Proteomic Dynamics of Breast Cancer Cell Lines Identifies Potential Therapeutic Protein Targets.

Treatment and relevant targets for breast cancer (BC) remain limited, especially for triple-negative BC (TNBC). We identified 6091 proteins of 76 human BC cell lines using data-independent acquisition (DIA). Integrating our proteomic findings with prior multi-omics datasets, we found that including proteomics data improved drug sensitivity predictions and provided insights into the mechanisms of action. We subsequently profiled the proteomic changes in nine cell lines (five TNBC and four non-TNBC) treated with EGFR/AKT/mTOR inhibitors. In TNBC, metabolism pathways were dysregulated after EGFR/mTOR inhibitor treatment, while RNA modification and cell cycle pathways were affected by AKT inhibitor. This systematic multi-omics and in-depth analysis of the proteome of BC cells can help prioritize potential therapeutic targets and provide insights into adaptive resistance in TNBC.

Sodium houttuyfonate modulates the lung Th1/Th2 balance and gut microbiota to protect against pathological changes in lung of ovalbumin-induced asthmatic mice.

OBJECTIVE: The gut-lung axis involves microbial and product interactions between the lung and intestine. Antibiotics for chronic asthma can cause intestinal dysbiosis, disrupting this axis. Sodium houttuyfonate (SH) has diverse biological activities, including modifying gut microbiota, antibacterial, and anti-inflammatory. This study aims to explore the relationship between SH, CD4+ T cells, and gut microbiota. METHODS: Allergic asthma was experimentally induced in mice through injection and inhalation of ovalbumin. After the administration of different amounts of SH, ELISA was utilized to ascertain the levels of inflammatory cytokines in the serum, flow cytometry was used to examine the levels of Th1/Th2 cytokines in CD4+ cells from lung tissues. The expression of T-bet and GATA3 in lung tissue was determined by Western blotting and quantitative real-time PCR assay. Gut microbiota was determined by 16S rRNA gene sequencing. RESULTS: The results showed that SH can alleviate pulmonary injury in asthmatic mice, reducing serum levels of IL-4, IL-5, and IL-13 while simultaneously increasing IFN-γ. Furthermore, SH has been observed to modulate the balance of Th1/Th2 cells by up-regulating the mRNA and protein expression of T-bet but down-regulating GATA3 in the lung tissues of asthmatic mice, thereby promoting the differentiation of Th1 cells. Additionally, SH can regulate the variety and composition of gut microbiota especially genus Akkermansia in asthmatic mice. CONCLUSION: SH can alleviate asthma through the regulation of Th1/Th2 cells and gut microbiota.

Src family kinases (SFKs) and cell polarity in the testis.

Non-receptor Src family kinases (SFKs), most notably c-Src and c-Yes, are recently shown to be expressed by Sertoli and/or germ cells in adult rat testes. Studies have shown that SFKs are involved in modulating the cell cytoskeletal function, and involved in endocytic vesicle-mediated protein endocytosis, transcytosis and/or recycling as well as intracellular protein degradation events. Furthermore, a knockdown to SFKs, in particular c-Yes, has shown to induce defects in spermatid polarity. These findings, coupled with emerging evidence in the field, thus prompt us to critically evaluate them to put forth a developing concept regarding the role of SFKs and cell polarity, which will become a basis to design experiments for future investigations.

LncRNA TUG1 alleviates cardiac hypertrophy by targeting miR-34a/DKK1/Wnt-ß-catenin signalling.

