The multi-herbal decoction SH003 alleviates LPS-induced acute lung injury by targeting inflammasome and extracellular traps in neutrophils.

BACKGROUND: Acute lung injury (ALI) is a devastating condition caused by sepsis, pneumonia, trauma, and more recently, COVID-19. SH003, an herbal formula consisted of Astragalus membranaceus, Angelica gigas and Trichosanthes kirilowii, is known for its effects on cancer and immunoregulation. HYPOTHESIS/PURPOSE: Previous studies show SH003 exerts a promising anti-inflammatory effect. This study investigates the effect of modified SH003 on ALI using in silico, in vivo, and in vitro models. STUDY DESIGN AND METHODS: We performed in silico-based analysis of SH003 on ALI-related pathways. C57BL/6 mice were intraperitoneally subjected to lipopolysaccharide (LPS) to induce septic ALI, followed by oral administration of SH003 for 2 weeks. Dexamethasone was used as the positive control. Human peripheral blood-derived polymorphonuclear neutrophils (PMN) were used to investigate the effect and mechanisms of SH003 on neutrophil extracellular trap (NET) formation. RESULTS: Network pharmacology analysis suggested SH003 regulates lung inflammation by modulating NET formation. SH003 significantly reduced mortality in sepsis in vivo by inhibiting local and systemic inflammation, likely via nuclear factor kappa B and mitogen-activated protein kinase pathways-mediated inflammasome suppression. SH003 also decreased NET-related markers in lung tissues and inhibited LPS- and phorbol myristate acetate-induced NET formation in PMN. Cytometry time-of-flight analysis confirmed regulation of NETosis-related pathways by SH003. CONCLUSION: SH003 effectively inhibits excessive immune responses in the lung by suppressing inflammasome activation and NET formation. These findings suggest SH003 as a potential therapeutic agent for septic ALI.

Prognostic significance of SASP-related gene signature of radiation therapy in head and neck squamous cell carcinoma.

In this study,we developed and validated the clinical significance of senescence SASP related gene signature and explored its association with radiation therapy (RT) in patients with head and neck squamous cell carcinoma (HNSCC). First, we searched the three published review literature associated with senescence associated secretory phenotype (SASP) and selected all 81 genes to develop SASP related gene signature. Then, 81 SASP related genes were adapted to gene expression dataset from TCGA. HNSCC patients of TCGA were classified into clusters 1 and 2 via unsupervised clustering according to SASP related gene signature. Kaplan-Meier plot survival analysis showed that cluster 1 had a poorer prognosis than cluster 2 in 5-years overall survival and recurrence-free survival. Similarly, cluster 1 showed a worse prognosis than cluster 2 in three validation cohorts. (E-MTAB-8588, FHCRC and KHU). Cox proportional hazards regression observed that the senescence SASP related signature was an independent prognostic factor for HNSCC patients. We also established a nomogram using a relevant clinical parameter and a risk score. Time-dependent receiver operating characteristic (ROC) analysis was carried out to assess the accuracy of the prognostic risk model and nomogram. Senescence SASP related gene signature was associated with the response to RT. Therefore, subsequent, in vitro experiments further validated the association between senescence SASP related gene signature and RT in HNSCC. In conclusion, we developed a senescence SASP related gene signature, which could predict survival of HNSCC patients, and this gene signature provides new clinical evidence for the accurate diagnosis and targeted RT of HNSCC.

A case report on hemopneumothorax caused by acupuncture at Huatuo-Jiaji points.

Acupuncture is generally safe; however, severe side effects, such as syncope and pneumothorax (PTX), have sometimes been reported. No cases of hemopneumothorax following acupuncture have been reported in Korea. This study reports a case of progression and prognosis of hemopneumothorax after acupuncture in a patient who visited a hospital for digestive disorders and underwent acupuncture treatment at the Huatuo-Jiaji points to control the autonomic nerves. The patient complained of shortness of breath and chest pain after acupuncture. However, neither the patient nor the doctor suspected PTX. Chest radiography, conducted after a day, confirmed hemopneumothorax of the right lung, and the patient was immediately hospitalized. During hospitalization, oxygen therapy and medication were administered, and the patient was discharged 6 days later. However, PTX recurred, and the patient was rehospitalized. The patient was discharged after 4 days, and it was confirmed that he was completely cured, as evident from both radiation findings and patient symptoms on day 20. This study demonstrates that physicians should pay more attention to and be aware of PTX and its symptoms when performing acupuncture on the thoracic chest.

p53 activation enhances the sensitivity of non-small cell lung cancer to the combination of SH003 and docetaxel by inhibiting de novo pyrimidine synthesis.

