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Introduction: The purpose of this study was to observe the effect of N-acetylcysteine (NAC) on oxidative stress (OS), intracellular Mycobacterium tuberculosis (MTB) load, apoptosis, and autophagy of macrophages infected with H37Rv MTB. In addition, we explored the possible mechanism of action, to provide a rationale for the use of NAC in the treatment of tuberculosis., Methodology: We divided THP-1 macrophages into four groups: control, control + NAC, H37Rv, and H37Rv + NAC. OS, apoptosis, autophagy and intracellular MTB colony-forming unit (CFU) indexes were measured at 0, 4, 24, and 48 hours, respectively. Then, various indicator changes were systematically compared., Results: The levels of reactive oxygen species (ROS), malondialdehyde (MDA), apoptosis rate, and LC3II/ β-actin ratio in the H37Rv group increased at 4 hours and reached their peak at 48 hours. The ROS and MDA in the H37Rv + NAC group were lower than those in the H37Rv group. CFU in the H37Rv + NAC group increased at 24 hours and decreased at 48 hours after treatment with NAC, relative to the H37Rv group. In addition, the H37Rv + NAC group showed a decrease in LC3II/β-actin ratio 48 hours after NAC treatment, compared to the H37Rv group., Conclusions: MTB infection can lead to an increase in macrophage OS, apoptosis, and autophagy levels. However, after treatment with NAC, the growth of MTB in macrophages is inhibited, and OS and autophagy levels are reduced. The antioxidant effect and inhibitory effect of NAC on MTB are related to MTB-mediated macrophage OS and autophagy., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Renchun Su, Min Qiao, Tianhui Gao, Jingtao Gao, Lihui Nie, Shanshan Li, Yufeng Wang, Yu Pang, Qi Li.)

Lung cancer remains the tumor with the highest global incidence and mortality rates. Current primary treatment modalities encompass targeted therapy, immunotherapy, and chemotherapy; however, a subset of patients derives no benefit from these interventions. Recently, the HER2-targeting antibody drug Disitamab vedotin (RC48) was approved and introduced primarily for gastric and bladder cancers, with minimal investigation in the field of lung cancer. This study demonstrates that FOXA1 directly binds to the promoter region of HER2, influencing the HER2/PI3K/AKT signaling pathway, which consequently modulates factors that foster lung cancer proliferation and impede apoptosis. Unlike FOXA1, HER2 does not influence the expression of FOXA1. Intriguingly, in lung cancer cells, RC48 not only impacts the HER2/PI3K/AKT pathway but also affects the FOXA1/HER2/PI3K/AKT pathway, thereby exerting a robust antitumor effect. In clinical specimens, heightened expressions of FOXA1 and HER2 correlate positively with clinical progression and poorer prognosis. These findings suggest that FOXA1 may serve as a potential biomarker or therapeutic target in future non-small cell lung cancer (NSCLC) treatments, and ongoing research may position RC48 as a transformative agent in lung cancer therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Ginkgo biloba L. is a relict plant endemic to China that is commonly considered a "living fossil". It contains unique medicinal compounds that play important roles in its response to various stresses and help maintain human health. Ginkgo terpenoids are known to be important active ingredients but have received less attention than flavonoids. Hence, this review focuses on recent progress in research on the pharmacological effects of ginkgo terpenoid and the bioactivities of different terpenoid monomers. Many key structural genes, enzyme-encoding genes, transcription factors, and noncoding RNAs involved in the ginkgo terpenoid pathway were identified. Finally, many external factors (ecological factors, hormones, etc.) that regulate the biosynthesis and metabolism of terpenoids were proposed. All these findings improve the understanding of the biosynthesis, accumulation, and medicinal functions of terpenoids. Finally, this review includes an in-depth discussion regarding the limitations of terpenoid-related studies and potential future research directions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

Turmeric, a traditional medicinal herb, is commonly used as a dietary and functional ingredient. This study aimed to investigate the effect of turmeric polysaccharides (TPs) on intestinal immunity and gut microbiota in cyclophosphamide (Cy)-induced immunosuppressed BALB/c mice. We verified that the oral administration of TPs-0 and TPs-3 (200 and 400 mg/kg, bw) improved thymus and spleen indexes, increased the whole blood immune cells (WBC) and lymph count index, and stimulated the secretion of serum immunoglobulin IgG. More importantly, TPs-0 and TPs-3 could repair intestinal immune damage and reduce intestinal inflammation. The specific mechanism is ameliorating the intestinal pathological damage, promoting CD4 + T cell secretion, regulating the expression of related cytokines, and reducing the level of critical proteins in the NF-κB/iNOS pathway. Interestingly, the intake of TPs-0 and TPs-3 significantly increased the content of short-chain fatty acids (SCFAs). Moreover, TPs-0 and TPs-3 relieved the intestinal microbiota disorder via the proliferation of the abundance of Lactobacillus and Bacteroides and the inhibition of Staphylococcus . Cumulatively, our study suggests that TPs-0 and TPs-3 can relieve intestinal immune damage by repairing the immune barrier and regulating intestinal flora disorders. TPs have potential applications for enhancing immunity as a functional food.

