Hemizygosity of transsulfuration genes confers increased vulnerability against acetaminophen-induced hepatotoxicity in mice.

The key mechanism for acetaminophen hepatotoxicity is cytochrome P450 (CYP)-dependent formation of N-acetyl-p-benzoquinone imine, a potent electrophile that forms protein adducts. Previous studies revealed the fundamental role of glutathione, which binds to and detoxifies N-acetyl-p-benzoquinone imine. Glutathione is synthesized from cysteine in the liver, and N-acetylcysteine is used as a sole antidote for acetaminophen poisoning. Here, we evaluated the potential roles of transsulfuration enzymes essential for cysteine biosynthesis, cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CTH), in acetaminophen hepatotoxicity using hemizygous (Cbs(+/-) or Cth(+/-)) and homozygous (Cth(-/-)) knockout mice. At 4 h after intraperitoneal acetaminophen injection, serum alanine aminotransferase levels were highly elevated in Cth(-/-) mice at 150 mg/kg dose, and also in Cbs(+/-) or Cth(+/-) mice at 250 mg/kg dose, which was associated with characteristic centrilobular hepatocyte oncosis. Hepatic glutathione was depleted while serum malondialdehyde accumulated in acetaminophen-injected Cth(-/-) mice but not wild-type mice, although glutamate-cysteine ligase (composed of catalytic [GCLC] and modifier [GCLM] subunits) became more activated in the livers of Cth(-/-) mice with lower Km values for Cys and Glu. Proteome analysis using fluorescent two-dimensional difference gel electrophoresis revealed 47 differentially expressed proteins after injection of 150 mg acetaminophen/kg into Cth(-/-) mice; the profiles were similar to 1000 mg acetaminophen/kg-treated wild-type mice. The prevalence of Cbs or Cth hemizygosity is estimated to be 1:200-300 population; therefore, the deletion or polymorphism of either transsulfuration gene may underlie idiosyncratic acetaminophen vulnerability along with the differences in Cyp, Gclc, and Gclm gene activities.

Real-World Safety and Effectiveness of Letermovir in Patients Undergoing Allogenic Hematopoietic Stem Cell Transplantation: Final Results of Post-Marketing Surveillance in Japan.

BACKGROUND AND OBJECTIVE: Cytomegalovirus (CMV) is a common opportunistic infection after allogenic hematopoietic stem cell transplantation (allo-HSCT). Letermovir, an inhibitor of CMV DNA terminase, is approved for CMV prophylaxis in allo-HSCT patients. We report the final results of post-marketing surveillance of letermovir in Japan. METHODS: The case report forms were drafted in part by the Japanese Data Center for Hematopoietic Cell Transplantation using data elements in the Transplant Registry Unified Management Program and sent to individual HSCT centers to decrease the burden of reporting. Hematopoietic stem cell transplantation patients who received letermovir between May 2018 and May 2022 were registered. Data collected included physician-assessed adverse events/adverse drug reactions and clinical effectiveness (development of CMV disease, CMV antigen status, and use of preemptive therapy). RESULTS: A total of 821 HSCT patients were included in the safety analyses. Adverse drug reactions occurred in 11.33% of patients, with serious adverse drug reactions in 3.05%. The five most common adverse drug reactions were nausea (1.58%), renal impairment (1.46%), and acute graft versus host disease, CMV test positive, and hepatic function abnormal (0.61% each). A total of 670 patients were eligible for effectiveness analyses. Among these patients, 16.57% and 28.66% required preemptive therapy through week 14 and week 48, respectively. In addition, relatively few patients developed CMV disease throughout the follow-up period (1.34% at week 14 and 3.85% at week 48). CONCLUSIONS: This final analysis of post-marketing surveillance with up to 48 weeks follow-up period in Japan provides further evidence supporting the safety profile and effectiveness of letermovir for CMV prophylaxis in patients undergoing allo-HSCT in real-world settings.

