Targeting ABCB6 with nitidine chloride inhibits PI3K/AKT signaling pathway to promote ferroptosis in multiple myeloma.

Since multiple myeloma (MM) remains a cureless malignancy of plasma cells to date, it becomes imperative to develop novel drugs and therapeutic targets for MM. We screened a small molecule library comprising 3633 natural product drugs, which demonstrated that Nitidine Chloride (NC), an extract from traditional Chinese medicine Zanthoxylum nitidum. We used Surface Plasmon Resonance-High Performance Liquid Chromatography-Protein Mass Spectrometry (SPR-HPLC-MS), Cellular Thermal Shift Assay (CETSA), molecular docking, and SPR assay to identify the potential targets of NC, in which ABCB6 was the unique target of NC. The effects of ABCB6 on cellular proliferation and drug resistance were determined by CCK8, western blot, flow cytometry, site-mutation cells, transmission electron microscopy, immunohistochemistry staining and xenograft model in vitro and in vivo. NC induced MM cell death by promoting ferroptosis. ABCB6 is the direct target of NC. ABCB6 expression was increased in MM samples compared to normal controls, which was significantly associated with MM relapse and poor outcomes. VGSK was the inferred binding epitope of NC on the ABCB6 protein. In the ABCB6-mutated MM cells, NC did not display cancer resistance, implying the vital role of ABCB6 in NC's bioactivity. Moreover, the silencing of ABCB6 significantly inhibited MM cell growth. Mechanistically, the direct binding of NC to ABCB6 suppressed PI3K/AKT signaling pathway to promote ferroptosis. In conclusion, ABCB6 can be a potential therapeutic target and prognostic biomarker in MM, while NC can be considered a novel drug for MM treatment.

Prediction of exacerbation frequency of AECOPD based on next-generation sequencing and its relationship with imbalance of lung and gut microbiota: a protocol of a prospective cohort study.

INTRODUCTION: Patients with frequent acute exacerbation phenotype chronic obstructive pulmonary disease (AECOPD) have a higher hospitalisation rate than infrequent exacerbation, the disease progresses quickly and treatment is more difficult. At present, it is impossible to predict patients with COPD with frequent acute exacerbation phenotypes. The composition of the lower respiratory tract flora and the intestinal flora is closely related to AECOPD, but the specific association mechanism between them is not very clear. This study used metagenomic next-generation sequencing (mNGS) technology to explore the microbial characteristics of the intestinal tract and airways of patients with COPD, and analyse the correlation between the sequencing results and inflammatory factors, immune factors and nutritional factors. METHODS AND ANALYSIS: This will be a prospective cohort study. We intend to recruit 152 patients with stable COPD. In the baseline, we will detect the participants' induced sputum and faecal flora through mNGS, and changes in blood immune levels, and the patient's condition is evaluated. Every 2 months, we will check the number of acute exacerbation through the phone range. After 12 months, we will check again the changes in the blood immune level, evaluate the patient's condition and count the number of episodes. ETHICS AND DISSEMINATION: This study has been approved by the ethics committee of Guangdong Provincial Hospital of Traditional Chinese Medicine (approval number ZF2019-219-03). The results of the study will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (ChiCTR2000032870).

Herbal Medicine, Gut Microbiota, and COVID-19.

Coronavirus Disease 19 (COVID-19) is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has grown to a worldwide pandemic with substantial mortality. The symptoms of COVID-19 range from mild flu-like symptoms, including cough and fever, to life threatening complications. There are still quite a number of patients with COVID-19 showed enteric symptoms including nausea, vomiting, and diarrhea. The gastrointestinal tract may be one of the target organs of SARS-CoV-2. Angiotensin converting enzyme 2 (ACE2) is the main receptor of SARS-CoV-2 virus, which is significantly expressed in intestinal cells. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Intestinal flora imbalance and endotoxemia may accelerate the progression of COVID-19. Many herbs have demonstrated properties relevant to the treatment of COVID-19, by supporting organs and systems of the body affected by the virus. Herbs can restore the structure of the intestinal flora, which may further modulate the immune function after SARS-CoV-2 infection. Regulation of intestinal flora by herbal medicine may be helpful for the treatment and recovery of the disease. Understanding the role of herbs that regulate intestinal flora in fighting respiratory virus infections and maintaining intestinal flora balance can provide new ideas for preventing and treating COVID-19.

