Research progress on the antitumor effects of harmine.

Harmine is a naturally occurring ß-carboline alkaloid originally isolated from Peganum harmala. As a major active component, harmine exhibits a broad spectrum of pharmacological properties, particularly remarkable antitumor effects. Recent mechanistic studies have shown that harmine can inhibit cancer cell proliferation and metastasis through epithelial-to-mesenchymal transition, cell cycle regulation, angiogenesis, and the induction of tumor cell apoptosis. Furthermore, harmine reduces drug resistance when used in combination with chemotherapeutic drugs. Despite its remarkable antitumor activity, the application of harmine is limited by its poor solubility and toxic side effects, particularly neurotoxicity. Novel harmine derivatives have demonstrated strong clinical application prospects, but further validation based on drug activity, acute toxicity, and other aspects is necessary. Here, we present a review of recent research on the action mechanism of harmine in cancer treatment and the development of its derivatives, providing new insights into its potential clinical applications and strategies for mitigating its toxicity while enhancing its efficacy.

Clinical characteristics and long-term prognosis of elderly onset Crohn's disease. / è€å¹´èµ·ç— å ‹ç½—æ©ç— çš„ä¸´åºŠç‰¹ç‚¹åŠè¿œæœŸé¢„åŽ.

OBJECTIVES: With the increase in aging population in China, elderly Crohn's disease (CD) patients need to receive more attention. This study aims to explore the clinical characteristics and disease process of elderly onset CD (EOCD) patients in a single center. METHODS: From January 2002 to January 2022, a total of 221 patients with CD from the Seventh Medical Center of Chinese PLA General Hospital were enrolled. According to the Montreal CD classification standard, the patients were further divided into 4 groups: an EOCD group (≥60 years old, n=25), a middle age onset CD (MOCD) group (40-59 years old, n=46), a young onset CD (YOCD) group (17-40 years old, n=131), and a childhood onset CD (COCD) group (6-16 years old, n=19). We compared the clinical characteristics and long-term prognosis among them. RESULTS: Females were predominant in the EOCD group (15/25, 60%). The number of people without smoking in the EOCD group (80%) was lower than that in COCD group (100%), higher than that in the YOCD group (70.2%) and the MOCD group (69.6%) (all P<0.05). Patients with perianal diseases at diagnosis were rare in the EOCD group (0%), lower than that in the COCD group (21.1%) and the YOVD group (19.8%) (all P<0.05). Stenosis was the most common disease behavior in the EOCD group (63.0%), significantly higher than that in the COCD group (15.8%), the YOCD group (36.6%) and the MOCD group (43.5%) (all P<0.05). The EOCD group was easier to be misdiagnosed as tumor (24%), higher than that in the COCD group (0%), the YOCD group (6.9%) and the MOCD group (19.6%) (all P<0.05). The EOCD group was prone to comorbidities (52%), and 20% of them were complicated with multiple comorbidities (P<0.05). During the follow-up, the all-cause mortality of EOCD was 12%, and the CD-related mortality was 8%, which was significantly higher than the other groups (all P<0.05). The use of immunosuppressants in the EOCD group (4.8%) was lower than that in the COCD group (12.8%), the YOCD group (16.8%) and the MOCD group (16.1%), but there was no statistical significance among the 4 groups (P=0.467). In addition, there was no significant difference in the rate of intestinal resection among the 4 groups (P=0.062). CONCLUSIONS: In EOCD patients, females were predominant, smoking was less common, and they were prone to comorbidity. At the initial stage of diagnosis, it is easy to be misdiagnosed as tumor, and the disease behavior mainly showed stricture type, less complicated with perianal diseases. During the follow-up, all-cause mortality and CD-related mortality of EOCD patients were significantly higher than those of the non-elderly onset CD patients.

FOXO1 orchestrates the intestinal homeostasis via neuronal signaling in group 3 innate lymphoid cells.