The current study was designed to explore the role and underlying mechanism of lncRNA taurine up-regulated gene 1 (TUG1) in cardiac hypertrophy. Mice were treated by transverse aortic constriction (TAC) surgery to induce cardiac hypertrophy, and cardiomyocytes were treated by phenylephrine (PE) to induce hypertrophic phenotype. Haematoxylin-eosin (HE), wheat germ agglutinin (WGA) and immunofluorescence (IF) were used to examine morphological alterations. Real-time PCR, Western blots and IF staining were used to detect the expression of RNAs and proteins. Luciferase assay and RNA pull-down assay were used to verify the interaction. It is revealed that TUG1 was up-regulated in the hearts of mice treated by TAC surgery and in PE-induced cardiomyocytes. Functionally, overexpression of TUG1 alleviated cardiac hypertrophy both in vivo and in vitro. Mechanically, TUG1 sponged and sequestered miR-34a to increase the Dickkopf 1 (DKK1) level, which eventually inhibited the activation of Wnt/ß-catenin signalling. In conclusion, the current study reported the protective role and regulatory mechanism of TUG1 in cardiac hypertrophy and suggested that TUG1 may serve as a novel molecular target for treating cardiac hypertrophy.

Network pharmacology-based study of the protective mechanism of conciliatory anti-allergic decoction on asthma.

BACKGROUND: This study aimed to explore the underlying anti-asthma pharmacological mechanisms of conciliatory anti-allergic decoction (CAD) with a network pharmacology approach. METHODS: Traditional Chinese medicine related databases were utilized to screen the active ingredients of CAD. Targets of CAD for asthma treatment were also identified based on related databases. The protein-protein interaction network, biological function and KEGG pathway enrichment analysis, and molecular docking of the targets were performed. Furthermore, an asthma mouse model experiment involving HE staining, AB-PAS staining, and ELISA was also performed to assess the anti-asthma effect of CAD. RESULTS: There were 77 active ingredients in CAD, including quercetin, kaempferol, stigmasterol, luteolin, cryptotanshinone, beta-sitosterol, acacetin, naringenin, baicalin, and 48 related targets for asthma treatment, mainly including TNF, IL4, IL5, IL10, IL13 and IFN-γ, were identified with ideal molecular docking binding scores by network pharmacology analysis. KEGG pathway analysis revealed that these targets were directly involved in the asthma pathway, Th1 and Th2 cell differentiation, and signaling pathways correlated with asthma (NF-κB, IL17, T cell receptor, TNF, JAK-STAT signaling pathways, etc.). Animal experiments also confirmed that CAD could attenuate inflammatory cell invasion, goblet cell hyperplasia and mucus secretion. The levels of the major targets TNF-α, IL4, IL5, and IL13 can also be regulated by CAD in an asthma mouse model. CONCLUSION: The anti-asthma mechanism of CAD possibly stemmed from the active ingredients targeting asthma-related targets, which are involved in the asthma pathway and signaling pathways to exhibit therapeutic effects.

Antifibrotic effects of a novel pirfenidone derivative in vitro and in vivo.

BACKGROUND: Idiopathic pulmonary fibrosis is a lethal fibrosing interstitial pneumonia characterized by progressive worsening of dyspnea and lung function with poor prognosis. Since pirfenidone was approved for IPF treatment, the search for more effective candidates has been greatly intensified. METHODS: In this study, the antifibrotic effects and mechanisms of compound PBD-617, the ideal candidate discovered in our previous work, were investigated on transforming growth factor-ß1 (TGF-ß1)-induced human embryonic lung fibroblasts (HELF) and on bleomycin (BLM)-induced pulmonary fibrotic rats. RESULTS: Oral administration with PBD-617 decreased the levels of collagen I, collagen III and matrix metalloproteinase 7, and inhibited the protein expression of α-smooth muscle actin in BLM-induced pulmonary fibrosis rats. Furthermore, PBD-617 suppressed the expression of TGF-ß1, phosphorylated Smad3, phosphorylated p38 and activator protein 1 on TGF-ß1-induced HELF, while the regulation could be rescued by using p38 agonist p79350. CONCLUSION: PBD-617 not only inhibited TGF-ß1-induced HELF proliferation, but also attenuated BLM-induced pulmonary fibrosis in rats, with efficacy to some extent higher than that of pirfenidone at the same effective dosage. PBD-617 attenuated pulmonary fibrosis effectively by suppressing activation of TGF-ß1/Smad3 and p38 signaling pathways.

Baicalein attenuates vinorelbine-induced vascular endothelial cell injury and chemotherapeutic phlebitis in rabbits.

