The mRNA stability of PIEZO1, regulated by METTL3 via m6A modification in a YTHDF2-dependent manner, facilitates the progression of diabetic retinopathy.

Diabetic retinopathy (DR) is the major ocular complication of diabetes mellitus caused by chronic hyperglycemia, which leads to incurable blindness. Currently, the effectiveness of therapeutic interventions is limited. This study aimed to investigate the function of piezo-type mechanosensitive ion channel component 1 (PIEZO1) and its potential regulatory mechanism in DR progression. The results showed that PIEZO1 expression was upregulated in the retinal tissues of streptozotocin-induced diabetic mice and high glucose (HG)-triggered Müller cells. Functionally, the knockdown of PIEZO1 improves the abnormal retinal function of diabetic mice and impedes inflammatory cytokine secretion and gliosis of Müller cells under HG conditions. Mechanistic investigations utilizing RIP-qPCR, MeRIP-qPCR, and luciferase reporter assays demonstrated that PIEZO1 was a downstream target of methyltransferase-like 3 (METTL3). These studies revealed that METTL3-mediated N6-methyladenosine (m6A) modification within the coding sequence of PIEZO1 mRNA significantly shortened its half-life. In HG-stimulated cells, there was a negative regulatory relationship between PIEZO1 and YTH domain family 2 (YTHDF2), a recognized m6A reader. The loss of YTHDF2 resulted in an extended half-life of PIEZO1 in cells with overexpression of METTL3, indicating that the effect of METTL3 on the mRNA stability of PIEZO1 was dependent on YTHDF2. Taken together, this study demonstrated the protective role of the PIEZO1 silencing in DR development, and the degradation of PIEZO1 mRNA is accelerated by METTL3/YTHDF2-mediated m6A modification.

Early development of de novo hepatocellular carcinoma after direct-acting agent therapy: Comparison with pegylated interferon-based therapy in chronic hepatitis C patients.

Patients with chronic hepatitis C who achieve a sustained viral response after pegylated interferon therapy have a reduced risk of hepatocellular carcinoma, but the risk after treatment with direct-acting antivirals is unclear. We compared the rates of early development of hepatocellular carcinoma after direct-acting antivirals and after pegylated interferon therapy. We retrospectively analysed 785 patients with chronic hepatitis C who had no history of hepatocellular carcinoma (211 treated with pegylated interferon, 574 with direct-acting antivirals) and were followed up for at least 24 weeks after antiviral treatment. De novo hepatocellular carcinoma developed in 6 of 574 patients receiving direct-acting antivirals and in 1 of 211 patients receiving pegylated interferon. The cumulative incidence of early hepatocellular carcinoma development did not differ between the treatment groups either for the whole cohort (1.05% vs 0.47%, P = .298) or for those patients with Child-Pugh Class A cirrhosis (3.73% vs 2.94%, P = .827). Multivariate analysis indicated that alpha-fetoprotein level >9.5 ng/mL at the time of end-of-treatment response was the only independent risk factor for early development of hepatocellular carcinoma in all patients (P < .0001, hazard ratio 176.174, 95% confidence interval 10.768-2882.473) and in patients treated with direct-acting agents (P < .0001, hazard ratio 128.402, 95% confidence interval 8.417-1958.680). In conclusion, the rate of early development of hepatocellular carcinoma did not differ between patients treated with pegylated interferon and those treated with direct-acting antivirals and was associated with the serum alpha-fetoprotein level at the time of end-of-treatment response.

Acute cytomegalovirus pneumonia and hepatitis presenting during acute HIV retroviral syndrome.

Cytomegalovirus (CMV) disease is a frequent opportunistic infection that usually occurs in the late stages of HIV infection as a result of reactivation of a latent infection. We report a case of a 23-year-old man with acute retroviral syndrome complicated by coexisting CMV pneumonia and CMV hepatitis, which were documented by histopathological examination. His CMV pneumonia and hepatitis were assumed to be primary CMV diseases owing to the absence of CMV IgG antibody. To the best of our knowledge, this is the first case of simultaneous CMV pneumonia and hepatitis occurring as primary CMV diseases during primary HIV infection. This case indicates that invasive CMV diseases such as pneumonia and hepatitis should be considered even in patients with primary HIV infection.

Building new function into glycine receptors: a structural model for the activation of the glycine-gated chloride channel.

1. The glycine receptor chloride channel mediates inhibitory neurotransmission and is a member of the ligand-gated ion channel superfamily, which includes the nicotinic acetylcholine receptor channel. 2. Activation of these channels involves a movement of the pore-lining second membrane-spanning domain with respect to the remainder of the protein. 3. The present review considers the evidence that the loops that connect this domain with the rest of the protein act as crucial components of the channel activation mechanism.

Characterization of membrane transport processes: lessons from the study of BSP, bilirubin, and fatty acid uptake.

