modification with the maleimide moiety had no effect on the drug loading efficiency or drug release properties. Compared to unmodified Lip/Dox, M-Lip/Dox was retained longer at the tumor site, it was taken up by 4T1 cells to a significantly greater extent, and exhibited stronger inhibitory effect against 4T1 cells. The in vivo imaging results showed that the retention time of M-Lip at the tumor was significantly longer than that of Lip. In addition, M-Lip/Dox also showed significantly higher anticancer efficacy and lower cardiotoxicity than Lip/Dox in mice bearing 4T1 tumor xenografts. Thus, the modification strategy with maleimide may be useful for achieving higher efficient liposome for tumor therapy.

Clinical Analysis of Thrombocytopenia following Transcatheter Occlusion of a Patent Ductus Arteriosus.

BACKGROUND: Our aim is to analyze the correlation between severe thrombocytopenia and the diameter of patent ductus arteriosus (PDA) and residual shunt after PDA closure. METHODS: The patients with severe thrombocytopenia (platelet count <50 × 109/L) following transcatheter occlusion of a PDA from January 2010 to December 2018 in the Children's Hospital of Chongqing Medical University were collected. And the high-risk factors, diagnosis, treatment, and prognosis of severe thrombocytopenia were analyzed. RESULTS: A total of 1,581 children with transcatheter occlusion of a PDA were collected; 22 (1.39%) of the enrolled patients had severe thrombocytopenia. Further data analysis showed that the median diameter of PDA (6.7 [IQR: 1.63]) mm in children with severe thrombocytopenia was significantly larger than that in children without severe thrombocytopenia (3.6 ± 1.7 mm, p < 0.001). Furthermore, the incidence of thrombocytopenia in children with residual shunt after operation (10.9%) was significantly higher than that in children without residual shunt (0.2%, p < 0.001). The mean time of thrombocytopenia was found to be 2.4 ± 1.3 days after intervention. All patients with thrombocytopenia were treated by methylprednisolone with or without platelet transfusion and recovered without major organ hemorrhage. CONCLUSIONS: Severe thrombocytopenia following transcatheter occlusion of a PDA may be related to the larger diameter of PDA and residual shunt. If early detection of severe thrombocytopenia is obtained, our study supports a good prognosis if appropriate measures are implemented.

Association between rosacea and smoking: A systematic review and meta-analysis.

Rosacea is a chronic inflammatory disease of the centrofacial region. However, the association between rosacea and smoking remains controversial. To evaluate the association between rosacea and smoking, we performed a systematic review and meta-analysis. A comprehensive systematic search of literature published before October 15, 2020 on online databases (including Web of Science, PubMed, Cochrane Library, and Embase) was performed. The pooled odds ratios (ORs) were calculated. 12 articles were included, covering 80 156 controls and 54 132 patients with rosacea. Tobacco consumption was not found to increase the risk of rosacea. However, using subtype analysis (involving 5 articles), we found there was a decreased risk of rosacea in current smokers but an increased risk in ex-smokers. In addition, smoking appears to increase the risk of papulopustular rosacea and phymatous rosacea. Analysis of all included studies also showed that ex-smoking was associated with an increased risk, while current smoking was associated with a reduced risk of rosacea. In order to prevent many diseases, including rosacea, the public should be encouraged to avoid smoking.

Pathogenicity of novel goose-origin astrovirus causing gout in goslings.

BACKGROUND: A novel goose-origin astrovirus (GoAstV) has broken out across China in recent years, causing gout in goslings with a mortality rate of around 50%. However, our understanding of the dynamic distribution, tissue tropism and pathogenesis of GoAstV is incomplete. In order to assess its pathogenicity, one-day-old goslings were inoculated separately with GoAstV via oral and subcutaneous injection routes. RESULTS: Clinical symptoms, gross and microscopic lesions, blood biochemical parameters and viral loads were detected and recorded for 20 days after infection. Typical gout was observed in experimental goslings. GoAstV can be replicated in tissues and cause pathological damage, especially in the kidney, liver, heart and spleen. Virus-specific genomic RNA was detected in blood, cloacal swabs and all representative tissues, and virus shedding was detected up to 20 days after inoculation, suggesting that GoAstV has a wide tissue tropism and spread systematically after inoculation. The viral copy numbers examined in kidney were the highest, followed by spleen and liver. CONCLUSION: This experiment determined the accurate value of viral loads and biochemical indicators of GoAstV-induced goslings. These findings increase our understanding of the pathogenicity of GoAstV in goslings and provide more reference for future research.