Chemotherapy is one of the major strategies for cancer treatment. Several antineoplastic drugs including vinorelbine (VRB) are commonly intravenously infused and liable to cause serious phlebitis. The therapeutic drugs for preventing this complication are limited. In this study, the mechanism of baicalein (BCN) was investigated on VRB-induced phlebitis in vivo and vascular endothelial cell injury in vitro. Treatment with BCN obviously attenuated vascular endothelial cell loss, edema, inflammatory cell infiltration and blood clots, and reduced the serum levels of TNF-α, IL-1ß, IL-6 and ICAM-1 in the rabbit model of phlebitis induced by intravenous injection of VRB compared with vehicle. Further tests in vitro demonstrated that BCN lessened VRB-induced endothelial cell apoptosis, decreased intracellular ROS levels, suppressed phosphorylation of p38 and eventually inhibited activation of NF-κB signaling pathway. And these effects could be reversed by p38 agonist P79350. These results suggested that BCN exerted the protective effects against VRB-induced endothelial disruption in the rabbit model of phlebitis via inhibition of intracellular ROS generation and inactivation of p38/NF-κB pathway, leading to the decreased production of pro-inflammatory cytokines. Thus, BCN could be used as a potential agent for the treatment of phlebitis.

Antihepatofibrotic Effects of Aqueous Extract of Prunella vulgaris on Carbon Tetrachloride-Induced Hepatic Fibrosis in Rats.

Prunella vulgaris has been widely used in the folk medicine of Northeastern Asian countries for the treatment of acute liver injury and infectious hepatitis. In the present study, the protective effect of aqueous extract from P. vulgaris was investigated on carbon tetrachloride-induced hepatic fibrosis in vivo. Our data showed that the administration of aqueous extract from P. vulgaris at doses of 50, 100, and 200 mg/kg significantly reduced the elevated serum levels of alanine aminotransferase, aspartate aminotransferase, type III precollagen, and hyaluronic acid in rats with hepatic fibrosis. In addition, aqueous extract from P. vulgaris also reduced the incidence of liver lesions and the formation of fibrous septa, and remarkably decreased the serum levels of inflammatory cytokines, platelet derived growth factor, interleukin-4, interleukin-8, and tumor necrosis factor alpha. Furthermore, aqueous extract from P. vulgaris significantly inhibited the activation of hepatic stellate cells by regulating the expression of α smooth muscle actin, transforming growth factor ß 1, and smad2 and also decreased the deposition of extracellular matrix proteins via regulating the expressions of tissue inhibitor of metalloproteinase-1, matrix metalloproteinase-2,-13. Real-time polymerase chain reaction further revealed that post-treatment with aqueous extract from P. vulgaris decreased the elevated levels of miR-34a and miR-199a-5p in hepatic fibrosis rats. These results demonstrated that aqueous extract from P. vulgaris alleviates carbon tetrachloride-induced hepatic fibrosis by inhibiting the activation of hepatic stellate cells, promoting collagenolysis and regulating fibrosis-related microRNAs.

MicroRNA-203 accelerates apoptosis in LPS-stimulated alveolar epithelial cells by targeting PIK3CA.

The pathogenesis of endotoxin-induced acute lung injury (ALI) remains obscure and has not been well elucidated hitherto. Recently, microRNAs have distinct expression profiles in innate immunity, inflammation, and infection. However, the functions of microRNAs in ALI remain unknown. In this study, the functions of microRNAs in the development of ALI were investigated to identify potential drug targets. MicroRNA-203 (miR-203) expression in the lung tissues of lipopolysaccharide (LPS)-challenged mice was found to be significantly upregulated and peaked 5d post-LPS injection. MiR-203 overexpression in A549 cells significantly promoted cell apoptosis by inducing S-phase cell-cycle arrest. MiR-203 overexpression also inhibited the protein expression of phosphoinositide 3-kinase catalytic subunit alpha (PIK3CA), a direct target of miR-203 identified by bioinformatics, thereby suppressing the PI3K/Akt pathway. Moreover, repressed miR-203 effectively attenuated LPS-induced interstitial pneumonia. Therefore, regulating or inhibiting miR-203 may be of therapeutic potential in pneumonia and ALI.

