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Berberine, an isoquinoline alkaloid isolated from the Chinese herb Coptis chinensis and other Berberis plants, has a wide range of pharmacological properties. Berberine can be used to treat many diseases, such as cancer and digestive, metabolic, cardiovascular, and neurological diseases. Berberine has protective capacities in digestive diseases. It can inhibit toxins and bacteria, including Helicobacter pylori, protect the intestinal epithelial barrier from injury, and ameliorate liver injury. Berberine also inhibits the proliferation of various types of cancer cells and impedes invasion and metastasis. Recent evidence has confirmed that berberine improves the efficacy and safety of chemoradiotherapies. In addition, berberine regulates glycometabolism and lipid metabolism, improves energy expenditure, reduces body weight, and alleviates nonalcoholic fatty liver disease. Berberine also improves cardiovascular hemodynamics, suppresses ischemic arrhythmias, attenuates the development of atherosclerosis, and reduces hypertension. Berberine shows potent neuroprotective effects, including antioxidative, antiapoptotic, and anti-ischemic. Furthermore, berberine exerts protective effects against other diseases. The mechanisms of its functions have been extensively explored, but much remains to be clarified. This article summarizes the main pharmacological actions of berberine and its mechanisms in cancer and digestive, metabolic, cardiovascular, and neurological diseases.

Background Mental disorders, one of the leading causes of the global health-related burden, which has been exacerbated by the emergence of the COVID-19 pandemic (2019–2021). In this study, we aim to provide global, regional, and national estimates of the mental disorders burden from 1990 to 2021, including during the COVID-19. Methods We collected data from the Global Burden of Disease Study 2021 (GBD 2021) on the incidence, disability-adjusted life years (DALYs), age-standardized incidence rate (ASIR), and age-standardized DALY rate (ASR) of 12 mental disorders from 204 countries and regions. The socio-demographic index (SDI) was used to evaluate the correlation between mental disorders burden and different regions. We utilized joinpoint regression analysis to estimate the average annual percentage change (AAPC). Results In 2021, there were 444,397,716 incident cases and 155,418,119 DALYs globally from mental disorders. From 1990 to 2021, there was an upward trend in both ASIR [15.23% (12.97–17.60%)] and ASR [17.28% (15.06–19.44%)]. In 2021, the highest ASIR was observed in Central Sub-Saharan Africa (8706.11), while the lowest was in East Asia (3340.99). Australia (2787.87) had the highest ASR. Nationally, Greenland, Greece, the United States, and Australia had the highest ASRs. During the COVID-19 pandemic, aside from East Asia, both the ASIR showed an upward trend in the five SDI and other GBD regions. In 2021, the ASR for females was higher than that for males. Among the 12 subtypes, major depressive disorder (557.87) and anxiety disorders (524.33) had the highest ASR. Major depressive disorder ranked first in ASR in 13 of the 21 regions worldwide. Despite the overall upward trend in DALYs for mental disorders [AAPC: 5.96; 95%CI: (4.99, 6.92)], the ASR exhibited varying trends among different subtypes, with anxiety disorders experiencing the most significant increase. Conclusions GBD 2021 showed that the burden of mental disorders has increased over the past three decades, with notable regional disparities. High SDI regions and females should be paid more attention. To alleviate future burdens, providing comprehensive mental health support, establishing effective mental health knowledge dissemination and tailored interventions are in great need. Clinical trial number Not applicable.

The sex-determining region Y (SRY)-box (SOX) family has a crucial role in carcinogenesis and cancer progression. However, the role of SOX12 and the mechanism by which it is dysregulated in colorectal cancer (CRC) remain unclear. Here we analyzed SOX12 expression patterns in two independent CRC cohorts (cohort I, n  = 390; cohort II, n  = 363) and found that SOX12 was significantly upregulated in CRC, indicating a poor prognosis in CRC patients. Overexpression of SOX12 promoted CRC cell proliferation and metastasis, whereas downregulation of SOX12 hampered CRC aggressiveness. Mechanistically, SOX12 facilitated asparagine synthesis by transactivating glutaminase ( GLS ), glutamic oxaloacetic transaminase 2 ( GOT2 ), and asparagine synthetase ( ASNS ). Downregulation of GLS, GOT2, and ASNS blocked SOX12-mediated CRC cell proliferation and metastasis, whereas ectopic expression of GLS, GOT2, and ASNS attenuated the SOX12 knockdown-induced suppression of CRC progression. In addition, serial deletion, site-directed mutagenesis, luciferase reporter, and chromatin immunoprecipitation (ChIP) assays indicated that hypoxia-inducible factor 1α (HIF-1α) directly binds to the SOX12 promoter and induces SOX12 expression. Administration of l -asparaginase decreased SOX12-mediated tumor growth and metastasis. In human CRC samples, SOX12 expression positively correlated with GLS, GOT2, ASNS, and HIF-1α expression. Based on these results, SOX12 may serve as a prognostic biomarker and l -asparaginase represents a potential novel therapeutic agent for CRC.

