Background and Aim Rifampicin is the most common pathogenic factor in anti‐tuberculosis drug‐induced liver injury (AT‐DILI), the mechanisms that it promotes hepatocyte damage in AT‐DILI are not yet to be thoroughly elucidated. In this study, we investigated the potential molecular mechanisms for ferroptosis involving rifampicin hepatotoxicity. Methods Animal and cell injury models of rifampicin were constructed, and the toxicity of rifampicin was assessed by physicochemical staining and cell viability assay. Next, flow cytometry was employed to detect changes in ferroptosis‐related markers, and Western blotting was used to detect protein expression. Then, the important role of autophagy and ferroptosis was verified with small molecule compound intervention. Results We found that ferritinophagy‐induced ferroptosis participates in the toxicity of rifampicin, and the mechanism is that rifampicin precisely activates high‐throughput autophagy, which leads to the massive degradation of ferritin and the increase of free iron. Moreover, rifampicin exhibited conspicuous inhibition of Human 71 kDa heat shock cognate protein (HSPA8) that is intimately associated with Microtubule‐associated protein light chain 3 isoform B (LC3B) expression, in turn, HSPA8 inducer attenuated intracellular autophagy flux. Of note, inducing HSPA8 or inhibition of autophagy and ferroptosis considerably relieved the hepatotoxicity of rifampicin in mouse model. Conclusions The present study highlights the crucial roles of the HSPA8 and autophagy in ferroptotic cell death driving by rifampicin, particularly illumines multiple promising regulatory nodes for therapeutic interventions in diseases involving AT‐DILI.
BACKGROUND Mycobacterium paragordonae ( M. paragordonae ), a slow-growing, acid-resistant mycobacterial species, was first isolated from the sputum of a lung infection patient in South Korea in 2014. Infections caused by M. paragordonae are rare. CASE SUMMARY Herein, we report the case of a 53-year-old patient who presented with fever and low back pain. Lumbar nuclear magnetic resonance imaging revealed the destruction of the lumbar vertebra with peripheral abscess formation. After anti-infective and diagnostic anti-tuberculosis treatment, the patient had no further fever, but the back pain was not relieved. Postoperatively, the necrotic material was sent for pathological examination, and all tests related to tuberculosis were negative, but pus culture suggested nontuberculous mycobacteria. The necrotic tissue specimens were subjected to metagenomic next-generation sequencing, which indicated the presence of M. paragordonae . Finally, the infecting pathogen was identified, and the treatment plan was adjusted. The patient was in good condition during the follow-up period. CONCLUSION M. paragordonae , a rare nontuberculous mycobacterium, can also cause spinal infections. In the clinic, it is necessary to identify nontuberculous mycobacteria for spinal infections similar to Mycobacterium tuberculosis .
Background COVID-19 is a disease caused by SARS-CoV-2, which can cause mild to serious infections in humans. We aimed to explore the effect of growth hormone (GH)/estrogen/androgen in normal human lung epithelial BEAS-2B cells on COVID-19-type proinflammatory responses. Methods A BEAS-2B COVID-19-like proinflammatory cell model was constructed. After that, the cells were treated with GH, 17β-estradiol (E2), and testosterone (Tes) for 24 h. CCK-8 assays were utilized to evaluate cell viability. The mRNA expression of ACE2, AGTR1, TMRRSS2, and ISG15 and the protein expression of ACE2, AGTR1, TMRRSS2, and ISG15 were measured by qRT‒PCR and Western blotting, respectively. ELISAs were performed to determine IL-6, MCP-1, MDA and SOD expression. Flow cytometry was used to measure ROS levels. Finally, MAPK/NF-κB pathway-related factor expression was evaluated. Results The COVID-19-type proinflammatory model was successfully constructed, and 1000 ng/mL RBD treatment for 24 h was selected as the condition for the model group for subsequent experiments. After RBD treatment, cell viability decreased, the mRNA expression of ACE2, AGTR1, TMRRSS2, and ISG15 and the protein expression of ACE2, AGTR1, TMRRSS2, and ISG15 increased, IL-6, MCP-1, MDA and ROS levels increased, and MDA levels decreased. The mRNA levels of MAPK14 and RELA increased, but the protein levels did not change significantly. In addition, phospho-MAPK14 and phospho-RELA protein levels were also increased. Among the tested molecules, E2 had the most pronounced effect, followed by GH, while Tes showed the opposite effect. Conclusion GH/E2 alleviated inflammation in a COVID-19-type proinflammatory model, but Tes showed the opposite effect.
Human hepatitis B virus (HBV) infection, a primary cause of cirrhosis and liver cancer worldwide, remains a global public health concern due to the associated high morbidity and mortality rates. 1,2 Generally, HBV infection can be controlled by reverse-transcriptase inhibitors (nucleos (t) ide analogs [NAs]) and interferon (IFN) therapy. However, both these medications are available in limited quantities for eliminating HBV. Although antiviral therapy can efficaciously inhibit viral replication and significantly delay disease progression in patients infected with HBV, it is not curative and must be taken for a long period or even a lifetime. 3 Furthermore, once antiviral therapy is discontinued, new intact virus particles can be resynthesized, resulting from the covalently closed circular DNA (cccDNA). 4 Another major cause of the long-term existence of HBV is the dysfunction of the adaptive immune response, and the principal mechanism at play here is the immune tolerance induced by multiple viral antigens (e.g. HBV surface antigen, e antigen, core antigen). 5 Consequently,
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