Protein arginine methyltransferase 5 (PRMT5) acts as an oncogene in liver cancer, yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined. Here, we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8⁺ T-cell-mediated antitumor immunity both in vivo and in vitro. Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule, fibrinogen-like protein 1 (FGL1). Mechanistically, PRMT5 catalyzed symmetric dimethylation of transcription factor 12 (TCF12) at arginine 554 (R554), prompting the binding of TCF12 to FGL1 promoter region, which transcriptionally activated FGL1 in tumor cells. Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression, which promoted CD8⁺ T-cell-mediated antitumor immunity. Notably, combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice. Collectively, our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.

BACKGROUND: The switch/sucrose nonfermentable chromatin-remodeling (SWI/SNF) complex is a pivotal chromatin remodeling complex, and the genomic alterations (GAs) of the SWI/SNF complex are observed in several cancer types, correlating with multiple biological features of tumor cells. However, their role in liver metastasis of non-small cell lung cancer (NSCLC) remains unclear. Our study aims to investigate the role and potential mechanisms underlying NSCLC liver metastasis induced by the GAs of SWI/SNF complex. METHODS: The GAs of SWI/SNF complex in NSCLC cell lines (H1299, H23 and H460) were identified by whole-exome sequencing (WES). ARID1A knockout H1299 cell was constructed with the CRISPR/Cas9 technology. The mouse model of liver metastasis from NSCLC was established to simulate lung cancer liver metastasis and observe the metastasis rate under different gene mutation conditions. RNA sequencing and Western blot were conducted for differential gene expression analysis. Immunohistochemistry (IHC) analysis was used to assess protein expression levels of SWI/SNF-regulated target molecules in mouse liver metastases. RESULTS: WES analysis revealed intracellular gene mutations. The animal experiments demonstrated a correlation between the GAs of SWI/SNF complex and a higher liver metastasis rate in immunodeficient mice. Transcriptome sequencing and Western blot analysis showed upregulated expression of ALDH1A1 and APOBEC3B in SWI/SNF-mut cells, particularly in ARID1A-deficient H460 and H1299 sgARID1A cells. IHC staining of mouse liver metastases further demonstrated elevated expression of ALDH1A1 in the H460 and H1299 sgARID1A group. CONCLUSIONS This study underscores the critical role of the GAs of SWI/SNF complex, such as ARID1A and SMARCA4, in promoting liver metastasis of lung cancer cells. The GAs of SWI/SNF complex may promote liver-specific metastasis by upregulating ALDH1A1 and APOBEC3B expression, providing novel insights into the molecular mechanisms underlying lung cancer liver metastasis.
Animals ; Mice ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/genetics* ; Mutation ; Liver Neoplasms/genetics*

Heart failure is the terminal stage of all kinds of heart diseases. Despite the use of a variety of traditional drug standard treatment, the prognosis is still not ideal, and there is an urgent need for the update and improvement of new drugs and treatment methods. In recent years, angiotensin receptor-enkephalase inhibitors (Sacubitril/Valsartan), sodium-glucose cotransporter 2 inhibitors (SGLT-2i), soluble guanoside cyclase agonists (Vericiguat) and myocardial myosin activators omecamtiv mecarbil have been developed successively. SGLT2 inhibitors can improve ventricular load, reduce fibrosis and affect myocardial metabolism. sGC agonists play an anti-heart failure role by enhancing l-ARg-No-SGC-CGMP signaling pathway, improving myocardial and vascular function, reversing ventricular hypertrophy and fibrosis, slowing ventricular remodeling, and reducing ventricular afterload through systemic and pulmonary vasodilation. In addition, fineridone, a novel salt corticosteroid receptor antagonist, has also been reported in clinical studies in the field of heart failure. Therefore, it is the direction and hope for the development of heart failure in the future to select appropriate drugs for different types of patients with heart failure and carry out individualized treatment according to the optimized process of heart failure.

Cardiomyopathy is a disease with abnormal myocardial structure and function. For a long time, due to the limited understanding of cardiomyopathies, cardiomyopathies are treated empirically based on symptoms (such as heart failure, arrhythmia, etc.). Over years, with the improvement of diagnosis technology and the discover of disease mechanism, a variety of drugs have been approved, such as tafamidis, patisiran and Inotersen. Many more drugs have completed preliminary safety and efficacy verification and entered Phase III trials. In addition, some cutting-edge technologies are also being developed, such as siRNA drug patisiran, CRISPR/Cas9 gene editing technology drug NTLA-2001, stem cell therapy, etc. This article discusses two cardiac problems that may be caused by cardiomyopathy: myocardial hypertrophy and cardiac remodeling, and introduces the pharmacology and related research of the latest drugs for these diseases.

COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development. No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections. We report herein that a macrolide antibiotic, carrimycin, potently inhibited the cytopathic effects (CPE) and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229E, OC43, and SARS-CoV-2. Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection. In support of this notion, metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA. Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.

No abstract available.
Gallbladder*

Objective To identify the common Sarcophagidae species of necrophagous flies in Luoyang by DNA barcoding and 28S ribosomal RNA(28S rRNA) gene and evaluate its effectiveness for forensic practice. Methods Eighteen Sarcosaprophagous flies were collected and classified by entomologists with traditional morphological characteristics. The DNA of flies was extracted with Chelex-100 method. The fragments of mitochondrial cytochromec oxidase subunit I (COI) and 28S rRNA gene were amplified and sequenced. Twenty corresponding species (China and South Korea) were loaded from Barcode of Life Data System (BOLD) and added to the alignment. All the sequences were analyzed by MEGA 7.0 software package for nucleotide composition, genetic distance computation and phylogenetic tree construction. Results Eighteen Sarcosaprophagous flies were classified into 5 species of 3 genera. The result of amplification with 18 samples showed that length of the obtained COI and 28S rRNA gene sequences were 646bp and 721bp, respectively. And the result of alignment on BLAST online showed that index of similarity of the same species was above 99%. The thirty-eight COI sequences of Sarcosaprophagous flies were clustered into five groups by a neighbor-joining (NJ) tree on value of Bootstrap 1000. The intraspecific difference in COI was 0 to 0.022 while the interspecific difference ranged from 0.057 to 0.090 excluding Sarcophaga Africa and Sarcophaga haemorrhoidalis, which was 0~0.086. The NJ tree of 28S rRNA showed Sarcophaga peregrine and Sarcophaga portschinskyi sequences were obviously clustered into two groups and the others a group. Conclusion For the five sarcophagous flies in this study, the DNA barcoding based on COI gene were able to effectively identify the Sarcophaga peregrine, Sarcophaga dux and Sarcophaga portschinskyi, while 28S rRNA gene can only differentiate Sarcophaga peregrine from others. DNA barcoding based on COI gene and 28S rRNA gene can be used as supplemental molecular markers for identifying these species.

OBJECTIVETo study retrospectively the clinical efficacy on pediatric recurrent pneumonia treated with point application in summer for the prevention in winter, as well as the relationship of age, sick duration, attack frequency and skin reaction with the clinical efficacy.

METHODSOne hundred and thirty-five cases of pediatric recurrent pneumonia were divided into a one-year group, a two-year group and a three-year group, 45 cases in each one according to the duration of treatment. The acupoints for the application were Dingchuan (EX-B1), Feishu (BL 13), Gaohuang (BL 43) and Danzhong (CV 17) with the same herbal plaster (prepared with rhizome corydalis, semen brassicae, euphorbia kansui and asarum sieboldii at the ratio of 2:2:1:1) on the first day of each of the three periods of the hot season, 2 to 4 h in each treatment. The attack frequency and change rate were observed before and after treatment in the three groups. The clinical efficacy was assessed in the three groups.

RESULTS(1) After treatment, the attack frequency of pediatric pneumonia was reduced apparently in the three groups (all P < 0.01). The result in the three-year group was less than that in the one-year group and the two-year group and the change rate was the highest (all P < 0.01). (2) After treatment, the sick duration was shortened apparently in the three groups (P < 0.05, P < 0.01). The result in the three-year group was the most remarkable, statistically and significantly different as compared with the other two groups (both P < 0.01). (3) The total effective rate in the three-year group was better than that in either of the other two groups [84.4% (35/45) vs 51.1% (23/45, P < 0.01), 84.4% (35/45) vs 71.1% (32/45, P < 0.05)]. (4) The total effective rate in the children aged from 4 to 7 years was better than that in the group aged from 8 to 10 years and the group aged from 11 to 14 years [79. 7% (47/59) vs 71.7% (33/46, P < 0.05); 79.7% (47/59) vs 43.3% (13/30, P < 0.01)]. (5) The total effective rate in the children with the sick duration ≥ 4 year was lower than that in the group with the sick duration <2 years and that 2 to 4 years (both P < 0. 01). (6) The total effective rate in the children with the annual attack frequency of 2 to 4 times was better than that with the frequency ≥ 4 times (P < 0.01). (7) For the cases with skin reaction after treatment, the total effective rate was better than that in the cases without reaction (P < 0.05).

CONCLUSIONThe point application in summer for the prevention in winter reduces the attack frequency of pediatric pneumonia, shortens the sick duration and has achieved the better significant efficacy in the cases of lower age, shorter sick duration, less attack frequency and moderate skin reaction.

Acupuncture Points ; Adolescent ; Child ; Child, Preschool ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Humans ; Male ; Pneumonia ; drug therapy ; prevention & control ; Seasons ; Treatment Outcome