BACKGROUND: Identifying molecular biomarkers for predicting responses to anti-cancer drugs can enhance treatment precision and minimize side effects. This study investigated the novel cancer-targeting mechanism of combining SH003, an herbal medicine, with docetaxel in non-small cell lung cancer (NSCLC) cells. Also, the present study aimed to identify the genetic characteristics of cancer cells susceptible to this combination. METHODS: Cell viability was analyzed by WST-8 assay. Apoptosis induction, BrdU incorporation, and cell cycle analysis were performed using flow cytometry. Metabolites were measured by LC-MS/MS analysis. Real-time PCR and western blotting evaluated RNA and protein expression. DNA damage was quantified through immunofluorescence. cBioPortal and GEPIA data were utilized to explore the mutual co-occurrence of TP53 and UMPS and UMPS gene expression in NSCLC. RESULTS: The combination treatment suppressed de novo pyrimidine nucleotide biosynthesis by reducing the expression of related enzymes. This blockade of pyrimidine metabolism led to DNA damage and subsequent apoptosis, revealing a novel mechanism for inducing lung cancer cell death with this combination. However, some lung cancer cells exhibited distinct responses to the combination treatment that inhibited pyrimidine metabolism. The differences in sensitivity in lung cancer cells were determined by the TP53 gene status. TP53 wild-type lung cancer cells were effectively inhibited by the combination treatment through p53 activation, while TP53 mutant- or null-type cells exhibited lower sensitivity. CONCLUSIONS: This study, for the first time, established a link between cancer cell genetic features and treatment response to simultaneous SH003 and docetaxel treatment. It highlights the significance of p53 as a predictive factor for susceptibility to this combination treatment. These findings also suggest that p53 status could serve as a crucial criterion in selecting appropriate therapeutic strategies for targeting pyrimidine metabolism in lung cancer.

Mycoproteins and their health-promoting properties: Fusarium species and beyond.

Filamentous fungal mycoproteins have gained increasing attention as sustainable alternatives to animal and plant-based proteins. This comprehensive review summarizes the nutritional characteristics, toxicological aspects, and health-promoting effects of mycoproteins, focusing on those derived from filamentous fungi, notably Fusarium venenatum. Mycoproteins are characterized by their high protein content, and they have a superior essential amino acid profile compared to soybeans indicating excellent protein quality and benefits for human nutrition. Additionally, mycoproteins offer enhanced digestibility, further highlighting their suitability as a protein source. Furthermore, mycoproteins are rich in dietary fibers, which have been associated with health benefits, including protection against metabolic diseases. Moreover, their fatty acids profile, with significant proportions of polyunsaturated fatty acids and absence of cholesterol, distinguishes them from animal-derived proteins. In conclusion, the future of mycoproteins as a health-promoting protein alternative and the development of functional foods relies on several key aspects. These include improving the acceptance of mycoproteins, conducting further research into their mechanisms of action, addressing consumer preferences and perceptions, and ensuring safety and regulatory compliance. To fully unlock the potential of mycoproteins and meet the evolving needs of a health-conscious society, continuous interdisciplinary research, collaboration among stakeholders, and proactive engagement with consumers will be vital.

Synthesis, Antiproliferative Activity and Molecular Docking Analysis of Both Enantiomerically Pure Decursin Derivatives as Anticancer Agents.

Using (S)-decursinol isolated from root of Angelica gigas Nakai (AGN), we semi-synthesized and evaluated a series of both enantiomerically pure decursin derivatives for their antiproliferative activities against A549 human lung cancer cells. All synthesized compounds showed a broad spectrum of inhibitory activities against the growth of A549 cells. Especially, compound (S)-2d with (E)-(furan-3-yl)acryloyl group showed the most potent activity (IC50: 14.03 µM) against A549 cancer cells as compared with the reference compound, decursin (IC50: 43.55 µM) and its enantiomer, (R)-2d (IC50: 151.59 µM). Western blotting assays indicated that (S)-2d more strongly inhibited Janus kinase 1 (JAK1) and signal transducer and activator of transcription activation 3 (STAT3) phosphorylation than decursin in a dose-dependent manner, while having no effect on CXCR7 overexpression and total STAT3 level. In addition, (S)-2d induced cell cycle arrest at G1 phase and subsequent apoptotic cell death in A549 cancer cells. Our combined analysis of molecular docking studies and biological data suggests that the inhibition of JAK1 with (S)-2d resulted in loss of STAT3 phosphorylation and inhibition of cell growth in A549 cancer cells. These overall results strongly suggest that (S)-2d (MRC-D-004) as a novel JAK1 inhibitor may have therapeutic potential in the treatment of A549 human lung cancers by targeting the JAK1/STAT3 signaling pathway.

Optimized combination of Cervus nippon (Sika deer), Angelica (Dangui), and Rehmannia (Suk-jihwang) mitigates LPS-induced inflammation: exploring signaling pathways through plasma metabolomics.

