Preserved autism-associated behaviors and dopaminergic neuron hyperactivity in DAT-IRES-Cre mice after valproate exposure.

The synaptic transmission of memory engrams is important for their roles in memory storage and retrieval, and can be regulated by multiple neuronal adhesion molecules. This study focuses on the roles of neuronal pentraxin (NPTX) family members (NPTX1 and NPTX2), which are biomarkers for cognitive decline, in the synaptic transmission of Fos-(F-RAM) and Npas4-(N-RAM)-dependent engrams formed during contextual fear conditioning in the dentate gyrus. Utilizing robust activity marking (RAM) system, contextual fear conditioning, conditional knockout (cKO) technology and electrophysiological recording, we analyzed the characteristic of miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs) in engram cells of wild-type and Nptxs cKO mice. Nptx1 cKO leads to an increased amplitude and frequency of mEPSCs and decreased amplitude of mIPSCs in F-RAM neurons, as well as an elevated mEPSC frequency and reduced mIPSC frequency in N-RAM neurons. In contrast, Nptx2 cKO results in a decreased mEPSC frequency and increased mIPSC frequency in both F-RAM and N-RAM neurons. Nptx1 cKO increased engram activity while Nptx2 cKO decreased engram activity. These findings reveal the distinct roles of the NPTX family in regulating the synaptic transmission of the fear engrams.

Comparison of rod photoreceptor outer segment renewal in wild type and Tmem138-deficient mice using AAV-delivered Dendra2-tagged rhodopsin.

Myocardin-related transcription factor A contributes to diabetic nephropathy by activating integrin β2 in macrophages.

ALDH2 deficiency increases susceptibility to acetaminophen-induced liver injury through gut microbiota dysbiosis and altered bile acid metabolism.

Renal ischemia-reperfusion (I/R) remains a leading cause of acute renal failure in both native and transplanted kidneys. Hypoxia-inducible factor (HIF)-1α is a protective factor against renal I/R injury (rIRI). However, the downstream mechanisms through which HIF-1α exerts its protective effects in rIRI remain to be fully elucidated. rIRI was induced in heterozygous HIF-1α knockout (hKO) mice. To establish an in vitro model of rIRI, a human tubular cell line (HK2) was subjected to hypoxia-reoxygenation (H/R). rIRI-induced hKO mice exhibited elevated serum creatinine levels compared with rIRI-induced wild-type (WT) mice. Furthermore, tubular cell death was observed earlier in WT mice during the initial phase of I/R, whereas it was reduced in hKO mice. Phagocytosis of damaged tubular cells by macrophages was diminished in hKO mice, suggesting that the clearance of cellular debris plays a critical role in renal tissue repair and regeneration. Furthermore, glutathione-specific γ-glutamyl cyclotransferase 1 (CHAC1), a known cell death inducer, was upregulated in the tubular cells of WT mice but not hKO mice following I/R. The overexpression of CHAC1 in HK2 cells induced cell death, whereas siRNA-mediated CHAC1 knockdown attenuated cell death in HK2 cells subjected to H/R. These findings collectively suggest that CHAC1 plays a pivotal role in regulating tubular cell death during rIRI. Our findings indicate that controlled cell death induction is essential for rIRI recovery. CHAC1, a key factor in this process, is a potential therapeutic target for rIRI.NEW & NOTEWORTHY Here, we reported that HIF-1α upregulates glutathione-specific γ-glutamyl cyclotransferase 1 (CHAC1), a regulator of cell death and oxidative stress, in rIRI. Our results suggested that CHAC1 plays a pivotal role in regulating tubular cell death during rIRI, and the controlled tubular cell death induced by CHAC1 is essential for rIRI recovery. This proposes novel mechanisms underlying rIRI recovery.

Arylacetamide deacetylase deficiency potentiates ketoconazole-induced inhibition of triazolam metabolism in mice.