Postbiotics: emerging therapeutic approach in diabetic retinopathy.

Diabetic retinopathy (DR) is a prevalent microvascular complication in diabetic patients that poses a serious risk as it can cause substantial visual impairment and even vision loss. Due to the prolonged onset of DR, lengthy treatment duration, and limited therapeutic effectiveness, it is extremely important to find a new strategy for the treatment of DR. Postbiotic is an emerging dietary supplement which consists of the inactivate microbiota and its metabolites. Numerous animal experiments have demonstrated that intervention with postbiotics reduces hyperglycemia, attenuates retinal peripapillary and endothelial cell damage, improves retinal microcirculatory dysfunction, and consequently delays the progression of DR. More strikingly, unlike conventional probiotics and prebiotics, postbiotics with small molecules can directly colonize the intestinal epithelial cells, and exert heat-resistant, acid-resistant, and durable for storage. Despite few clinical significance, oral administration with postbiotics might become the effective management for the prevention and treatment of DR. In this review, we summarized the basic conception, classification, molecular mechanisms, and the advances in the therapeutic implications of postbiotics in the pathogenesis of DR. Postbiotics present great potential as a viable adjunctive therapy for DR.

Magnifying Endoscopy With Narrow Band Imaging for Graft Failure and Disease Recurrence in Patients With Crohn Disease After Intestinal Transplantation: 2 Case Reports.

Crohn disease (CD) is one of the most common causes of short bowel syndrome and intestinal failure. Intestinal transplantation (IT) is sometimes needed for patients with CD who develop intestinal failure after multiple intestinal resections resulting from CD-related complications, such as uncontrollable bleeding and penetrating diseases. However, there have been few case reports concerning the endoscopic surveillance of patients with CD after IT. In this article, we present 2 patients with CD who underwent IT because of short bowel syndrome with intestinal failure. We administered posttransplantation immunosuppressants and conducted regular follow-up magnifying endoscopy with narrow-band imaging (ME-NBI). Both cases demonstrated favorable outcomes after surveillance with ME-NBI. In this report, we outline our post-IT follow-up strategies applying the VENCH scoring system, which is based on endoscopic features using ME-NBI to predict graft rejection. Our approach could effectively distinguish between acute cellular rejection and non-rejection, particularly disease recurrence of underlying CD. This study was approved by the institutional review board of Far Eastern Memorial Hospital (FEMH-105023-F). The patients provided written informed consent for publication.

Long-Term Outcomes of Esophageal Squamous Neoplasia with Muscularis Mucosa Involvement after Endoscopic Submucosal Dissection.

Ambiguity exists over treatment and surveillance strategies after endoscopic submucosal dissection (ESD) for esophageal squamous cell neoplasia (ESCN) with unfavorable histologic features. This study investigated the long-term outcomes of ESD in high-risk ESCN patients. We retrospectively included early ESCN patients treated with ESD at two medical centers in Taiwan between August 2010 and December 2023. Demographic, endoscopic and pathological data were collected. Among 146 patients (mean age 59.17 years) with 183 lesions, 73 (50%) had a history of head and neck cancer (HNC). En bloc and R0 resections were achieved in 100% and 95.6% of the lesions, respectively. The 5-year overall survival (OS), disease-specific survival (DSS) and local recurrence rates were 42.7%, 94.7% and 11%. R0 resections were significantly associated with recurrence in a univariate analysis (HR: 0.19, 95% CI: 0.06-0.66, p = 0.008). Alcohol abstinence was independently associated with lower recurrence (HR: 0.34, 95% CI: 0.16-0.73, p = 0.006). Patients with pT1a-MM (muscularis mucosa invasion) had comparable OS (p = 0.82), DSS (p = 0.617) and recurrence (p = 0.63) rates to those with pT1a-EP/LPM (epithelium/lamina propria invasion). The long-term outcomes of ESCN patients after ESD for expanded indications were satisfactory. ESD could be considered in selected ESCN patients involving the muscularis mucosa, notably among high-risk HNC patients.