This study aimed to determine the optimal combination of three anti-inflammatory materials [i.e., Cervus nippon Temminck (CT), Angelica gigas Nakai (AN), and Rehmannia glutinosa (RG)] for the strongest anti-inflammatory potential. Eighteen combinations of the three materials were tested in LPS-stimulated RAW264.7 cells via assessing nitric oxide (NO). The best combination from in vitro studies was administered to LPS-treated C57BL/6J mice for five days. Subsequently, plasma metabolites were profiled by bioinformatics analyses and validations. As results, 2, 20, and 50 µg/mL of CT, AN, and RG (TM) were the most effective combination suppressing inflammation. In mice, TM mitigated hepatic inflammatory markers. Similarly, the metabolomics indicated that TM may suppress NF-κB signaling pathway, thereby alleviating hepatic inflammation. TM also decreased systemic and hepatic pro-inflammatory cytokines. Collectively, we found the optimal combination of TM for mitigating inflammation; thus further studies on safety, mechanisms, and clinical models are warranted for human applications. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01476-x.

SH003 Enhances the Anti-cancer Effects of Dabrafenib on Lung Cancer Harboring BRAF G469A Mutation by Inhibiting the MAPK Signaling Pathway.

BACKGROUND/AIM: BRAF mutations are relatively uncommon in lung cancer. However, the majority of therapies targeting BRAF mutations have been developed exclusively for lung cancer patients with V600E mutations, limiting their effectiveness in treating tumors with the non-V600E BRAF mutations. As a result, there is a need to explore effective therapeutic strategies for patients with lung cancer carrying non-V600 BRAF mutations. Therefore, this study aims to identify a combination treatment approach that effectively targets lung cancer with G469A non-V600 BRAF alteration. MATERIALS AND METHODS: The efficacy of drug treatments was assayed using a patient-derived xenograft (PDX) mouse model. Histological analysis was performed using hematoxylin and eosin and immunohistochemical staining. Cell viability and growth were determined using the WST-8 and colony formation assays. Protein levels and apoptosis were analyzed using western blot and flow cytometry, respectively. RESULTS: We demonstrated that the lung cancer cells harboring the non-V600E G469A mutation were responsive to the combination of SH003 and dabrafenib. By utilizing patient-derived xenograft (PDX) models, we identified that this combined treatment induces apoptosis and exhibits antitumor effects through the reduction of ERK signals. The synergistic effect of the combination treatment on BRAF G469A lung cancer cells was consistent with its effects on PDX models, suggesting that the molecular mechanism of apoptosis involves a decrease in the MEK/ERK signaling pathway. CONCLUSION: The SH003 and dabrafenib combination can be potentially developed as an effective treatment strategy for addressing lung cancer patients with the BRAF G469A mutation.

Stigmasterol Exerts an Anti-Melanoma Property through Down-Regulation of Reactive Oxygen Species and Programmed Cell Death Ligand 1 in Melanoma Cells.

Cancer immunotherapy as a promising anti-cancer strategy has been widely studied in recent years. Stigmasterol (STIG), a phytosterol, is known to have various pharmacological effects, including anti-inflammatory effects. However, the pharmacological role of STIG on melanoma immunotherapy has not been investigated. The present study demonstrates the anti-melanoma potency of STIG through the regulation of PD-L1 levels. The results reveal that STIG reduces reactive oxygen species (ROS) levels induced by hydrogen peroxide and increases glutathione levels decreased by α-MSH in B16F10 cells. Moreover, STIG significantly decreases melanin content and tyrosinase activities elevated by α-MSH. It also suppresses nitric oxide production induced by α-MSH. Additionally, STIG induces apoptosis with the up-regulation of PARP activation. STIG inhibits IFN-γ-induced PD-L1 expression and STAT1 phosphorylation levels. STIG also reverses the up-regulation of PD-L1 and phosphorylated STAT1 levels augmented by cisplatin, and STIG enhances CD8(+) T-cell-mediated cell death against B16F10 cells. These findings represent the first evidence of pro-apoptotic activity of STIG on melanoma cells through the down-regulation of ROS and PD-L1 pathways. Therefore, STIG may be an effective candidate for melanoma immunotherapy.