Cytomegalovirus (CMV) infection is common after allogenic hematopoietic stem cell transplantation and causes both directly and indirectly a serious disease that frequently results in the death or severe outcomes for the affected patient. Letermovir is a drug that inhibits CMV replication and infection and can be administered to prevent CMV infection in at-risk patients undergoing allogenic hematopoietic stem cell transplantation. After it was approved in Japan, a post-marketing surveillance was started in order to confirm the safety profile and effectiveness of letermovir in clinical practice in Japan. The data collected included the adverse drug reactions during treatment and the effectiveness of letermovir. In this article, we describe the final results of this survey. The most common adverse drug reactions were nausea (1.58% of patients), renal impairment (1.46%), and acute graft versus host disease, CMV test positive, and hepatic function abnormal (0.61% each). There were few cases of myelosuppression, which is frequently seen in patients treated with ganciclovir/valganciclovir, and blood cells recovered steadily over time. Cytomegalovirus antigens were detected in 38.36% of patients through 48 weeks. Preemptive therapy was initiated to 28.66% of patients for up to 48 weeks. Cytomegalovirus disease was infrequent, occurring in 3.85% of patients. Overall, these findings are in alignment with the currently approved product label and provide further evidence supporting the consistent safety profile and effectiveness of letermovir for CMV prophylaxis in patients in Japan undergoing allogenic hematopoietic stem cell transplantation in clinical practice.

The mitochondrial unfolded protein response regulates hippocampal neural stem cell aging.

Aging results in a decline in neural stem cells (NSCs), neurogenesis, and cognitive function, and evidence is emerging to demonstrate disrupted adult neurogenesis in the hippocampus of patients with several neurodegenerative disorders. Here, single-cell RNA sequencing of the dentate gyrus of young and old mice shows that the mitochondrial protein folding stress is prominent in activated NSCs/neural progenitors (NPCs) among the neurogenic niche, and it increases with aging accompanying dysregulated cell cycle and mitochondrial activity in activated NSCs/NPCs in the dentate gyrus. Increasing mitochondrial protein folding stress results in compromised NSC maintenance and reduced neurogenesis in the dentate gyrus, neural hyperactivity, and impaired cognitive function. Reducing mitochondrial protein folding stress in the dentate gyrus of old mice improves neurogenesis and cognitive function. These results establish the mitochondrial protein folding stress as a driver of NSC aging and suggest approaches to improve aging-associated cognitive decline.

The hepatic integrated stress response suppresses the somatotroph axis to control liver damage in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) can be ameliorated by calorie restriction, which leads to the suppressed somatotroph axis. Paradoxically, the suppressed somatotroph axis is associated with patients with NAFLD and is correlated with the severity of fibrosis. How the somatotroph axis becomes dysregulated and whether the repressed somatotroph axis impacts liver damage during the progression of NAFLD are unclear. Here, we identify a regulatory branch of the hepatic integrated stress response (ISR), which represses the somatotroph axis in hepatocytes through ATF3, resulting in enhanced cell survival and reduced cell proliferation. In mouse models of NAFLD, the ISR represses the somatotroph axis, leading to reduced apoptosis and inflammation but decreased hepatocyte proliferation and exacerbated fibrosis in the liver. NAD+ repletion reduces the ISR, rescues the dysregulated somatotroph axis, and alleviates NAFLD. These results establish that the hepatic ISR suppresses the somatotroph axis to control cell fate decisions and liver damage in NAFLD.

The mitochondrial metabolic checkpoint in stem cell aging and rejuvenation.

Stem cell aging contributes to aging-associated tissue degeneration and dysfunction. Recent studies reveal a mitochondrial metabolic checkpoint that regulates stem cell quiescence and maintenance, and dysregulation of the checkpoint leads to functional deterioration of aged stem cells. Here, we present the evidence supporting the mitochondrial metabolic checkpoint regulating stem cell aging and demonstrating the feasibility to target this checkpoint to reverse stem cell aging. We discuss the mechanisms by which mitochondrial stress leads to stem cell deterioration. We speculate the therapeutic potential of targeting the mitochondrial metabolic checkpoint for rejuvenating aged stem cells and improving aging tissue functions.