Ethnopharmacological Relevance: An herbal pair is a classic form of clinical dispensing in Traditional Chinese Medicine (TCM), often used in prescriptions to enhance the effect or reduce potential side effects. It is the smallest component unit of Chinese medicine prescription and an essential bridge between Chinese medicine and prescription. Curcumae Rhizoma (called Ezhu in Chinese) is a representative TCM herb that promotes blood circulation and removes blood stasis. It has been used in Chinese medicine for thousands of years. Ezhu is generally used in clinical applications as a part of a "drug pair" to treat heartburn, stomach pain, tumour, amenorrhea and abdominal pain caused by blood stasis, qi stagnation and injury., Aims of the Review: This review aims to summarize the latest and comprehensive situation of the biological activity and clinical application of drug pairs containing Ezhu, find the law of Ezhu compatibility application, and discuss the rationalization of Ezhu drug compatibility. For Ezhu, herb pairs to provide a theoretical basis for clinical research in TCM and serve as a research foundation for developing new drugs., Materials and Methods: Using a self-built prescription database and Apriori algorithm for association rule mining. A systematic search for studies on herb pairs containing Ezhu was carried out by using the internet databases of PubMed, CNKI, Baidu Scholar, Google Scholar and Web of Science, as well as other relevant textbooks, reviews and documents (e.g. Chinese Pharmacopoeia, 2020 edition, Chinese herbal classic books and PhD and MSc theses, etc.). Among them with keywords including "Curcumae Rhizoma", "Ezhu", "herb pairs", "clinical application", etc. and their combinations. Moreover, the t-copula function was used to analyse the dose-coupling effect of five drug pairs, including Ezhu., Results: The preliminary statistical analysis retrieved Ezhu prescriptions from self-built prescription database and internet databases. The results showed that the compatibility frequency of Ezhu with the other five Chinese medicines was high. Most of these selected herbal combinations are used to treat internal diseases. In this paper, the progress of the ethnopharmacology of Ezhu was reviewed, emphasizing the changes in bioactive components and compatibility of Chinese traditional medicine combinations such as Ezhu and Astragalus Curcuma (Sparganium stoloniferum Buch. -Ham; called Sanleng in Chinese), Ezhu and Astragali Radix (Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao, Astragalus membranaceus (Fisch.) Bge.; called Huangqi in Chinese). Some other varieties, such as Ezhu and Rhizoma Chuanxiong (Ligusticum chuanxiong Hort.; called Chuanxiong in Chinese), Trionycis Carapax (Trionyx sinensis Wiegmann; called Biejia in Chinese), and Coptidis Rhizoma (Coptis chinensis Franch., Coptis deltoidea C. Y. Cheng et Hsiao, Coptis teeta Wall.; called Huanglian in Chinese), are also recorded in ancient books but rarely researched. The dose of Ezhu is strongly correlated with the amount of Sanleng, Huangqi, Biejia, Chuanxiong and Huanglian, respectively. Furthermore, there was a positive correlation between them., Conclusions: The bioactive components and compatibility effects of Ezhu herb pairs were studied in detail using data mining and t-copula function analysis. Ezhu and Astragalus Curcuma (Sanleng) mainly treat gynecological disorders by activating blood circulation and relieving congestion. Ezhu and Astragali Radix (Huangqi) drug pair and Ezhu and Trionycis Carapax (Biejia) drug pair are all commonly used in the clinical treatment of tumors, the former is mainly used clinically for the treatment of digestive tract-related inflammation and tumors, liver cancer and gynecological tumors, and the latter is commonly used for the treatment of malignant tumors, such as liver cancer and mammary cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Liver injury, the main factor in the pathogenesis of most liver diseases, is a known contributor to acute liver failure, liver fibrosis, or liver cancer. Curcuma phaeocaulis Val. (PEZ) has been broadly used in treating liver injury with satisfying therapeutic effects; however, the mechanism is still unclear., Aim of the Study: This study aimed to explore the mechanism of PEZ in ameliorating thioacetamide (TAA)-induced zebrafish liver injury based on a comprehensive method integrating network-based computational prediction and experimental validations., Materials and Methods: Ultrahigh-performance liquid chromatography-quadrupole exactive mass spectrometry/mass spectrometry (UPLC-Q-Exactive MS/MS) analysis was used to analyze components in raw and vinegar-processed PEZ (VPEZ). Network pharmacology was used to construct a compound-target network for liver injury to predict the possible biological targets of PEZ along with potential signaling pathways. TAA-induced zebrafish larvae liver injury model was established, and the anti-liver injury effect of PEZ by a series of indexes was measured, including liver phenotype analysis, histopathological analysis of liver tissues, and biochemical indexes analysis. Remarkably, the predicted pathway by network pharmacology was further validated using RT-qPCR and Western blotting analyzes in animal experiments., Results: 40 chemical constituents derived from PEZ were identified, while 45 chemical components derived from VPEZ were identified. Based on it, 565 genes related to these identified compounds in PEZ and 1023 genes linked to liver injury were collected by network pharmacology. Critically, KEGG analysis indicated that the TLR4/MyD88/NF-κB signaling pathway was recommended as one of the main pathways related to the anti-liver injury effect of