Diosmetin-7-O-ß-D-glucopyranoside from Pogostemonis Herba alleviated SARS-CoV-2-induced pneumonia by reshaping macrophage polarization and limiting viral replication.

ETHNOPHARMACOLOGICAL RELEVANCE: Viral pneumonia is the leading cause of death after SARS-CoV-2 infection. Despite effective at early stage, long-term treatment with glucocorticoids can lead to a variety of adverse effects and limited benefits. The Chinese traditional herb Pogostemonis Herba is the aerial part of Pogostemon Cablin (Blanco) Benth., which has potent antiviral, antibacterial, anti-inflammatory, and anticancer effects. It was used widely for treating various throat and respiratory diseases, including COVID-19, viral infection, cough, allergic asthma, acute lung injury and lung cancer. AIM OF THE STUDY: To investigate the antiviral and anti-inflammatory effects of chemical compounds from Pogostemonis Herba in SARS-CoV-2-infected hACE2-overexpressing mouse macrophage RAW264.7 cells and hACE2 transgenic mice. MATERIALS AND METHODS: The hACE2-overexpressing RAW264.7 cells were exposed with SARS-CoV-2. The cell viability was detected by CCK8 assay and cell apoptotic rate was by flow cytometric assay. The expressions of macrophage M1 phenotype markers (TNF-α and IL-6) and M2 markers (IL-10 and Arg-1) as well as the viral loads were detected by qPCR. The mice were inoculated intranasally with SARS-CoV-2 omicron variant to induce viral pneumonia. The levels of macrophages, neutrophils, and T cells in the lung tissues of infected mice were analyzed by full spectrum flow cytometry. The expressions of key proteins were detected by Western blot assay. RESULTS: Diosmetin-7-O-ß-D-glucopyranoside (DG) presented the strongest anti-SARS-CoV-2 activity. Intervention with DG at the concentrations of 0.625-2.5 µM not only reduced the viral replication, cell apoptosis, and the productions of inflammatory cytokines (IL-6 and TNF-α) in SARS-CoV-2-infected RAW264.7 cells, but also reversed macrophage polarity from M1 to M2 phenotype. Furthermore, treatment with DG (25-100 mg/kg) alleviated acute lung injury, and reduced macrophage infiltration in SARS-COV-2-infected mice. Mechanistically, DG inhibited SARS-COV-2 gene expression and HK3 translation via targeting YTHDF1, resulting in the inactivation of glycolysis-mediated NF-κB pathway. CONCLUSIONS: DG exerted the potent antiviral and anti-inflammatory activities. It reduced pneumonia in SARS-COV-2-infected mice via inhibiting the viral replication and accelerating M2 macrophage polarization via targeting YTHDF1, indicating its potential for COVID-19 treatment.

Postbiotics in rheumatoid arthritis: emerging mechanisms and intervention perspectives.

Rheumatoid arthritis (RA) is a prevalent chronic autoimmune disease that affects individuals of all age groups. Recently, the association between RA and the gut microbiome has led to the investigation of postbiotics as potential therapeutic strategies. Postbiotics refer to inactivated microbial cells, cellular components, or their metabolites that are specifically intended for the microbiota. Postbiotics not only profoundly influence the occurrence and development of RA, but they also mediate various inflammatory pathways, immune processes, and bone metabolism. Although they offer a variety of mechanisms and may even be superior to more conventional "biotics" such as probiotics and prebiotics, research on their efficacy and clinical significance in RA with disruptions to the intestinal microbiota remains limited. In this review, we provide an overview of the concept of postbiotics and summarize the current knowledge regarding postbiotics and their potential use in RA therapy. Postbiotics show potential as a viable adjunctive therapy option for RA.

Use of Period Analysis to Timely Assess Five-Year Relative Survival for Patients with Ovarian Cancer from Taizhou, Eastern China.