Immunotherapy (excluding checkpoint inhibitors) for stage I to III non-small cell lung cancer treated with surgery or radiotherapy with curative intent.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common lung cancer, accounting for approximately 80% to 85% of all cases. For people with localised NSCLC (stages I to III), it has been speculated that immunotherapy may be helpful for reducing postoperative recurrence rates, or improving the clinical outcomes of current treatment for unresectable tumours. This is an update of a Cochrane Review first published in 2017 and it includes two new randomised controlled trials (RCTs). OBJECTIVES: To assess the effectiveness and safety of immunotherapy (excluding checkpoint inhibitors) among  people  with localised NSCLC of stages I to III who received curative intent of radiotherapy or surgery. SEARCH METHODS: We searched the following databases (from inception to 19 May 2021): CENTRAL, MEDLINE, Embase, CINAHL, and five trial registers. We also searched conference proceedings and reference lists of included trials. SELECTION CRITERIA: We included RCTs conducted in adults (≥ 18 years) diagnosed with  NSCLC stage I to III after surgical resection, and those with unresectable locally advanced stage III NSCLC receiving radiotherapy with curative intent. We included participants who underwent primary surgical treatment, postoperative radiotherapy or chemoradiotherapy if the same strategy was provided for both intervention and control groups. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible trials, assessed risk of bias, and extracted data. We used survival analysis to pool time-to-event data, using hazard ratios (HRs). We used risk ratios (RRs) for dichotomous data, and mean differences (MDs) for continuous data, with 95% confidence intervals (CIs). Due to clinical heterogeneity (immunotherapeutic agents with different underlying mechanisms), we combined data by applying random-effects models. MAIN RESULTS: We included 11 RCTs involving 5128 participants (this included 2 new trials with 188 participants since the last search dated 20 January 2017). Participants who underwent surgical resection or received curative radiotherapy were randomised to either an immunotherapy group or a control group. The immunological interventions were active immunotherapy Bacillus Calmette-Guérin (BCG) adoptive cell transfer (i.e. transfer factor (TF), tumour-infiltrating lymphocytes (TIL), dendritic cell/cytokine-induced killer (DC/CIK), antigen-specific cancer vaccines (melanoma-associated antigen 3 (MAGE-A3) and L-BLP25), and targeted natural killer (NK) cells. Seven trials were at high risk of bias for at least one of the risk of bias domains. Three trials were at low risk of bias across all domains and one small trial was at unclear risk of bias as it provided insufficient information. We included data from nine of the 11 trials in the meta-analyses involving 4863 participants. There was no evidence of a difference between the immunotherapy agents and the controls on any of the following outcomes: overall survival (HR 0.94, 95% CI 0.84 to 1.05; P = 0.27; 4 trials, 3848 participants; high-quality evidence), progression-free survival (HR 0.94, 95% CI 0.86 to 1.03; P = 0.19; moderate-quality evidence), adverse events (RR 1.12, 95% CI 0.97 to 1.28; P = 0.11; 4 trials, 4126 evaluated participants; low-quality evidence), and severe adverse events (RR 1.14, 95% CI 0.92 to 1.40; 6 trials, 4546 evaluated participants; low-quality evidence).  Survival rates at different time points showed no evidence of a difference between immunotherapy agents and the controls. Survival rate at 1-year follow-up (RR 1.02, 95% CI 0.96 to 1.08; I2 = 57%; 7 trials, 4420 participants; low-quality evidence), 2-year follow-up (RR 1.02, 95% CI 0.93 to 1.12; 7 trials, 4420 participants; moderate-quality evidence), 3-year follow-up (RR 0.99, 95% CI 0.90 to 1.09; 7 trials, 4420 participants; I2 = 22%; moderate-quality evidence) and at 5-year follow-up (RR 0.98, 95% CI 0.86 to 1.12; I2 = 0%; 7 trials, 4389 participants; moderate-quality evidence).  Only one trial reported overall response rates. Two trials provided health-related quality of life results with contradicting results.  AUTHORS' CONCLUSIONS: Based on this updated review, the current literature does not provide evidence that suggests a survival benefit from adding immunotherapy (excluding checkpoint inhibitors) to conventional curative surgery or radiotherapy, for people with localised NSCLC (stages I to III). Several ongoing trials with immune checkpoints inhibitors (PD-1/PD-L1) might bring new insights into the role of immunotherapy for people with stages I to III NSCLC.

Enhancing Charge Separation through Oxygen Vacancy-Mediated Reverse Regulation Strategy Using Porphyrins as Model Molecules.

Highly efficient charge separation has been demonstrated as one of the most significant steps playing decisive roles in enhancing the overall efficiency of photoelectrochemical (PEC) processes. In this study, by employing 5,10,15,20-tetrakis (4-carboxyphenyl) porphyrin-Ni (NiTCPP) as a prototype, an oxygen vacancy (Vo)-mediated reverse regulation strategy is proposed for tuning hole transfer, which in turn can accelerate the transport of electrons and thus enhancing charge separation. The optimal NiO/NiTCPP system exhibits much higher (≈40 times) photocurrent and longer (≈13 times) lifetime of charge carriers compared with those of pure NiTCPP. Furthermore, the electron transfer kinetic rate constant (Keff ) is quantitatively determined by an efficient scanning photoelectrochemical microscopy (SPECM). The Keff of the optimal system has a 5.7-fold improvement. In addition, the similar enhancement in charge separation from other semiconductors (CoTCPP and FeTCPP) are also observed, indicating that the Vo-mediated reverse regulation strategy is a promising pathway for tuning the properties of light harvesters in solar energy conversion.

Cross-Linked Surface Engineering to Improve Iron Porphyrin Catalytic Activity.