Network pharmacology study to explore the multiple molecular mechanism of SH003 in the treatment of non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the leading causes of human death worldwide. Herbal prescription SH003 has been developed to treat several cancers including NSCLC. Due to the multi-component nature of SH003 with multiple targets and pathways, a network pharmacology study was conducted to analyze its active compounds, potential targets, and pathways for the treatment of NSCLC. METHODS: We systematically identified oral active compounds within SH003, employing ADME criteria-based screening from TM-MC, OASIS, and TCMSP databases. Concurrently, SH003-related and NSCLC-associated targets were amalgamated from various databases. Overlapping targets were deemed anti-NSCLC entities of SH003. Protein-protein interaction networks were constructed using the STRING database, allowing the identification of pivotal proteins through node centrality measures. Empirical validation was pursued through LC-MS analysis of active compounds. Additionally, in vitro experiments, such as MTT cell viability assays and western blot analyses, were conducted to corroborate network pharmacology findings. RESULTS: We discerned 20 oral active compounds within SH003 and identified 239 core targets shared between SH003 and NSCLC-related genes. Network analyses spotlighted 79 hub genes, including TP53, JUN, AKT1, STAT3, and MAPK3, crucial in NSCLC treatment. GO and KEGG analyses underscored SH003's multifaceted anti-NSCLC effects from a genetic perspective. Experimental validations verified SH003's impact on NSCLC cell viability and the downregulation of hub genes. LC-MS analysis confirmed the presence of four active compounds, namely hispidulin, luteolin, baicalein, and chrysoeriol, among the eight compounds with a median of > 10 degrees in the herb-compounds-targets network in SH003. Previously unidentified targets like CASP9, MAPK9, and MCL1 were unveiled, supported by existing NSCLC literature, enhancing the pivotal role of empirical validation in network pharmacology. CONCLUSION: Our study pioneers the harmonization of theoretical predictions with practical validations. Empirical validation illuminates specific SH003 compounds within NSCLC, simultaneously uncovering novel targets for NSCLC treatment. This integrated strategy, accentuating empirical validation, establishes a paradigm for in-depth herbal medicine exploration. Furthermore, our network pharmacology study unveils fresh insights into SH003's multifaceted molecular mechanisms combating NSCLC. Through this approach, we delineate active compounds of SH003 and target pathways, reshaping our understanding of its therapeutic mechanisms in NSCLC treatment.

Current Characteristics of Herbal Medicine Interventions for Cancer on Clinical Databases: A Cross-Sectional Study.

BACKGROUND: The utilization of herbal medicine has been noteworthy for treating cancer; however, there is not enough information regarding the characteristics of clinical trials of herbal medicine interventions. This study aimed to evaluate the characteristic of registered trials using herbal medicine interventions for cancer. METHODS: A cross-sectional study was performed via the website ClinicalTrials.gov, ISRCTN registry, Chinese clinical trial registry, and international clinical trials registry platform to gather associated registered clinical trials using an advanced search with the developed keyword strategy as of March 26, 2023. All obtainable information from the trials was collected without any restrictions to conduct a comprehensive review. RESULTS: A total of 169 registered trials were included for evaluation. Of all trials, 102 trials were eligible for this study. Countries from Asia registered the most trials (62.75%), and hospitals sponsored most of the trials (42.16%). Randomized, Phase 2, interventional trials were dominant, and approximately 64.71% of the trials anticipated recruiting less than 100 participants. More than half of the trials were from 2016 to 2023 (53.92%). While 45 trials were completed, only 16 trials had results for further analysis. According to the completed results, the types of herbal medicines from the trials mainly focused on lung, breast, and colorectal cancer. CONCLUSION: This study is the first to explore the characteristics of clinical trials of herbal medicine for cancer registered in large clinical databases. The acquired trials had relatively informative data; however, better-designed trials may be needed for health professionals to consider herbal medicine as an option when treating cancer patients.

Effectiveness of electroacupuncture on anxiety: a systematic review and meta-analysis of randomized controlled trials.

This systematic review and meta-analysis aimed to comprehensively evaluate the effectiveness of electroacupuncture (EA) for patients with anxiety. Randomized controlled trials (RCTs) on the treatment of anxiety by EA up to November 2022 were searched and collected from nine databases. Hamilton Anxiety Rating Scale (HAMA), self-rating anxiety scale (SAS), and adverse reactions were used as outcome indicators. The quality of relevant articles was evaluated using the Cochrane Collaboration's risk of bias tool. The quality of evidence for each outcome was classified as "low risk," "unclear risk," or "high risk." RevMan 5.0 was used for data analysis. A total of 633 articles were identified from nine electronic databases; 37 RCTs were included, which measured anxiety changes by using EA alone compared to the control group. For the main outcome, EA significantly reduced the HAMA score [Mean difference (MD):-1.13 (95% CI:-2.55-0.29), I2:80%], and the quality of evidence was moderate. EA significantly reduced the SAS score (MD:-3.47 (95% CI,-6.57--0.36), I2:88%), and the quality of evidence was moderate. Our meta-analysis shows that EA reduces HAMA and SAS. This study suggests that EA can relieve anxiety. For various uses, additional research is needed on its effect when combined with other treatments. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=345658, identifier (CRD42022345658).