The neuro-immune regulation is associated with homeostasis of the intestine. Intestinal group 3 innate lymphoid cells (ILC3s) are tissue-resident lymphocytes whose functions are affected by the intestine niche. However, how a gut neuronal signal coordinates the immune response of ILC3s is largely unknown. Here, we found that cyclic adenosine monophosphate (cAMP) signaling exacerbated the inflammatory response and attenuated the expression level of the transcription factor forkhead box O1 (FOXO1) in ILC3s. Deficiency of FOXO1 drove the hyperactivation of ILC3s and resulted in gut inflammation independently of T cells. Mechanistically, FOXO1 promoted the transcription of neuropeptide receptor VIPR2 and inhibited the transcription of adrenoceptor ADRA2A in ILC3s. FOXO1-related regulation of VIPR2 and ADRA2A signaling balanced the activation of ILC3s under steady condition or during colitis. Moreover, chronic stress elevated cAMP level and downregulated FOXO1 level, exacerbating intestinal inflammation. Our findings reveal that FOXO1 balances the activation of ILC3s via VIP and adrenergic signaling and regulates intestinal homeostasis.

PtMo-Au Metalloenzymes Regulated Tumor Microenvironment for Enhanced Sonodynamic/Chemodynamic/Starvation Synergistic Therapy.

The clinical application of sonodynamic therapy (SDT) is greatly limited by the low quantum yield of sonosensitizers and tumor microenvironment (TME). Herein, PtMo-Au metalloenzyme sonosensitizer is synthesized by modulating energy band structure of PtMo with Au nanoparticles. The surface deposition of Au simultaneously solves the carrier recombination and facilitates the separation of electrons (e- ) and holes (h+ ), effectively improving the reactive oxygen species (ROS) quantum yield under ultrasound (US). The catalase-like activity of PtMo-Au metalloenzymes alleviates hypoxia TME, thus enhancing the SDT-induced ROS generation. More importantly, tumor overexpressed glutathione (GSH) can serve as the hole scavenger, which is accompanied by a persistent depletion of the GSH, thus inactivating GPX4 for the accumulation of lipid peroxides. The distinctly facilitated SDT-induced ROS production is coupled with chemodynamic therapy (CDT)-induced hydroxyl radicals (•OH) to exacerbate ferroptosis. Furthermore, Au with glucose oxidase mimic activity can not only inhibit intracellular adenosine triphosphate (ATP) production and induce tumor cell starvation but also generate H2 O2 to facilitate CDT. In general, this PtMo-Au metalloenzyme sonosensitizer optimizes the defects of conventional sonosensitizers through surface deposition of Au to regulate TME, providing a novel perspective for US-based tumor multimodal therapy.

Non-Negligible Role of Trace Elements in Influenza Virus Infection.

Influenza virus has continuously spread around the globe for more than 100 years since the first influenza epidemic in 1918. The rapid and unpredictable gene variation of the influenza virus could possibly bring about another pandemic in future, which might threaten to overwhelm us without adequate preparation. Consequently, it is extremely urgent to identify effective broad-spectrum antiviral treatments for a variety of influenza virus variants. As essential body components, trace elements are great potential candidates with an as yet poorly understood ability to protect the host from influenza infection. Herein, we have summarized the present state of knowledge concerning the function of trace elements in influenza virus replication along with an analysis of their potential molecular mechanisms. Modulation of host immune responses to the influenza virus is one of the most common modes to achieve the anti-influenza activity of trace elements, such as selenium and zinc. Simultaneously, some antioxidant and antiviral signal pathways can be altered with the participation of trace elements. More interestingly, some micro-elements including selenium, zinc, copper and manganese, directly target viral proteins and regulate their stability and activity to influence the life cycle of the influenza virus. Further verification of the antiviral effect and the mechanism will promote the application of trace elements as adjuvants in the clinic.

SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surface.