PEZ. Experimentally, PEZ could alleviate TAA-induced liver injury. Compared to the liver injury model group without any treatment, the treatment of PEZ significantly reduced the expression of both mRNA and protein targets in the TLR4/MyD88/NF-κB signaling pathway. In addition, the effect of VPEZ was more significant than that of the raw one., Conclusion: The raw and vinegar-processed PEZ could ameliorate TAA-induced zebrafish liver injury through TLR4/MyD88/NF-κB signaling pathway., Competing Interests: Declaration of competing interest We confirm that another journal has not published this manuscript. The authors declare no competing financial interest regarding the publication of this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Turmeric is widely used worldwide, and there are many examples of its use in treating hepatobiliary diseases. The gut-liver axis is a bidirectional relationship between gut microorganisms and the liver that is closely related to the pathogenesis of hepatobiliary diseases. This review systematically summarizes the components of turmeric. It links the studies on turmeric affecting gut microorganisms to its effects on liver and biliary diseases to explain the potential mechanism of turmeric's regulation of the gut-liver axis. Besides, ethnopharmacology, phytochemicals, and clinical adverse events associated with turmeric have been researched. Furthermore, turmeric is a safe agent with good clinical efficacy and without apparent toxicity at a certain amount. By summarizing the influence of turmeric on the liver by regulating the gut-liver axis, especially the gut microbiota, it provides a preclinical basis for using turmeric as a safe and effective therapeutic agent for the prevention and treatment of hepatobiliary diseases based on the gut-liver axis. However, more efforts should be made to exploit its clinical application further.

Background: In the fight against tuberculosis, besides chemotherapy, the regulation of oxidative stress (OS) has also aroused people's interest in host-oriented therapy. However, there is limited research on the genes involved in reactive oxygen species (ROS) production and clearance in macrophages infected with Mycobacterium tuberculosis (MTB). This study analyzes and explores this to provide a basis for exploring new targets for antituberculosis treatments., Methods: We established a macrophage model infected with MTB, counted intracellular bacteria, and determined the ROS produced using flow cytometry. We conducted ribonucleic acid sequencing, screened differentially expressed genes through transcriptomic methods, and validated the expression of them through reverse transcription-quantitative polymerase chain reaction., Results: The ROS of macrophages increased with intracellular bacteria at 4 h after infection with MTB and reached its peak at 48 h, surpassing the uninfected macrophages ( p < 0.05). A total of 1,613 differentially expressed genes were identified after infection with MTB, of which 458 were associated with ROS, with over 50% involved in the response of organelles and biological processes to stimuli. We analyzed and identified six genes. After macrophage infection with MTB, the expression of CAMK2B increased, whereas the expression of CYBB decreased ( p < 0.05). The expression of GPX3 and SOD2 increased, whereas the expression of CAT decreased ( p < 0.05)., Conclusion: The ROS-related differentially expressed genes between MTB infected and uninfected macrophages may be related to some organelles and involved in various biological processes, molecular functions, and signaling pathways. Among them, CAMK2B, GPX3 , and SOD2 may be related to ROS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Su, Yuan, Gao, Liu, Shu, Wang, Pang and Li.)

Purpose: Unsatisfactory efficacies of currently recommended anti- Mycobacterium abscessus complex (MABC) treatment regimens have led to development of novel drugs to combat MABC infections. In this study, we evaluated in vitro antimicrobial activities of bedaquiline (BDQ) and four oxazolidinones against MABC isolates., Methods: The resazurin microplate assay was performed to determine minimum inhibitory concentrations (MICs) of BDQ and four oxazolidinones, including tedizolid (TZD), sutezolid (SZD), delpazolid (DZD), and linezolid (LZD), against 65 MABC isolates. A checkerboard method was used to investigate efficacies of various antimicrobial drug combinations., Results: BDQ MICs for MABC isolates ranged from <0.031 to 1 µg/mL, while MIC 50 and MIC 90 values were 0.125 µg/mL and 0.25 µg/mL, respectively. TZD MIC 50 and MIC 90 values for MABC isolates were 1 µg/mL and 4 µg/mL, respectively, which were fourfold lower than corresponding LZD values (P < 0.001). DZD MIC 90 values for MABC isolates was 8 µg/mL, which were 0.5-fold lower than corresponding LZD values (P < 0.01). MICs of BDQ, SZD, and LZD for M. abscessus subspecies massiliense isolates were significantly lower than corresponding MICs for M. abscessus subspecies abscessus isolates (P < 0.05). Notably, use of oxazolidinones (DZD, SZD, LZD, or TZD) with BDQ against MABC isolates led to reduction of the oxazolidinone median MIC range from 4 to 0.125 µg/mL to 1-0.031 µg/mL., Conclusion: These results demonstrated excellent BDQ inhibitory activity against MABC isolates. TZD exhibited stronger antimicrobial efficacy against MABC isolates as compared to efficacies of DZD, SZD, and LZD. Importantly, MICs of oxazolidinones were markedly decreased when they were combined with BDQ, thus suggesting that combinations of BDQ and oxazolidinones may be effective treatments for MABC infections., Competing Interests: The authors declare no conflicts of interest in this work., (© 2023 Gao et al.)