An Acetylation Switch of the NLRP3 Inflammasome Regulates Aging-Associated Chronic Inflammation and Insulin Resistance.

It is well documented that the rate of aging can be slowed, but it remains unclear to which extent aging-associated conditions can be reversed. How the interface of immunity and metabolism impinges upon the diabetes pandemic is largely unknown. Here, we show that NLRP3, a pattern recognition receptor, is modified by acetylation in macrophages and is deacetylated by SIRT2, an NAD+-dependent deacetylase and a metabolic sensor. We have developed a cell-based system that models aging-associated inflammation, a defined co-culture system that simulates the effects of inflammatory milieu on insulin resistance in metabolic tissues during aging, and aging mouse models; and demonstrate that SIRT2 and NLRP3 deacetylation prevent, and can be targeted to reverse, aging-associated inflammation and insulin resistance. These results establish the dysregulation of the acetylation switch of the NLRP3 inflammasome as an origin of aging-associated chronic inflammation and highlight the reversibility of aging-associated chronic inflammation and insulin resistance.

Mitochondrial Stress-Initiated Aberrant Activation of the NLRP3 Inflammasome Regulates the Functional Deterioration of Hematopoietic Stem Cell Aging.

Aging-associated defects in hematopoietic stem cells (HSCs) can manifest in their progeny, leading to aberrant activation of the NLRP3 inflammasome in macrophages and affecting distant tissues and organismal health span. Whether the NLRP3 inflammasome is aberrantly activated in HSCs during physiological aging is unknown. We show here that SIRT2, a cytosolic NAD+-dependent deacetylase, is required for HSC maintenance and regenerative capacity at an old age by repressing the activation of the NLRP3 inflammasome in HSCs cell autonomously. With age, reduced SIRT2 expression and increased mitochondrial stress lead to aberrant activation of the NLRP3 inflammasome in HSCs. SIRT2 overexpression, NLRP3 inactivation, or caspase 1 inactivation improves the maintenance and regenerative capacity of aged HSCs. These results suggest that mitochondrial stress-initiated aberrant activation of the NLRP3 inflammasome is a reversible driver of the functional decline of HSC aging and highlight the importance of inflammatory signaling in regulating HSC aging.

Dietary deprivation of each essential amino acid induces differential systemic adaptive responses in mice.

SCOPE: Dietary deprivation of essential amino acids (EAAs) in mammals is known to cause reductions in food intake and body weight. The aim of this study was to determine whether and how mice respond to deprivation of individual EAA species. METHODS AND RESULTS: Dietary deprivation of any single EAA (not non-EAA) in mice led to progressive weight loss in the order of Ile(-) > Val(-) > Thr(-) > Leu(-) > Trp(-) > His(-) > Phe(-) > Met(-) > Lys(-) , which correlated with the reduction in food intake. Decreased levels of the deprived EAAs as well as increased levels of all or some of the other amino acids were detected in the serum, although these levels differed among the diets examined. Serum biochemistry identified significant increases in creatine phosphokinase, blood urea nitrogen, alanine aminotransferase, and aspartate aminotransferase, and decreases in glucose and triglycerides; computed tomography revealed a marked reduction in abdominal/femoral fat and muscle depots; histology identified diffuse myofiber atrophy in the rectus femoris muscle, all in that approximate order. In contrast, amino acid response, autophagy, and ubiquitination marker genes as well as amino acid transporter genes were induced in both deprived EAA-specific and tissue-specific manners. CONCLUSION: Dietary deprivation of individual EAAs induced systemic adaptive responses that differed in magnitude and molecular machinery.