Genetic polymorphisms are associated with the development of nonalcoholic fatty liver disease (NAFLD). Semaphorin7a (Sema7a) deficiency in mouse peritoneal macrophages reduces fatty acid (FA) oxidation. Here, we identified 17 individuals with SEMA7A heterozygous mutations in 470 patients with biopsy-proven NAFLD. SEMA7A heterozygous mutations increased susceptibility to NAFLD, steatosis severity, and NAFLD activity scores in humans and mice. The Sema7aR145W mutation (equivalent to human SEMA7AR148W) significantly induced small lipid droplet accumulation in mouse livers compared with WT mouse livers. Mechanistically, the Sema7aR145W mutation increased N-glycosylated Sema7a and its receptor integrin ß1 proteins in the cell membranes of hepatocytes. Furthermore, Sema7aR145W mutation enhanced its protein interaction with integrin ß1 and PKC-α and increased PKC-α phosphorylation, which were both abrogated by integrin ß1 silencing. Induction of PKCα_WT, but not PKCα_dominant negative, overexpression induced transcriptional factors Srebp1, Chrebp, and Lxr expression and their downstream Acc1, Fasn, and Cd36 expression in primary mouse hepatocytes. Collectively, our findings demonstrate that the SEMA7AR148W mutation is a potentially new strong genetic determinant of NAFLD and promotes intrahepatic lipid accumulation and NAFLD in mice by enhancing PKC-α-stimulated FA and triglyceride synthesis and FA uptake. The inhibition of hepatic PKC-α signaling may lead to novel NAFLD therapies.

[Effect of scalp acupuncture stimulation on mood and sleep in children with autism spectrum disorder].

OBJECTIVE: To observe the effects of penetrating technique of scalp acupuncture on emotion, sleep and function development in children of autism spectrum disorder (ASD). METHODS: A total of 60 SAD children aged 3 to 6 years were randomized in a control group (music education rehabilitation,n=30) and an observation group (penetrating technique of scalp acupuncture + music education rehabilitation,n=30). In the two groups, the treatment for 3 months was as 1 course, and 2 courses of treatment were required. Before and after treatment, the changes were observed in childhood autism rating scale (CARS), emotion regulation subscale (ER), children's sleep habits questionnaire (CSHQ) and children autism and psycho-educational profile for autistic and developmentally disabled children (C-PEP-3), separately. RESULTS: Compared with the scores before treatment, CARS score, the score of each subscale of CSHQ, e.g. bedtime resistance, sleep onset delay, irregular sleep duration, sleep anxiety, parasomnias and daytime sleepiness as well as the total score of CSHQ were all reduced in children of two groups (P<0.05); and the score of ER and C-PEP-3 were all increased (P<0.05) after 6 months' treatment. Compared with the control group, ER score was increased in 3 and 6 months after treatment (P<0.05), CARS score was reduced (P<0.05) and C-PEP-3 score was increased obviously (P<0.05) 6 months after treatment in the observation group; but the scores of the subscale for night waking and sleep disordered breathing did not changed noticeably (P > 0.05). CONCLUSION: Penetrating technique of scalp acupuncture improves the emotion and sleep disorder and promotes the function development in ASD children.

Prediction and Risk Factors for Prognosis of Cirrhotic Patients with Hepatic Encephalopathy.

BACKGROUND AND AIMS: Hepatic encephalopathy (HE) is characterized by recurrence and poor quality of life. Acute-on-chronic liver failure (ACLF) mainly occurs in patients with chronic liver diseases and often presents with HE. Several predictive models have been proposed to predict the outcomes of these patients. Our study is aimed at identifying associated risk factors and the prognostic accuracies of predictive models in HE patients with or without ACLF. METHODS: Patients with liver cirrhosis were retrospectively enrolled. Risk factors were evaluated by multivariate regression analyses. The predictive capabilities of models were calculated using the receiver operating characteristic (ROC) curve analyses and compared by the DeLong tests. Outcomes were defined as in-hospital mortality, HE severity, and ACLF occurrence. RESULTS: In multivariate regression analyses, serum biomarkers neutrophil and total bilirubin (TBIL) were independently correlated with in-hospital death. Alanine aminotransferase (ALT) and blood urea nitrogen (BUN) were independent serum biomarkers associated with HE severity. Hemoglobin, TBIL, BUN, and international normalized ratio (INR) were significant indicators associated with ACLF incidence. For prediction of in-hospital mortality, Child-Pugh was superior to the others in the whole patients, while NLR showed the best capability in the ACLF group. CONCLUSION: In cirrhotic patients present with HE, BUN is a risk factor associated with HE severity and ACLF incidence. Child-Pugh and NLR scores may be effective prognosticators in patients with HE.