Ethnopharmacological Relevance: Cyperi Rhizoma (CR) derives from the rhizome or tuber of Cyperus rotundus L. of Cyperaceae. It is an herbal medicine which has been widely used in different healthcare systems like in China, India, Iran, and Japan. In Chinese medicine, CR could promote the flow of Qi in the Liver and Sanjiao channels, regulate menstruation and alleviate pain. Clinically, CR is used for depression, flatulence, hypochondriac pain, and dysmenorrhea. Thus, it has a long history and significant curative effect for the treatment of various Qi stagnation symptoms., Aim of This Review: This review focuses on explaining the major antidepressant mechanisms of CR, and assessing the shortcomings of existing work. Besides, clinical applications, pharmacological effects and their corresponding chemical compositions and quality control of CR have been researched., Materials and Methods: The search terms "Cyperus rotundus L." was used to obtain the literatures from electronic databases such as Web of Science, ScienceDirect, PubMed, and China National Knowledge Infrastructure (CNKI). The information provided in this review to illustrate material basis of CR were only limited to papers which reported on the chemical compositions and pharmacological effects simultaneously., Result: The study showed that CR has significant application in Qi stagnation, like depressed liver, stomach, and bowel disorders, etc. in different countries or districts. Aqueous extract, EtOH extract, essential oil, total oligomeric flavonoids and five other extracts were effective constituents displaying pharmacological activities such as antibacterial, antioxidant, neuroprotective, antihemolytic, and anti-inflammatory effect. 41 kinds of specific components like α-cyperone, nootkatone exhibited corresponding pharmacological activities mentioned above. Different concentrations of ethanol extract, essential oil, decoction of CR and monomer composition like α-cyperone, rotunduside G had anti-depressant effects., Conclusions: In the present study, we have provided scientific information and research developments on traditional uses, phytochemical compositions and corresponding pharmacological activities, and quality control status on CR. The antidepression effect and its corresponding chemical compositions were generalized separately. The pharmacological activities studies should be more focused on the reflection of traditional clinical values. CR could be a significant potential herbal medicine to develop antidepressant drugs with lower side effects., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aim: Fluoroquinolones (FQs) are the cornerstone in treating drug-resistant tuberculosis (TB); the prevalence of TB among the population is diverse in different regions, understanding the relationship between resistance pattern and molecular characteristic of FQs in preextensive drug-resistant (pre-XDR) clinical isolates is limited in China. Methods: A total of 141 pre-XDR clinical isolates from different individuals stored at the National Clinical Centre were collected from the Beijing Chest Hospital, minimal inhibitory concentrations of levofloxacin (Lfx) and moxifloxacin (Mfx) as well as sequences of quinolone-resistant determining regions in gyrA and gyrB genes were examined. Results: One hundred twelve pre-XDR clinical isolates were resistant to both Lfx and Mfx, molecular analyses showed that 87.50%, 0.89%, and 6.25% of the pre-XDR clinical isolates harbored FQ resistance mutations in gyrA , gyrB , and in both. We found five amino acid mutation positions in gyrA and four in gyrB , The mutation position in gyrA included codons 94, 91, 90, 88, and 74, and in gyrB included codons 504, 500, 512, and 501. Codon 94 of gyrA was the most prevalent mutation (83.04%), containing the Asp amino acid substitution with Gly (50.89%), Asn (15.17%), Ala (8.93%), Tyr (6.25%), and His (1.79%). Conclusions: The mutations of gyrA were most common and the frequency of Asp94Gly was the highest in pre-XDR clinical isolates in Beijing, China. The mutations at codon 94 significantly contributed to the resistance to both Lfx and Mfx in pre-XDR clinical isolates and may cause a high resistance level.

