Redox imbalance and metabolic defects in the context of Alzheimer disease

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Redox imbalance and metabolic defects in the context of Alzheimer disease

During aging, a progressive failure of energy metabolism occurs resulting in brain hypometabolism. This condition, combined with redox disturbance, contributes to increase neuronal cell vulnerability ultimately leading to neurodegeneration. Down syndrome and Alzheimer disease neuropathologies present several molecular similarities, among which perturbation of redox homeostasis and reduced energy production are major players that accelerate neuronal damage.


Redox reactions play a critical role for intracellular processes, including pathways involved in metabolism and signaling. Reactive oxygen species (ROS) act either as second messengers or generators of protein modifications, fundamental mechanisms for signal transduction. Disturbance of redox homeostasis is associated with many disorders. Among these, Alzheimer's disease is a neurodegenerative pathology that presents hallmarks of oxidative damage such as increased ROS production, decreased activity of antioxidant enzymes, oxidative modifications of macromolecules, and changes in mitochondrial homeostasis. Interestingly, alteration of redox homeostasis is closely associated with defects of energy metabolism, involving both carbohydrates and lipids, the major energy fuels for the cell. As the brain relies exclusively on glucose metabolism, defects of glucose utilization represent a harmful event for the brain. During aging, a progressive perturbation of energy metabolism occurs resulting in brain hypometabolism. This condition contributes to increase neuronal cell vulnerability ultimately resulting in cognitive impairment. The current review discusses the crosstalk between alteration of redox homeostasis and brain energy defects that seems to act in concert in promoting Alzheimer's neurodegeneration.

Natural history and clinical features of hepatitis C virus infection during childhood: A nationwide, observational survey in Japan

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Natural history and clinical features of hepatitis C virus infection during childhood: A nationwide, observational survey in Japan

In the present study, 10.4% of Japanese children infected with hepatitis C virus transmitted from mother to child cleared the infection 3.1 years after birth. We also showed that direct-acting antiviral agent therapy is a safe and highly effective treatment. Direct-acting antiviral agent treatment should be provided to prevent transmission from mother to child.


Abstract

Aim

Few data on spontaneous clearance rates of cases of mother-to-child transmission of hepatitis C viral (HCV) infection are available in Japan. Furthermore, the treatment courses of interferon-based and direct-acting antiviral agent (DAA) therapies for children are also unclear. Our aim was thus to clarify the long-term natural progression of HCV infection and the treatment outcomes of children in Japan.

Methods

We conducted a combined multicenter, observational survey involving 65 pediatric institutions in Japan. Pediatric HCV infection cases with patients born between 1973 and 2021 were collected over the 11-year period from 2012 to 2022. A total of 563 patients were enrolled, with 190 excluded for having insufficient laboratory data or treatment information, resulting in 373 eligible cases.

Results

Of 328 cases of mother-to-child infection, 34 (10.4%) had spontaneous clearance, with a median time to spontaneous clearance of 3.1 years (range 0.9–7.2 years). Of the total 373 eligible cases, 190 received antiviral therapy (interferon-based therapy, 158; DAA therapy, 32). Sustained virologic response rates after first-line treatment were 75.3% (119/158) and 100% (32/32) for interferon-based therapy and DAA therapy, respectively, with the DAA group showing a shorter time from therapy initiation to viral negativity (2.7 vs. 1.0 months; p = 0.0031).

Conclusions

Approximately 10% of Japanese children infected by mother-to-child transmission achieve spontaneous resolution of HCV infection. Our findings indicate that DAA therapy is safe and highly effective in Japanese children, achieving higher sustained virologic response rates and shorter time to clearance of the virus compared with interferon-based therapy.

Genomic analysis of an aggressive hepatic leiomyosarcoma case following treatment for hepatocellular carcinoma

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Abstract

A 70-year-old man undergoing treatment for immunoglobulin G4-related disease developed a liver mass on computed tomography during routine imaging examination. The tumor was located in the hepatic S1/4 region, was 38 mm in size, and showed arterial enhancement on dynamic contrast-enhanced computed tomography. We performed a liver biopsy and diagnosed moderately differentiated hepatocellular carcinoma. The patient underwent proton beam therapy. The tumor remained unchanged but enlarged after 4 years. The patient was diagnosed with hepatocellular carcinoma recurrence and received hepatic arterial chemoembolization. However, 1 year later, the patient developed jaundice, and the liver tumor grew in size. Unfortunately, the patient passed away. Autopsy revealed that the tumor consisted of spindle-shaped cells exhibiting nuclear atypia and a fission pattern and tested positive for α-smooth muscle actin and vimentin. No hepatocellular carcinoma components were observed, and the patient was pathologically diagnosed with hepatic leiomyosarcoma. Next-generation sequencing revealed somatic mutations in CACNA2D4, CTNNB1, DOCK5, IPO8, MTMR1, PABPC5, SEMA6D, and ZFP36L1. Based on the genetic mutation, sarcomatoid hepatocarcinoma was the most likely pathogenesis in this case. This mutation is indicative of the transition from sarcomatoid hepatocarcinoma to hepatic leiomyosarcoma.