CD38 Causes Autophagic Flux Inhibition and Cardiac Dysfunction Through a Transcriptional Inhibition Pathway Under Hypoxia/Ischemia Conditions.

Induced autophagy is protective against myocardial hypoxia/ischemia (H/I) injury, but evidence regarding the extent of autophagic clearance under H/I and the molecular mechanisms that influence autophagic flux has scarcely been presented. Here, we report that CD38 knockout improved cardiac function and autophagic flux in CD38-/- mice and CD38-/- neonatal cardiomyocytes (CMs) under H/I conditions. Mechanistic studies demonstrated that overexpression of CD38 specifically downregulated the expression of Rab7 and its adaptor protein pleckstrin homology domain-containing protein family member 1 (PLEKHM1) through nicotinamide adenine dinucleotide (NAD)-dependent and non-NAD-dependent pathways, respectively. Loss of Rab7/PLEKHM1 impaired the fusion of autophagosomes and lysosomes, resulting in autophagosome accumulation in the myocardium and consequent cardiac dysfunction under H/I conditions. Thus, CD38 mediated autophagic flux blockade and cardiac dysfunction in a Rab7/PLEKHM1-dependent manner. These findings suggest a potential therapeutic strategy involving targeted suppression of CD38 expression.

ALBI versus child-pugh in predicting outcome of patients with HCC: A systematic review.

INTRODUCTION: Hepatocellular carcinoma (HCC) is an aggressive tumor type which results in poor prognosis. ALBI and Child-Pugh score have been widely applied for predicting prognosis in patients with liver diseases. We conducted a systematic review to compare the prognostic ability of ALBI versus Child-Pugh in HCC patients. AREAS COVERED: PubMed, EMBASE and Cochrane Library were explored. The data were extracted from every study. Studies investigating HCC patients and comparing the predicting ability between ALBI and Child-Pugh were analyzed. EXPERT OPINION: This systematic review revealed that ALBI showed better discriminative ability than Child-Pugh for predicting the prognosis in HCC patients. However, the predictive abilities of two scores should be improved. Except for the most common used serum biomarker AFP for diagnosis and surveillance of HCC, recent studies have also explored all aspects of HCC through genome-wide sequencing, exome sequencing, RNA sequencing and genome-wide methylation analysis which provide essential clues for genotyping of HCC. Further studies should explore biomarkers by advanced techniques to validate new prognostic tools for early diagnosis and prognosis of HCC. Moreover, multicenter prospective studies should be carried out to compare the prognostic values of predictive indicators in HCC population in the future.

The role of neutrophil to lymphocyte ratio for the assessment of liver fibrosis and cirrhosis: a systematic review.

INTRODUCTION: Neutrophil to lymphocyte ratio (NLR) is widely used to assess inflammatory diseases. We performed a systematic review to explore the prognostic role of NLR for the assessment of liver fibrosis and cirrhosis. Areas covered: We searched the PubMed and EMBASE databases for the eligible papers which explored the association between NLR and liver fibrosis/cirrhosis or investigated the prognostic value of NLR in cirrhotic patients. Expert commentary: In accordance with assessment of liver fibrosis stage, we classified papers into four subgroups by etiology. For the patients with nonalcoholic fatty liver disease (NAFLD) there was a significant association between NLR and fibrosis stage and nonalcoholic fatty liver disease activity score (NAS), while NLR had a negative correlation with fibrosis stage for the patients with chronic hepatitis B (CHB). As for the patients with and chronic hepatitis C (CHC), NLR might not be significantly associated with fibrosis stage. Moreover, NLR seemed to be significantly useful for predicting outcomes in cirrhotic patients. Hence, NLR might be associated with liver fibrosis stage, especially in patients with NAFLD. Furthermore, NLR might be a useful biomarker for evaluating the prognosis in cirrhotic patients.