Ethnopharmacological Relevance: Isatidis Radix (called Banlangen, BLG in Chinese) and Isatidis Folium (called Daqingye, DQY in Chinese) are common traditional edible-medicinal herbs in detoxifying for thousands of years, have been traditionally applied in traditional Chinese medicine for centuries. Both of them are bitter in taste, coolness in nature, acting on the heart and stomach channels. They are often used to treat influenza and other viral infectious diseases in clinic, as well as could treat fever, dizziness, and cough and sore throat caused by lung heat., Aims of the Review: This review aimed at summarizing the latest and comprehensive information of BLG and DQY on the ethnopharmacology, phytochemistry, pharmacology, toxicity and clinical application to explore the therapeutic potential of them. In addition, outlooks and perspective for possible future researches that related are also discussed., Materials and Methods: Related information concerning BLG and DQY were gathered from the internet database of Google Scholar, PubMed, Baidu Scholar, GeenMedical, CNKI and Web of Science, as well as other relevant textbooks, reviews, and documents (e.g., Chinese Pharmacopoeia, 2020 edition, Chinese herbal classic books and PhD and MSc thesis, etc.). Among of them with the keywords including "Isatis indigotica" "Isatidis Radix", "Isatidis Folium", "phytochemistry", "pharmacology", "toxicology", "clinical application" etc. and their combinations., Results: To date, 39 Chinese patent medicines containing BLG and/or DQY have been developed on basis of the data of NMPA. Besides, 304 and 142 compounds have been found in BLG and DQY, respectively. The main chemical differences between BLG and DQY were concentrated on alkaloids and lignans, such as indican, indirubin, (R, S)-epigoitrin, 4(3H)-quinazolinone, clemastanin B and isatindigotindolines A-D. In 2020 Edition ChP, (R, S)-goitrin and indirubin are now used as the official marker to monitor the quality of BLG and DQY, respectively. Modern pharmacology has mainly studied some monomer components such as 4(3H)-quinazolinone, clemastanin B, erucic acid and adenosine, etc., all of which have shown good effects. These active compounds can resist various viruses, such as influenza virus, respiratory syncytial virus, herpes simplex virus, etc.. By regulating the level of immunity and a variety of inflammatory factors, inhibit the growth and reproduction of the virus. At the same time, it is worth noting that different components of BLG and DQY lead to BLG is more powerful in antiviral and immunomodulatory activity than DQY, while DQY possesses a higher intensity than BLG in anti-oxidant activity., Conclusion: By collecting and collating a large number of literature and various data websites, we concluded that the common compounds are mainly alkaloids. Recent findings regarding the phytochemical and pharmacological properties of BLG and DQY have confirmed their traditional uses in antiviral, antibacterial and treatment immune diseases. Without doubt, their significant differences on ethnopharmacology, phytochemistry and pharmacology can be used as evidence of separate list of BLG and DQY. For shortcomings, some comprehensive studies should be well designed for further utilization of BLG and DQY., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Context: Processing with vinegar could enhance the efficacy and reduce the toxicity of Curcuma phaeocaulis Valeton. (Zingiberaceae), a Chinese herbal medicine with anti-inflammatory and antitumor activities., Objective: This study investigated the vinegar processing effects by evaluating anti-angiogenic effect and toxicity of C. phaeocaulis through zebrafish and rat models., Materials and Methods: Zebrafish embryos (AB and FLk-GFP strain) were applied to evaluate toxicity, cardiotoxicity and anti-angiogenic activity of volatile oil, and water decoction of the raw and vinegar-processed C . phaeocaulis. Meanwhile, a blood stasis syndrome rat model was applied to study the toxicity by measuring the ovarian and uterine coefficient., Results: Curcuma phaeocaulis volatile oil and its vinegar-processed products in zebrafish had an LC 50 of 67.315 and 95.755 μg/mL, respectively. Curcuma phaeocaulis water decoction and its vinegar-processed products had an LC 50 of 161.440 and 206.239 μg/mL, respectively. The toxicity of vinegar-processed products was significantly lower than the raw, and the development characteristic of zebrafish embryos at different times confirmed these results. The volatile oil of vinegar-processed products could inhibit the growth of intersegmental blood vessels at the dose of 20 μg/mL, while the raw materials did not exhibit such effect at the same concentration. The rat experiment also confirmed that the volatile oil could reduce toxicity of ovarian and uterine., Discussion and Conclusions: The study indicated that processing using vinegar could decrease toxicity and increase anti-angiogenic activity of C. phaeocaulis , which could be applied for clinical treatment. Further in-depth study on the synergism and detoxification mechanism of vinegar processing technology is needed.

Lung cancer is a serious threat to human health due to its high morbidity and mortality. microRNAs (miRNAs) are involved in the tumorigenesis and progression of lung cancer. In this study, we elucidated the role of miRNA-4507 (miR-4507) in the pathogenesis of non-small-cell lung cancer (NSCLC). miR-4507 is found to be upregulated in NSCLC cells (A549, H460). MTT, 5-ethynyl-2'-deoxyuridine (EdU), wound healing, and transwell assays were performed to evaluate NSCLC cell proliferation and migration. The results demonstrated that miR-4507 inhibition significantly decrease the proliferation and migration of NSCLC cells. Subsequently, a luciferase activity assay was conducted to verify the regulation of the predicted gene target of miR-4507, namely, TP53 . Mechanism experiments show that miR-4507 activates the PI3K/AKT signal. Further, we co-transfected miR-4507 mimics and TP53 plasmids and found that TP53 overexpression could recover the effects of miR-4507 mimics on proliferation, migration, and the PI3K/AKT signal activation. These results suggested that miR-4507 targets TP53 to facilitate the proliferation and migration of lung cancer cells through PI3K/AKT signal and that miR-4507 could serve as a potential target for NSCLC treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: The recurrence and metastasis of nasopharyngeal cancer (NPC) may be mainly attributed to the persistence of cancer stem cells (CSCs); however, the linkage mechanism has yet to be fully elucidated., Methods: The levels of miR-4721, FOXA1, and Nanog expression in NPC were detected by in situ hybridization and immunohistochemistry. In vivo and in vitro metastasis assays confirmed miR-4721 promotes cell migration and invasion. Tumor spheroid formation assay, side population (SP) assay, and ALDEFLUOR assay verified miR-4721 regulates cancer stem cell-like properties. Luciferase reporter assay showed that miR-4721 directly regulates FOXA1 and FOXA1 effects the promoter activity of miR-4721 and Nanog. Chromatin immunoprecipitation (ChIP) analysis and electrophoresis mobility shift assay (EMSA) revealed that FOXA1 combined the promoter region of human miR-4721 and Nanog and the possible mechanism was also analyzed., Results: In this study, a new mechanism of NPC tumorigenesis related to miR-4721 was verified. We found that miR-4721, FOXA1 and Nanog control their expressions through a negative feedback loop and then activate the downstream regulator of stem cell signaling to promote the enrichment and metastasis of NPC stem cells., Conclusion: These findings elucidate that the feedback loop of miR-4721/FOXA1/Nanog can regulate stemness and metastasis in NPC and may provide an experimental theoretical basis for metastasis and treatment resistance in NPC., (© 2021. The Author(s).)