OBJECTIVE: Ovarian cancer is a deadly gynecologic malignancy with a poor prognosis. It is essential to evaluate the early detection and screening programs of ovarian cancer via timely assessment of long-time survival, particularly in China where those data are incredibly limited. Here, we aimed to provide timely and accurately assessment of long-term survival estimate of ovarian cancer patients from eastern China. METHODS: Data of 770 ovarian cancer patients diagnosed between 2004-2018 were obtained from four cancer registries in Taizhou, eastern China, were included. We used period analysis to calculate five-year relative survival (RS) of aforementioned ovarian cancer patients for overall and the stratification by age at diagnosis and region. RESULTS: Our findings demonstrated that the overall five-year RS for ovarian cancer patients in Taizhou between 2014 and 2018 was 69.2%, while urban areas were higher compared to rural areas (77.6% vs. 64.9%). We also observed a significant age gradient with the five-year RS decreasing from 79.6% for age group < 55 years to 66.9% for age group > 74 years. Furthermore, we identified a clear upward trend of five-year RS over the study period, both overall and stratified by region and age at diagnosis. CONCLUSION: This is the first study in China using period analysis to provide the most up-to-date five-year RS for ovarian cancer patients from Taizhou, eastern China, which reaches 69.2% during 2014-2018. Our results provide valuable information for timely assessment of early detection and screening programs for ovarian cancer in eastern China.

Exosomal RBP4 potentiated hepatic lipid accumulation and inflammation in high-fat-diet-fed mice by promoting M1 polarization of Kupffer cells.

Exosomes containing various biological cargoes have potential to be novel diagnostic biomarkers for metabolic diseases. In this study, retinol-binding protein 4 (RBP4) was found to be enriched in serum exosomes, and its increased levels could be considered as an independent risk factor for the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Exosomal RBP4 (exo-RBP4), primarily derived from hepatocytes, significantly enhanced the M1-like polarization of Kupffer cells (KCs) via promoting the activation of NOX2 and NF-κB and reactive oxygen species (ROS) accumulation, resulting in the over-production of inflammatory cytokines including TNF-α. Subsequently, those excess cytokines remarkably increased the levels of intracellular free fatty acid uptake and lipogenesis-related genes (FAS and SREBP-1c) but decreased fatty acid degradation-related genes (CPT-1 and PPARα) in palmitic acid-treated LO2 cells. More notably, TNF-α significantly elevated RBP4 transcription by activating STAT3 in hepatocytes, playing a positive role in NAFLD development. Intravenous injection with RBP4 (50 µg/kg) potentiated hepatic lipid accumulation, M1-type KC proportion, and serum pro-inflammatory cytokine levels in the hepatic tissues of high-fat-diet-fed mice. Collectively, these data indicated that exo-RBP4 converted KCs to M1 subtype by mediating the NOX2/ROS/NF-κB pathway, subsequently promoting de novo lipogenesis in hepatocytes by TNF-α secretion to activate the JAK2/STAT3 signaling pathway. Therefore, this study uncovered a novel intercellular communication between the inflammatory microenvironment and lipid metabolism for fostering NAFLD progression and found the potential of exo-RBP4 as a novel diagnostic biomarker and therapeutic target for NAFLD.

Rgl-exomiR-7972, a novel plant exosomal microRNA derived from fresh Rehmanniae Radix, ameliorated lipopolysaccharide-induced acute lung injury and gut dysbiosis.