[Moxibustion at Baihui (GV 20) for intractable facial paralysis and its impacts on immunoglobulin].

OBJECTIVE: To observe the efficacy of moxibustion at Baihui (GV 20) on intractable facial paraly sis and the impacts on immune globulin IgA, IgG and IgM. METHODS: One hundred and twenty cases of intractable facial paralysis that was in compliance with the inclusive criteria were randomized into a moxibustion group and an acupuncture group, 60 cases in each one. In the moxibustion group, moxibustion was applied at Baihui (GV 20). In the acupuncture group, the patients were treated with acupuncture, once a day, the treatment of 15 days made one session in two groups. Before treatment and after 2 sessions treatment, the levels of IgA, IgG and IgM were detected respectively for the patients in two groups and compared. RESULTS: The difference in the levels of IgA, IgG and IgM was not significant for the patients between two groups (all P > 0.05) before treatment, but the levels of all three indices were increased significantly as compared with the normal reference values (all P < 0.05). Componed before the treatment, the levels of IgA, IgG and IgM were reduced significantly in two groups after treatment, indicating the significant difference (all P < 0.05). In comparison between two groups after the treatment, the levels of IgA, IgG and IgM in the moxibustion group were lower significantly than those in the acupuncture group, presenting the significant difference after treatment (all P < 0.05). CONCLUSION: The ottack of intractable facial paralysis is relevant with the abnormal increase of immunoglobulin. Moxibustion at Baihui (GV 20) reduces significantly the levels of IgA, IgG and IgM for the patients with intractable facial paraly sis, which is probably one of the mechanisms in the treatment of intractable facial paralysis.

[Effects of electroacupuncture on supplementary analgesia and improvement of adverse reactions induced by dolantin in oocyte retrieval].

OBJECTIVE: To observe the effect of electroacupuncture on supplementary analgesia and improvement of adverse reactions induced by dolantin in oocyte retrieval, and to provide scientific and effective evidence for application of electroacupuncture in oocyte retrieval. METHODS: One hundred and thirty-four patients undergoing in vitro fertilization and embryo transfer (IVF-ET) were randomly divied into an observation group and a a control group, 67 cases in each group. They were all received intramuscular injection of 50 mg dolantin at 30 mn before the operation, and then the observation group was treated with acupuncture at Baihui (GV 20), pain point (Extra, right), Sanyangluo (TE 8, right), Zusanli (ST 36, right) and ear uterus point (right ear). Pain point and Sanyangluo (TE 8) were received electroacupuncture stimulation after Deqi until the oocyte retrieval operation was finished, and the oocyte retrieval operation was performed in the control group after 30 min of injection of dolantin. The pain grade and score were observed and the adverse reactions during operation or 1 h and 2 h after the operation were recorded. RESULTS: The excellent analgesia rate was 97.0% (65/ 67) in the observation group and 92.5% (62/67) in the control group, with significant difference in the analgesia effect (P < 0.05). The pain grade and pain score in the observation group were both superior to those in the control group (both P < 0.05). There were fewer cases with the adverse reactions i.e. vertigo, sweating, nausea in the observation group than that in the control group during operation or 1 h and 2 h after the operation (all P < 0.05). CONCLUSION: In the oocyte retrieval operation, under the guidance of vaginal B ultrasound, electroacupuncture has a good intraoperative supplementary analgesia effect without intraoperative and postoperative adverse reactions induced by dolantin.