Cancer is a fatal disease with high mortality and low survival rate worldwide. At present, there is still no known cure for most cancers. Traditional Chinese medicine (TCM) represents a noteworthy reservoir for anticancer agents in drug discovery and development. Curcumae Rhizoma (called Ezhu in Chinese) is widely prescribed in TCM for anticancer therapy owing to its broad-spectrum antineoplastic activities. Especially, the terpenoids isolated from the essential oil of Curcumae Rhizoma form an integral part of cancer research and are well established as a potential anticancer agent. For example, β-elemene has been developed into a new drug for the treatment of solid tumors in China, and is currently undergoing clinical trials in the United States. The review aims to systematically summarize the recent advances on the anticancer effects and related molecular mechanisms of Curcumae Rhizoma, and its terpenoids (β-elemene, Furanodiene, Furanodienone, Germacrone, Curcumol, Curdione). In addition, we evaluated and compared the anticancer efficacy and clinical use of the terpenoids with combination therapies and traditional therapies. Therefore, this review provides sufficient evidence for the anticancer therapeutic potential of Curcumae Rhizoma and its terpenoids, and will contribute to the development of potential anticancer drugs., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Ethnopharmacological Relevance: Andrographis paniculata (Burm.f.) Nees is widely used all over the world, especially in subtropical regions such as India, Thailand, Vietnam, and China. As a traditional folk Chinese medicine, A. paniculata has been extensively utilized for the treatment of cold, fever, sore throat, cough, carbuncle, and sores, and it is commonly employed for 'clearing heat and resolving toxicity'. Typical symptoms of 'heat and toxicity' include swollen, painful gums, associated with virus-related diseases to a great extent. In vivo and in vitro experiments have demonstrated the potential antiviral properties of A. paniculata and identified its major active constituents against various viruses., Aim of the Study: This review focuses on connecting the traditional 'clearing heat and resolving toxicity' effect to compelling recent research advances on the antiviral effects of A. paniculata, explaining its major antiviral mechanisms, and assessing the shortcomings of existing work. Besides, ethnobotany, ethnopharmacological uses, phytochemicals, and toxicology of A. paniculata have been researched., Materials and Methods: The information about A. paniculata was collected from various sources including classic books about Chinese herbal medicine, and scientific databases including WEB OF SCIENCE, PubMed, ScienceDirect, Springer, ACS, SCOPUS, CNKI, CSTJ, and WANFANG., Results: In this review, the underlying mechanisms of antiviral effect mainly involve the regulation of virus entry, gene replication, and synthesis of functionally mature proteins. Also, A. paniculata is a safe agent without obvious toxicity. Ethnobotany, ethnopharmacological uses, and chemical constituents have been summarized., Conclusion: Andrographis paniculata (Burm.f.) Nees could be used as an imperative complementary medicine for the treatment of diverse virus infection, efforts should be made to gain insights into its antiviral properties., (Copyright © 2021 Elsevier B.V. All rights reserved.)

How the noisy expression of regulatory proteins affects timing of intracellular events is an intriguing fundamental problem that influences diverse cellular processes. Here we use the bacteriophage λ to study event timing in individual cells where cell lysis is the result of expression and accumulation of a single protein (holin) in the Escherichia coli cell membrane up to a critical threshold level. Site-directed mutagenesis of the holin gene generated phage variants that vary in their lysis times from 30 to 190 min. Observation of the lysis times of single cells reveals an intriguing finding-the noise in lysis timing first decreases with increasing lysis time to reach a minimum and then sharply increases at longer lysis times. A mathematical model with stochastic expression of holin together with dilution from cell growth was sufficient to explain the non-monotonic noise profile and identify holin accumulation thresholds that generate precision in lysis timing., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Siwu decoction (SWD), a traditional Chinese medicinal formula with over 1000 years of clinical history, is widely used for gynecological disease, especially blood deficiency syndrome, which is similar to anemia in modern medicine. In view of metabonomics being useful approach to investigate the potential mechanisms of action from the point of view of systems biology, in this study an ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry method was employed for a holistic evaluation of SWD on a blood-deficiency rat model induced by N-acetylphenylhydrazine and cyclophosphamide via plasma metabonomics study. Routine blood examination results showed that SWD could significantly improve the declining hemogram indices. Meanwhile, the plasma metabonomics profiles in different groups were analyzed and differentiating metabolites were primarily visualized through chemometric analysis. Seven biomarkers were identified in plasma samples of blood-deficiency rat model compared with the normal group. Five main metabolism pathways were suggested using the Kyoto Encyclopedia of Genes and Genomes Pathway Analysis and Pathway Activity Profiling algorithm analysis. This indicated that SWD played a therapeu role in blood deficiency by regulating the aberrant endogenous metabolites. To sum up, this study provides clear evidence that a metabonomics study could serve as a useful tool to elucidate the systematic therapeutic profiles and mechanisms for blood deficiency syndrome of Chinese herbal medicines., (© 2019 John Wiley & Sons, Ltd.)