Optimal treatment strategy and prognostic analysis of salvage liver transplantation for patients with early hepatocellular carcinoma recurrence after hepatectomy

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Abstract

Aim

We aimed to investigate the prognostic factors for salvage liver transplant in patients with early hepatocellular carcinoma recurrence after hepatectomy.

Methods

This retrospective analysis included 53 patients who underwent salvage living-donor liver transplantation between January 2007 and January 2018. There were 24 and 29 patients in the early (recurrence ≤24 months after primary liver resection) and the late recurrence groups, respectively.

Results

In the multivariate Cox regression model, pre-liver transplant downstaging therapy, early recurrence (ER) after primary liver resection , and recurrence-to-liver-transplant ≥12 months were independent risks to predict recurrent hepatocellular carcinoma recurrence after salvage living-donor liver transplantation. Compared with the late recurrence group, the ER group showed lower disease-free survival rates (p < 0.001); however, the overall survival rates did not differ between the two groups (p = 0.355). The 1-, 3-, and 5-year disease-free survival rates were 83.3%, 70.6%, and 66.2%, and 96.0%, 91.6%, and 91.6% in the early and late recurrence groups, respectively. When stratified by recurrence-to-liver transplant time and pre-liver transplant downstaging therapy in the ER group, disease-free survival and overall survival rates were significantly different.

Conclusion

ER after primary liver resection with advanced tumor status and a longer period of recurrence-to-liver-transplant (≥12 months) have a negative impact on salvage liver transplant. Our findings provide novel recommendations for treatment strategies and eligibility for salvage liver transplant candidates.

How enzyme‐centered approaches are advancing research on cyclic oligo‐nucleotides

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How enzyme-centered approaches are advancing research on cyclic oligo-nucleotides

Cyclic nucleotides serve as second messengers throughout kingdoms of life and regulate various pathways. Here, we review recent milestones in cyclic nucleotide biology, focusing on different enzyme folds that synthesize these signals, their regulatory mechanisms, and pleiotropic downstream signaling events. Our particular focus is on enzyme-centered approaches specifically targeting nucleotidyltransferases, which have enabled the discovery of novel cyclic nucleotides.


Cyclic nucleotides are the most diversified category of second messengers and are found in all organisms modulating diverse pathways. While cAMP and cGMP have been studied over 50 years, cyclic di-nucleotide signaling in eukaryotes emerged only recently with the anti-viral molecule 2´3´cGAMP. Recent breakthrough discoveries have revealed not only the astonishing chemical diversity of cyclic nucleotides but also surprisingly deep-rooted evolutionary origins of cyclic oligo-nucleotide signaling pathways and structural conservation of the proteins involved in their synthesis and signaling. Here we discuss how enzyme-centered approaches have paved the way for the identification of several cyclic nucleotide signals, focusing on the advantages and challenges associated with deciphering the activation mechanisms of such enzymes.

Genomic dissection of brown planthopper, Nilaparvata lugens (Hemiptera: Delphacidae) resistance in Indica rice genotypes

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Genomic dissection of brown planthopper, Nilaparvata lugens (Hemiptera: Delphacidae) resistance in Indica rice genotypes

New Nilaparvata lugens resistant genotypes were reported. Six BPH resistance genes showed significant association and these genes either alone or in combination could be introgressed into elite varieties with genomic approach to develop robust resistant rice varieties against N. lugens biotype 4. The identified genotypes could be useful for novel R genes identification, host–insect interaction and genomic studies.


Abstract

The population growth and the regular breakout of Nilaparvata lugens pose a significant risk to rice cultivation. Four different N. lugens biotypes have been identified worldwide, with biotype 4 being the most destructive and prevalent throughout Asia, particularly in India. Therefore, a rice variety with multiple resistance genes/alleles is required for effective management of N. lugens. Hence, 191 rice genotypes collected from various parts of India were evaluated for resistance to N. lugens. Further, SSR markers representing 23 different N. lugens resistant (R) genes were assayed to identify genomic regions associated with resistance. The results of the genetic analysis showed that the average genetic diversity value of all markers was 0.165 and polymorphic information content of 0.145 for all the markers used. The population structure and cluster analysis divided the studied genotypes into three distinct groups, with resistant genotypes grouped separately. These findings were confirmed by the principal coordinate analysis, which categorized resistant genotypes, moderately resistant genotypes, and susceptible genotypes into distinct components. Additionally, 90% of the genetic variation was between individuals of populations and 10% between the populations. Marker-trait association study through mixed linear model and generalized linear model identified six SSR markers such as RM6732 (Bph15), RM314 (Bph6), RM16999 (Bph6), RM7 (QBph3), RM401 (bph4), and RM7102 (Bph1), which were significantly associated with various phenotypic parameters, such as feeding mark, honeydew excretion, percent damage and nymphal survival. The resistant genes identified in these genotypes could help in the marker-assisted rice variety development with durable resistance against N. lugens.