Insulin resistance plays a key role in the development of type 2 diabetes and predates the development of frank hyperglycemia. Thyroid hormone (TH) signaling plays a critical role in glucose homeostasis, as both hyperthyroidism and hypothyroidism have been linked to the development of insulin resistance and diabetes. The mechanism behind the effects of TH action on insulin sensitivity is incompletely understood, but the liver is thought to play a key role. Indeed, resmetirom, a selective thyroid hormone receptor beta (THRβ) agonist, has recently been approved for treatment of liver fibrosis, and more THRβ agonists are currently in phase 2-3 clinical trials for use in metabolic dysfunction-associated fatty liver disease. As insulin resistance is closely associated with this disease, it is crucial that we understand the role of hepatic THRβ in glucose homeostasis. Thus, we hypothesized that TH, acting via the THRβ, is a key regulator of hepatic glucose metabolism. In wild-type (WT) and liver-specific THRβ knock-out (L-TRBKO) mice we analyzed the effect of changes in thyroid status and diet on glucose homeostasis and insulin signaling. Mice were assessed under basal conditions on a chow fed diet, under hypothyroid conditions using a propylthiouracil/low iodine diet with and without T3 treatment and following a high-fat diet. We measured glucose tolerance, hepatic insulin signaling, liver histology, energy expenditure and skeletal muscle metabolism. In high-fat diet fed WT and L-TRBKO mice we addidionally analyzed the effect of a single i.p. injection of T3. Finally we studied insulin signaling in human induced pluripotent stem cells differentiated to hepatocytes (iHeps) both with and without THRβ expression. In contrast to our hypothesis, we found that insulin signaling in mice was not impacted by the selective deletion of THRβ only in hepatocytes. Both WT and L-TRBKO mice have similar glucose homeostasis under basal conditions and developed hyperglycemia on a high-fat diet. Further, a single dose of T3 administered to high-fat diet fed insulin-resistant mice improves insulin sensitivity to the levels of control chow-fed mice in both WT and L-TRBKO male mice. This single dose of T3 also increased glucose transporter expression in skeletal muscle. In iHeps, THRβ1 was not required to activate insulin signaling, and T3 treatment did not affect insulin signaling. T3 signaling impacts glucose homeostasis independently of its actions through the THRβ1 in hepatocytes in both a murine and human model.

Integrated behavioral and biological assessment reveals 5-HT3 receptor-independent nausea/malaise-like responses in cisplatin-treated mice.

Exploring cannabinoid receptor CB1 autophagy and the obesity phenotype of p62-deficient mice.

Vitamin C-deficient gulo-/- mice exhibit increased susceptibility to Helicobacter pylori colonization and gastric pathology.

Aldh3a1-mediated detoxification of reactive aldehydes contributes to distinct muscle responses to amyotrophic lateral sclerosis progression.

Imaging pulmonary P-glycoprotein activity with aerosolized [99mTc]Tc-sestamibi in mice.

The depression-like state in Bst1/Cd157 knock-out mice is attenuated by double knock-out with Cd38.

Sexually dimorphic effects of SCFA-FFAR2 signaling on colitis-induced visceral hypersensitivity in mice.

Kidney Volume and Molecular Processes are Dynamic in ADPKD.

SOCS2 deficiency drives sex-specific remodeling of mineralized tissues.

Pathological cardiac hypertrophy is a key risk factor for heart failure (HF). Illustrating the pathogenesis of cardiac hypertrophy may contribute to the treatment of HF. Studies have emphasized that protein ubiquitination is a critical event in HF. In this study, we investigated the role of an E3 ubiquitin ligase, RNF123, in HF induced by angiotensin II (Ang II) infusion and transverse aortic constriction (TAC) surgery. Heart failure was induced by Ang II infusion or TAC surgery in wild-type and RNF123 knockout mice. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis combined with co-immunoprecipitation (Co-IP) was used to identify PRDX1 as an interacting protein of RNF123. The expression of RNF123 was significantly increased in cardiomyocytes of mice subjected to Ang II infusion or TAC surgery. RNF123 deficiency mitigated cardiac hypertrophy and dysfunction induced by Ang II infusion or TAC operation in mice. Invitro, RNF123 knockdown attenuated Ang II-induced hypertrophy, whereas RNF123 overexpression exacerbated the pathological alterations in neonatal rat ventricular myocytes (NRVMs). Mechanistically, LC-MS/MS and Co-IP assays revealed that RNF123 directly bound to the N-terminal domain of PRDX1 and added a K48-linked ubiquitin chain at the K7 site of PRDX1, subsequently facilitating PRDX1's proteasomal degradation. RNF123-mediated degradation of PRDX1 increased the ROS level in cardiomyocytes, driving the pathogenesis of myocardial hypertrophy. Our findings identified that cardiomyocyte RNF123 mediates pathological cardiac hypertrophy via ubiquitinating PRDX1 and highlighted that targeting RNF123 may represent a promising therapeutic strategy for HF.

Microglial GLUL loss worsens TBI outcomes by amplifying the arginine-citrulline pathway.

Hyperacetylation escalates myocardial susceptibility to ischemia reperfusion injury by mediating mitochondrial supercomplexes assembly in T2DM.