Metastasis is the major reason for the high mortality of colorectal cancer (CRC) patients and its molecular mechanism remains unclear. Here, we report a novel role of Homeobox A13 (HOXA13), a member of the Homeobox (HOX) family, in promoting CRC metastasis. The elevated expression of HOXA13 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in two independent CRC cohorts. Overexpression of HOXA13 promoted CRC metastasis whereas downregulation of HOXA13 suppressed CRC metastasis. Mechanistically, HOXA13 facilitated CRC metastasis by transactivating ATP-citrate lyase (ACLY) and insulin-like growth factor 1 receptor (IGF1R). Knockdown of ACLY and IGFIR inhibited HOXA13-medicated CRC metastasis, whereas ectopic overexpression of ACLY and IGFIR rescued the decreased CRC metastasis induced by HOXA13 knockdown. Furthermore, Insulin-like growth factor 1 (IGF1), the ligand of IGF1R, upregulated HOXA13 expression through the PI3K/AKT/HIF1α pathway. Knockdown of HOXA13 decreased IGF1-mediated CRC metastasis. In addition, the combined treatment of ACLY inhibitor ETC-1002 and IGF1R inhibitor Linsitinib dramatically suppressed HOXA13-mediated CRC metastasis. In conclusion, HOXA13 is a prognostic biomarker in CRC patients. Targeting the IGF1-HOXA13-IGF1R positive feedback loop may provide a potential therapeutic strategy for the treatment of HOXA13-driven CRC metastasis.

Genome-wide analysis of genomic signatures might reveal novel mechanisms for gastric cancer (GC) tumorigenesis. Here, we analysis structural variations (SVs) and mutational signatures via whole-genome sequencing of 168 GCs. Our data demonstrates diverse models of complex SVs operative in GC, which lead to high-level amplification of oncogenes. We find varying proportion of tandem-duplications (TDs) among individuals and identify 24 TD hotspots involving well-established cancer genes such as CCND1, ERBB2 and MYC . Specifically, we nominate a novel hotspot involving the super-enhancer of ZFP36L2 presents in approximately 10% GCs from different cohorts, the oncogenic role of which is further confirmed by experimental data. In addition, our data reveal a mutational signature, specifically occurring in noncoding region, significantly enriched in tumors with cadherin 1 mutations, and associated with poor prognoses. Collectively, our data suggest that TDs might serve as an important mechanism for cancer gene activation and provide a novel signature for stratification. Structural variations in gastric cancer impact progression. Here, the authors perform whole-genome sequencing on 168 gastric cancer patients and identified tandem-duplications of super-enhancer ZFP36L2 in 10% of gastric cancer, and mutational signatures in tumors with cadherin 1 mutations that associated with poor prognoses.

Following dramatic success in many types of advanced solid tumors, interest in immunotherapy for the treatment of colorectal cancer (CRC) is increasingly growing. Given the compelling long-term durable remission, two programmed cell death 1 (PD-1)-blocking antibodies, pembrolizumab and nivolumab (with or without Ipilimumab), have been approved for the treatment of patients with metastatic colorectal cancer (mCRC) that is mismatch-repair-deficient and microsatellite instability-high (dMMR-MSI-H). Practice-changing results of several randomized controlled trials to move immunotherapy into the first-line treatment for MSI-H metastasis cancer and earlier stage were reported successively in the past 2 years. Besides, new intriguing advances to expand the efficacy of immunotherapy to mCRC that is mismatch-repair-proficient and low microsatellite instability (pMMR-MSI-L) demonstrated the potential benefits for the vast majority of mCRC cases. Great attention is also paid to the advances in cancer vaccines and adoptive cell therapy (ACT). In this review, we summarize the above progresses, and also highlight the current predictive biomarkers of responsiveness in immunotherapy with broad clinical utility.