Recent efforts to identify plasma membrane transporters mediating the selective uptake of specific classes of organic anions have employed expression cloning techniques. The transporters identified by these procedures have, almost without exception, differed from putative transporters identified earlier by classical methods. In this review, the classical and molecular approaches to the identification of membrane transporters are examined and compared, with particular attention paid to the results obtained by each with respect to sulfobromophthalein, bilirubin, and fatty acid transport. The classical approach requires the initial identification and purification of a candidate transport protein, proof of its function as a transporter by antibody inhibition or liposome reconstitution studies, and following the cloning of its cDNA, genetic expression in transfected mammalian cells or in Xenopus laevis oocytes. Expression cloning affords more rapid identification of proteins which (by definition) influence uptake, avoids several potential artifacts (e.g., of conventional cDNA library screening techniques), and yields rapid access to sequence information and derived structural characteristics. However, it is ultimately necessary to express and purify the recombinant protein product, produce antibodies against synthetic peptides and/or the purified recombinant protein, use the antibodies to identify the subcellular location of the cloned protein, demonstrate that the protein binds the ligand of interest, and document that the protein mediates a facilitated process with the characteristics of the one under study. Hence, the two approaches ultimately require similar efforts. It is argued that the different putative BSP/bilirubin and fatty acid transporters identified by the two approaches may mediate different parallel transport pathways.

A case of cholestatic autoimmune hepatitis and acute liver failure: an unusual hepatic manifestation of mixed connective tissue disease and Sjögren's syndrome.

Although hepatomegaly is reported to occur occasionally in patients with mixed connective tissue disease (MCTD) or Sjögren's syndrome (SS), autoimmune liver diseases such as primary biliary cirrhosis, sclerosing cholangitis, and autoimmune hepatitis in association with MCTD or SS have rarely been described. We report a case of severe cholestatic autoimmune hepatitis presenting with acute liver failure in a 40-yr-old female patient suffering from MCTD and SS. The diagnosis of MCTD and SS was made at the age of 38. The patient presented severe jaundice and elevation of conjugated bilirubin. The patient denied alcohol and drug use and had no evidence of viral hepatitis. On the 8th day of her hospitalization, the patient developed grade III hepatic encephalopathy. She was diagnosed as autoimmune hepatitis presenting with acute liver failure based on clinical features, positive FANA and anti-smooth muscle antibodies, negative anti-mitochondrial antibodies, high titers of serum globulin, liver biopsy findings, and a good response to corticosteroid therapy, The patient was managed with prednisolone and the clinical symptoms, liver function test results, and liver biopsy findings showed much improvement after steroid therapy.

Ultrastructural changes of hepatic stellate cells in the space of Disse in alcoholic fatty liver.

BACKGROUND: Hepatic stellate cell (HSC) has been suggested to play a role in fibrogenesis in alcoholic liver disease. We evaluate the correlation with fibrogenesis and ultrastructure of hepatic stellate cells in alcoholic fatty liver. METHODS: We studied 6 patients with alcoholic fatty liver and 5 non-alcoholic fatty liver. The numbers of fat droplets in hepatic stellate cell was determined by electron microscopy. We also studied the grading of deposition of collagen fibers in the space of Disse. We were to evaluate the structure of hepatic stellate cells in the space of Disse by light and electron microscopy. RESULTS: Wider distribution of fat droplets in hepatic stellate cells in alcoholic fatty liver than in normal liver. The hypertrophied endoplasmic reticulum in hepatic stellate cells is a prominent findings in alcoholic fatty liver. We observed basement membrane-like materials in patients with alcoholic fatty liver with hepatic fibrosis. CONCLUSION: The results demonstrate that, in patients with alcoholic fatty liver by alcoholic liver injury, the hepatic stellate cells may play an important role in the fibrogenesis of perisinusoidal spaces in the liver.

A case of subcutaneous seeding of hepatocellular carcinoma after fine needle aspiration biopsy.

Cancer spread along the needle track following fine needle aspiration biopsy is said to be a rare complication. The authors report a case of subcutaneous implantation of hepatocellular carcinoma following ultrasono-guided fine needle aspiration biopsy. The patient, a 67-year-old Korean male was found to have a large hepatocellular carcinoma diagnosed by fine needle aspiration biopsy. Four months later, the patient felt two subcutaneous growing lumps at the previous aspiration site. The authors confirmed them histologically 11 months after aspiration.

Management of foreign bodies in the gastrointestinal tract: an analysis of 104 cases in children.

BACKGROUND AND STUDY AIMS: Ingested foreign bodies may be managed by endoscopy, observation, or surgery. The aim of the study was to investigate the methods of removal of foreign bodies according to type and location, success rates, and complications. PATIENTS AND METHODS: The charts of 104 children who had ingested foreign bodies were retrospectively reviewed. RESULTS: Of the patients, 80 (76.9%) were managed endoscopically. The overall success rate for endoscopic management was 98.8%. There were no complications during endoscopic interventions. In 23 cases the foreign bodies spontaneously passed through the gastrointestinal tract (22.1%). Surgical removal of a foreign body was done in only one case (0.96%). The majority of the foreign bodies which were located in the upper gastrointestinal tract could be removed endoscopically regardless of the nature of the material. Foreign bodies in the small and large intestine tended to pass through spontaneously without complications. CONCLUSIONS: It appears that the endoscopic approach is the preferable method for the extraction of upper gastrointestinal foreign bodies in child patients because of its high success rate, and that foreign bodies in the small and large intestine tend to be passed spontaneously without complications.