Ethnopharmacological Relevance: Curcuma phaeocaulis Val. (CP), as the vital medicines for blood-breaking and disorder-eliminating, has been widely used for hepatitis with good curative effects. Owing to the complexity of traditional Chinese medicine, the pharmacological mechanism of CP remains unclear. To solve this problem, a protein network module-based approach was proposed in this study., Materials and Methods: Firstly, the content of active components of CP was detected based on HPLC-DAD. Then the liver protection of CP on Con A-induced hepatitis was validated via the analysis of serum levels of ALT, AST and LDH and histological findings. Next, the targets of CP components obtained from TCMD database were predicted by STITCH and ChEMBL retrieval. In addition, the protein interaction network (PIN) of CP was constructed by Cytoscape based on protein-protein interaction of targets obtained from STRING database. Following the topological analysis of CP PIN, it showed to exhibit the properties of scale-free, small world, and modularity matched with the property of complex biological networks. Finally, the functional modules were identified by gene ontology enrichment analysis based on Molecular Complex Detection algorithm., Results: The functional modules indicated that the mechanism of CP acting on the hepatitis is significantly associated with NF-κB and TGF-β signaling pathway. More interestingly, curcumin, demethoxycurcumin and bisdemethoxycurcumin were the main active components of CP acting on the hepatitis, which were demonstrated to be associated with the inflammatory process that occurs during the progression of hepatitis., Conclusion: The protein network module-based approach is an efficient way to investigate the pharmacological mechanisms of CP., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Kruppel-like factor 4 (Klf4) was reported to have both tumor suppressive and oncogenic roles on tumorigenesis, which is depend on its subcellular localization. In this study, the expression and subcellular localization of Klf4 in non-small cell lung cancer (NSCLC) patients as well as its clinical significance were analyzed, and the expression and subcellular localization of Klf4 in A549 cells and A549/DDP cells were detected. The results showed that the expression of Klf4 in nucleus was related to the histological grade and clinical stage of NSCLC patients. Moreover, the subcellular localization of Klf4 is the independent risk factor for NSCLC, and the high expression of Klf4 in nucleus could lead to a poor prognosis, while the high expression of Klf4 in cytoplasm could lead to a prominent prognosis for NSCLC patients. In addition, the nuclear Klf4 expression in A549/DDP cells was higher than that in A549 cells, while the cytoplasmic Klf4 expression in A549/DDP cells was lower than that in A549 cells, indicating that the subcellular localization of Klf4 might be related to the resistance of A549 cells to cisplatin. The study indicates that Klf4 could be a potential therapeutic target in NSCLC., (Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Esophageal cancerrelated gene 4 (ECRG4) is down-regulated in esophageal squamous-cell carcinoma (ESCC) and inhibits the tumorigenicity of ESCC cells. Ubiquitin conjugating enzyme E2 (UBE2C), an E2 ubiquitin-conjugating enzyme, is upregulated in numerous human cancers, including ESCC., Methods: mRNA and protein expression was determined by real-time PCR and western blotting analysis, respectively. Cell apoptosis was assessed by Annexin V-fluorescein isothiocyanate staining and flow cytometry analysis., Results: By analyzing previous quantitative proteomics data on EC9706 cells, we found that UBE2C was significantly down-regulated in ECRG4 overexpressed cells. Western blotting analysis validated the proteomics results in both EC9706 and EC-18 cells. In addition, Pearson's correlation analysis demonstrated a negative correlation between the mRNA levels of ECRG4 and UBE2C in ESCC tissues. Then, we found that Nuclear Factor-κB (NF-κB) inhibitor, pyrriolidine-dithiocarbamate (PDTC), could inhibit NF-κB p65 nuclear translocation and UBE2C expression, which was partially reversed by ECRG4 silence. More importantly, UBE2C knockdown in TE-1 cells significantly inhibited cell proliferation and induced cell apoptosis, which was partially reversed by ECRG4 knockdown., Conclusions: ECRG4 down-regulated UBE2C expression in ESCC cells via NF-κB signaling. UBE2C was involved in the anti-proliferative and pro-apoptotic functions of ECRG4 in ESCC cells., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Esophageal cancer-related gene 4 (ECRG4) is a tumor suppressor gene associated with the prognosis of esophageal squamous-cell carcinoma (ESCC). Studies have reported that ECRG4 effectively inhibits the proliferation, migration and invasion of ESCC cells. In the current study, ectopic expression of ECRG4 significantly induced ESCC cell apoptosis. To further understand the molecular profile of ECRG4 overexpression in ESCC cells, tandem mass tag (TMT) labeling followed by LC-MS/MS analysis was applied on samples from ECRG4 overexpressed cells and control cells. Among the identified differentially expressed proteins, four up-regulated proteins (PLK1, CDK4, PLOD1 and PLOD2) associated with cell apoptosis, cell cycle and metastasis were chosen for the further investigation. The effects of ECRG4 protein levels on the expression of these four proteins were validated by manipulating the expression of ECRG4 in ESCC cells followed by Western blotting analysis. The immunohistochemical staining results showed a significant decrease in ECRG4 levels and a notable increase in the four proteins in ESCC samples as compared to matched esophageal tissues (n=75). More importantly, the protein levels of ECRG4 had a negative association with those of PLK1, CDK4, PLOD1 and PLOD2. Thus, our data suggested that the tumor-repressor functions of ECRG4 may be associated with PLK1, CDK4, PLOD1 and PLOD2, providing important insights into the molecular mechanisms of esophageal carcinogenesis., Competing Interests: None.