Quasi-two-dimensional (QTD) structural heterogeneous catalysts have attracted a broad interest in multidisciplinary research due to their unique structure, preeminent surface properties and outstanding catalytic performance. Herein, a HZIF@TCPP-Fe/Fe heterogeneous catalyst based on cross-linked surface engineering is constructed by supporting QTD TCPP-Fe/Fe ultra-thin metallized film (≈2 nm) on hollow skeleton of zeolite imidazolate frameworks. The designed QTD structure exhibits high efficiency for the catalytic oxidative dehydrogenation of aromatic hydrazides reactions which is the key technology in various industrial processes. Taking advantage of QTD structure with excellent accessibility, the metallized film with irregular defects not only enhances electron transfer during the reaction but also exposes more surface-active sites. Furthermore, the prepared HZIF@TCPP-Fe/Fe heterogeneous catalyst can be recycled and reused, which is of great significance in the field of green chemistry.

A Positive Feedback Loop Between Cancer Stem-Like Cells and Tumor-Associated Neutrophils Controls Hepatocellular Carcinoma Progression.

Tumor-associated neutrophils (TANs) play a crucial role in tumor development and progression in the cancer microenvironment. Despite increased understanding of TAN contributions to hepatocellular carcinoma (HCC) progression and prognosis, the direct interaction between TANs and HCC cells is not fully understood. In this study, we tested the effect of TANs on HCC cells in vitro and in vivo and investigated the mechanism of interaction between them. Our results showed that TANs secreted bone morphogenetic protein 2 and transforming growth factor beta 2 and triggered microRNA 301b-3p (miR-301-3p) expression in HCC cells, subsequently suppressed gene expression of limbic system-associated membrane protein (LSAMP) and CYLD lysine 63 deubiquitinase (CYLD), and increased stem cell characteristics in HCC cells. These TAN-induced HCC stem-like cells were hyperactive in nuclear factor kappa B signaling, secreted higher levels of chemokine (C-X-C motif) ligand 5 (CXCL5), and recruited more TAN infiltration, suggesting a positive feedback loop. In clinical HCC samples, increased TANs correlated with elevated miR-301b-3p, decreased LSAMP and CYLD expression, and increased nuclear p65 accumulation and CXCL5 expression, all of which predicted patient outcome. Conclusion: Our work identified a positive feedback loop governing cancer stem-like cells and TANs in HCC that controls tumor progression and patient outcome.

Sigma-2 Receptor-A Potential Target for Cancer/Alzheimer's Disease Treatment via Its Regulation of Cholesterol Homeostasis.

The sigma receptors were classified into sigma-1 and sigma-2 receptor based on their different pharmacological profiles. In the past two decades, our understanding of the biological and pharmacological properties of the sigma-1 receptor is increasing; however, little is known about the sigma-2 receptor. Recently, the molecular identity of the sigma-2 receptor has been identified as TMEM97. Although more and more evidence has showed that sigma-2 ligands have the ability to treat cancer and Alzheimer's disease (AD), the mechanisms connecting these two diseases are unknown. Data obtained over the past few years from human and animal models indicate that cholesterol homeostasis is altered in AD and cancer, underscoring the importance of cholesterol homeostasis in AD and cancer. In this review, based on accumulated evidence, we proposed that the beneficial roles of sigma-2 ligands in cancer and AD might be mediated by their regulation of cholesterol homeostasis.

Analysis of Chuanxiong Rhizoma substrate on production of ligustrazine in endophytic Bacillus subtilis by ultra high performance liquid chromatography with quadrupole time-of-flight mass spectrometry.

Ligustrazine was the active ingredient of the traditional Chinese medicine Chuanxiong Rhizoma. However, the content of ligustrazine is very low. We proposed a hypothesis that ligustrazine was produced by the mutual effects between endophytic Bacillus subtilis and the Ligusticum chuanxiong Hort. This study aimed to explore whether the endophytic B. subtilis LB5 could make use of Chuanxiong Rhizoma fermentation matrix to produce ligustrazine and clarify the mechanisms of action preliminarily. Ultra high performance liquid chromatography with quadrupole time-of-flight mass spectrometry analysis showed the content of ligustrazine in Chuanxiong Rhizoma was below the detection limit (0.1 ng/mL), while B. subtilis LB5 produced ligustrazine at the yield of 1.0268 mg/mL in the Chuanxiong Rhizoma-ammonium sulfate fermentation medium. In the fermented matrix, the reducing sugar had a significant reduction from 12.034 to 2.424 mg/mL, and rough protein content increased from 2.239 to 4.361 mg/mL. Acetoin, the biosynthetic precursor of ligustrazine, was generated in the Chuanxiong Rhizoma-Ammonium sulfate (151.2 mg/mL) fermentation medium. This result showed that the endophytic bacteria B. subtilis LB5 metabolized Chuanxiong Rhizoma via secreted protein to consume the sugar in Chuanxiong Rhizoma to produce a considerable amount of ligustrazine. Collectively, our preliminary research suggested that ligustrazine was the interaction product of endophyte, but not the secondary metabolite of Chuanxiong Rhizoma itself.