Plant-derived exosome-like nanoparticles (ELNs) have been proposed as a novel therapeutic tool for preventing human diseases. However, the number of well-verified plant ELNs remains limited. In this study, the microRNAs in ELNs derived from fresh Rehmanniae Radix, a well-known traditional Chinese herb for treating inflammatory and metabolic diseases, were determined by using microRNA sequencing to investigate the active components in the ELNs and the protection against lipopolysaccharide (LPS)-induced acute lung inflammation in vivo and in vitro. The results showed that rgl-miR-7972 (miR-7972) was the main ingredient in ELNs. It exerted stronger protective activities against LPS-induced acute lung inflammation than catalpol and acteoside, which are two well-known chemical markers in this herb. Moreover, miR-7972 decreased the production of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α), reactive oxygen species (ROS) and nitric oxide (NO) in LPS-exposed RAW264.7 cells, thereby facilitating M2 macrophage polarization. Mechanically, miR-7972 downregulated the expression of G protein-coupled receptor 161 (GPR161), activating the Hedgehog pathway, and inhibited the biofilm form of Escherichia coli via targeting virulence gene sxt2. Therefore, miR-7972 derived from fresh R. Radix alleviated LPS-induced lung inflammation by targeting the GPR161-mediated Hedgehog pathway, recovering gut microbiota dysbiosis. It also provided a new direction for gaining novel bioactivity nucleic acid drugs and broadening the knowledge on cross-kingdom physiological regulation through miRNAs.

The RNA-binding protein LRPPRC promotes resistance to CDK4/6 inhibition in lung cancer.

Kinase inhibitors against Cyclin Dependent Kinase 4 and 6 (CDK4/6i) are promising cancer therapeutic drugs. However, their effects are limited by primary or acquired resistance in virtually all tumor types. Here, we demonstrate that Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) controls CDK4/6i response in lung cancer by forming a feedback loop with CDK6. LRPPRC binds to CDK6-mRNA, increasing the stability and expression of CDK6. CDK6 and its downstream E2F Transcription Factor 1 (E2F1), bind to the LRPPRC promoter and elevate LRPPRC transcription. The activation of the LRPPRC-CDK6 loop facilitates cell cycle G1/S transition, oxidative phosphorylation, and cancer stem cell generation. Gossypol acetate (GAA), a gynecological medicine that has been repurposed as a degrader of LRPPRC, enhances the CDK4/6i sensitivity in vitro and in vivo. Our study reveals a mechanism responsible for CDK4/6i resistance and provides an enlightening approach to investigating the combinations of CDK4/6 and LRPPRC inhibitors in cancer therapy.

Pathogenic Roles of m6A Modification in Viral Infection and Virus-driven Carcinogenesis.

N6-methyladenosine (m6A) is a prevalent modification of RNA in eukaryotes, bacteria, and viruses. It is highly conserved and can affect the structure, localization, and biology functions of RNA. In recent years, multiple m6A methylation sites have been identified in the viral RNA genome and transcripts of DNA viruses. This modification occurs commonly during the primary infection and is dynamically regulated by a methyltransferase (writers), demethylase (eraser) and m6A-binding proteins (readers) within the host cells. The abnormal m6A modification not only affects the replication of pathogenic viruses and host immune response but also contributes to the pathogenesis of virus-induced cancers. In this review, we highlight recent advances on the mechanism of m6A modification on viral replication, host immune response and carcinogenesis to provide a novel insight for epigenetic prevention of viral infection and virus-driven carcinogenesis.

Implications of m6A methylation and microbiota interaction in non-small cell lung cancer: From basics to therapeutics.

N6-methyladenine (m6A) is one of the most common RNA epigenetic modifications in all higher eukaryotes. Increasing evidence demonstrated that m6A-related proteins, acted as oncogenes or tumor suppressors, are abnormally expressed in the cell lines and tissues of non-small cell lung cancer (NSCLC). In addition, lung as the special immune organ contacts with the outer environments and thereby inevitably suffers from different types of microbial pathogen attack. Those microbial pathogens affect the development, progression, and clinical outcomes of NSCLC via altering host m6A modification to disrupt pulmonary immune homeostasis and increase the susceptibility; conversely, host cells modulate m6A modification to repress bacterial colonization. Therefore, m6A harbors the potential to be the novel biomarkers and targets for predicting poor prognosis and chemotherapy sensitivity of patients with lung cancer. In this paper, we provided an overview of the biological properties of m6A-modifying enzymes, and the mechanistic links among lung microbiota, m6A modification and NSCLC. Although the flood of novel m6A-related inhibitors represents many dramatic improvements in NSCLC therapy, their efficacy and toxicity in NSCLC are explored to address these pivotal gaps in the field.