The chromosome 2 open reading frame 40 ( C2ORF40 ) gene is a candidate tumor suppressor gene for a variety of tumors. Previous results by the present authors revealed that the C2ORF40 protein is a secreted protein. However, the exact biological function of secreted C2ORF40 protein in carcinogenesis has not been thoroughly investigated. In the present study, the signal peptide sequence of the C2ORF40 cDNA was initially removed to produce secreted recombinant human C2ORF40 protein (rhC2ORF40). Soluble rhC2ORF40 was successfully expressed and purified, which was evaluated for the first time, to the best of our knowledge, for tumor-suppressing function in vivo in esophageal cancer. The present results revealed that soluble purified rhC2ORF40 was concentrated with a purity of >95%. Furthermore, rhC2ORF40 inhibited esophageal cancer cell growth in vivo in a dose-dependent manner compared with a control group (P<0.05). In addition, the present study demonstrated for the first time that rhC2ORF40 decreased telomerase activity using telomeric repeat amplification protocol-enzyme-linked immunosorbent assay (P<0.05), without affecting the expression levels of telomerase-component RNA (P>0.05), as shown with polymerase chain reaction. Overall, the present results demonstrated that soluble rhC2ORF40 inhibited tumor cell growth in vivo by decreasing telomerase activity in esophageal squamous cell carcinoma. Therefore, soluble rhC2ORF40 with a high purity and biological activity may be a potential biological therapy drug for esophageal cancer.

Objective: To evaluate the prognosis and predictive values of preoperative Glasgow prognostic score (GPS) for adenocarcinoma of esophagogastric junction(AEG) patients., Methods: A retrospective study of 322 AEG patients who received operation between January 2007 and March 2010 in Henan Provincial People's Hospital was performed. Clinical data, pathological characteristics, laboratory parameters and survival data were collected. The GPS was calculated based on C-reactive protein(CRP) and serum albumin(ALB) levels. Univariate and multivariate analysis were used to evaluate the prognostic value of GPS., Results: Among 322 patients, 0, 1, 2 of GPS were 192, 104 and 26 patients respectively. The median follow-up was 37 (4-73) months. In Kaplan-Meier analysis, median diseases-free survival (DFS) of GPS 0, 1, 2 was 47.0 (95% CI: 31.6-62.4), 15.0 (95% CI: 11.8-8.2) and 4.7 (95% CI: 3.8-5.6) months (P<0.01), and median overall survival (OS) was out of reach, 20.6 (95% CI: 15.8-25.4) and 7.0 (95% CI: 5.8-8.2) months (P<0.01). Univariate and multivariate analysis revealed that GPS was an independent predictor of DFS (P<0.01) and OS (P<0.01) of AEG., Conclusion: GPS is an effective predictor of survival in AEG.

Background/aims: Ketamine has been reported to exert anti-inflammatory effects on astrocytes stimulated by lipopolysaccharide (LPS) in vitro and in vivo. However, the mechanism has not been elicited clearly. The aim of this study was to investigate the effects of ketamine on TLR4 expression and NF-ĸB-p65 phosphorylation, as well as the production of proinflammatory cytokines in LPS challenged astrocytes., Methods: Astrocytes were stimulated with LPS (1µg/ ml) in the absence and presence of various concentrations of ketamine (10, 100, 1000µM). The concentrations of IL-1β, IL-6 and TNF-α were measured by ELISA, the expression of glial fibrillary acidic protein (GFAP) in astrocytes was detected by immunofluorescence staining, the level of phosphorylated NF-ĸB p65 and the expression of TLR4 were detected by western blotting., Results: LPS increased TLR4 expression and the phosphorylation of NF-ĸB p65 subunit as well as GFAP expression and the production of IL-1β, IL-6 and TNF-α in cultured astrocytes. Ketamine (100 and 1000 µM) reduced the expression of GFAP and the production of these proinflammatory cytokines, inhibited the expression of TLR4 and attenuated the phosphorylation of NF-ĸB p65 in astrocytes challenged by LPS., Conclusion: The inhibitory effects of ketamine on LPS-induced astrocytes activation and inflammation response may be mediated by suppressing NF-ĸB activation through reducing the expression of TLR4., (Copyright © 2012 S. Karger AG, Basel.)