GeGen QinLian decoction alleviate influenza virus infectious pneumonia through intestinal flora.

Influenza in humans is often accompanied by gastroenteritis-like symptoms. GeGen QinLian decoction (GQD), a Chinese herb formula, has been widely used to treat infectious diarrhea for centuries and has the effect of restoring intestinal flora. Studies have also reported that GQD were used to treat patients with influenza. However, whether regulating the intestinal flora is one of the ways GQD treats influenza has not been confirmed. In present research, we conducted a systemic pharmacological study, and the results showed that GQD may acts through multiple targets and pathways. In influenza-infected mice, GQD treatment reduced mortality and lung inflammation. Most importantly, the mortality and lung inflammation were also reduced in influenza-infected mice that have undergone fecal microbiota transplantation (FMT) from GQD (FMT-GQD) treated mice. GQD treatment or FMT-GQD treatment restores the intestinal flora, resulting in an increase in Akkermansia_muciniphila, Desulfovibrio_C21_c20 and Lactobacillus_salivarius, and a decrease in Escherichia_coli. FMT-GQD treatment inhibited the NOD/RIP2/NF-κB signaling pathway in the intestine and affected the expression of downstream related inflammatory cytokines in mesenteric lymph nodes (mLNs) and serum. In addition, FMT-GQD treatment showed systemic protection by restraining the inflammatory differentiation of CD4+ T cells. In conclusion, our study shows that GQD can affect systemic immunity, at least in part, through the intestinal flora, thereby protect the mice against influenza virus infectious pneumonia.

Carvacrol inhibits the excessive immune response induced by influenza virus A via suppressing viral replication and TLR/RLR pattern recognition.

ETHNOPHARMACOLOGICAL RELEVANCE: Carvacrol, a monoterpene phenol from Mosla chinensis Maxim, which is a commonly Chinese herbal medicine. The most important pharmacology of it is dispelling exogenous evils by increasing perspiration. And it is the gentleman medicine in the Chinese herbal compound prescription of Xin-Jia-Xiang-Ru-Yin, mainly for the treatment of summer colds with dampness including influenza virus A infection. AIM OF THE STUDY: Our preliminary study verified that the Xin-Jia-Xiang-Ru-Yin could inhibit acute lung injury of mice with influenza virus A infection. And there have been some reports implicating the high antimicrobial activity of carvacrol for a wide range of product preservation, but little research including the effects of it on viral infection. The aim of this study was to reveal the antiviral effects of carvacrol, the main constituent in Mosla chinensis Maxim. MATERIALS AND METHODS: Initially, C57BL/6 mice were grouped and intranasally administered FM1 virus to construct viral infection models. After treatment with ribavirin and carvacrol for 5 days, all mice were euthanized, and specimens were immediately obtained. Histology, flow cytometry and Meso Scale Discovery (MSD) analysis were used to analyze pathological changes in lung tissue, the expression levels of cytokines and the differentiation and proportion of CD4+ T cells subsets, while Western blot and qRT-PCR were used to detect the expression of related proteins and mRNA. RESULTS: Carvacrol attenuated lung tissue damage, the proportions of Th1, Th2, Th17 and Treg in CD4+ T cells and the relative proportions of Th1/Th2 and Th17/Treg cells. Carvacrol inhibited the expression of inflammation-associated cytokines including IFN-γ, IL-2, IL-4, IL-5, IL-12 and TNF-ɑ, IL-1, IL-10, IL-6. Decreased levels of TLR7, MyD88, IRAK4, TRAK6, NF-κB, RIG-I, IPS-I and IRF mRNA in carvacrol-treated mice were observed comparing to the mice in VC group. Further, the total expression of RIG-I, MyD88 and NF-κB proteins had increased significantly in the VC group but reduced obviously in the group treated with ribavirin or carvacrol. CONCLUSIONS: These results indicate that carvacrol is a potential alternative treatment for the excessive immune response induced by influenza virus A infection, the cold-fighting effect of Mosla chinensis Maxim may depend on the anti-virus of carvacrol.