Hypoxia induced drug resistance is a major obstacle in the development of effective cancer therapy. Our previous study revealed that hypoxia‐inducible factor‐1 (HIF‐1), the major transcriptional factor significantly activated by hypoxia, was overexpressed in gastric vincristine‐resistant cells SGC7901/vincristine (VCR) under normoxic conditions, which suggested that it was associated with drug resistance in gastric cancer cells. In the present study, a colony‐forming assay revealed that hypoxia and forced HIF‐1α expression increased maximal –8.9‐fold or –14.8‐fold of IC50 toward vincristine in gastric cancer cell lines SGC7901 and SGC7901/VCR, respectively (P < 0.01). Annexin‐V/propidium iodide staining analysis revealed hypoxia or forced HIF‐1α expression reduced apoptosis by 24% or 18% in SGC7901 cells (P < 0.05). Flow cytometry analysis of intracellular adriamycin revealed that hypoxia and forced expression of HIF‐1α increased –1.79‐fold or –2.36‐fold of the adriamycin releasing index, respectively (P < 0.05). However, resistance acquisition subject to hypoxia in vitro and in vivo was suppressed by blocking HIF‐1α expression with siRNA. We further demonstrated that HIF‐1 α overexpression showed a 1.85‐fold increased expression of Bcl‐2 and a 2.16‐fold decreased expression of Bax, and also showed significantly induced expression of p‐gp and MRP1, which indicated that HIF‐1α may confer hypoxia‐induced drug resistance via inhibition of drug‐induced apoptosis and decreases in intracellular drug accumulation. (Cancer Sci 2008; 99: 121–128)

Medicine has encountered unprecedented problems associated with changes in nature, society, and environment, as well as with new human quests for survival, longevity, and health. In the meantime, the development of medicine is facing challenges that resulted from the over-division and specialization of disciplines and the fragmentation of medical knowledge. To construct a new medical system that is more suitable for human health and disease treatment, holistic integrative medicine (HIM), which regards the human body as a holistic entity, organically integrates the most advanced knowledge and theories in each medical field and the most effective practices in various clinical specialties to revise and adjust on the basis of social, environmental, and psychological conditions. HIM is the inevitable and necessary direction for the future development of medicine. In this article, we illustrated the connotation of HIM, the differences between HIM and other medical conceptions, and the practice of HIM in recent years.

Background The diagnostic and prognostic significance of carcinoembryonic antigen (CEA), carbohydrate associated antigen 19–9 (CA19–9), alpha-fetoprotein (AFP) and cancer antigen 125 (CA125) in early gastric cancer have not been investigated yet. Thus, the present study aimed to explore the diagnostic and prognostic significance of the four tumor markers for early gastric cancer. Methods From September 2008 to March 2015, 587 early gastric cancer patients were given radical gastrectomy in our center. The clinicopathological characteristics were recorded. The association between levels of CEA and CA19–9 and clinicopathological characteristics and prognosis of patients were analyzed. Results There were 444 men (75.6%) and 143 women (24.4%). The median age was 57 years (ranged 21–85). The 1-, 3- and 5-year overall survival rate was 99.1%, 96.8% and 93.1%, respectively. The positive rate of CEA, CA19–9, AFP and CA125 was 4.3%, 4.8%, 1.5% and 1.9%, respectively. The positive rate of all markers combined was 10.4%. The associations between the clinicopathological features and levels of CEA and CA19–9 were analyzed. No significant association was found between CEA level and clinicopathological features. However, elevated CA19–9 level was correlated with female gender and presence of lymph node metastasis. Age > 60 years old, presence of lymph node metastasis and elevation of CEA level were independent risk factors for poor prognosis of early gastric cancer. Conclusions The positive rates of CEA, CA19–9, APF and CA125 were relatively low for early gastric cancer. Elevation of CA19–9 level was associated with female gender and presence of lymph node metastasis. Elevation of CEA level was an independent risk factor for the poor prognosis of early gastric cancer.