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Huntington's disease (HD) is associated with dysregulated choline metabolism, but the underlying mechanisms remain unclear. This study investigated the expression of key enzymes in this pathway in R6/2 HD mice and human HD postmortem brain tissues. We further explored the therapeutic potential of modulating choline metabolism for HD. Both R6/2 mice and HD patients exhibited reduced expression of glycerophosphocholine phosphodiesterase 1 (GPCPD1), a key enzyme in choline metabolism, in the striatum and cortex. The striatum of R6/2 mice also showed decreased choline and phosphorylcholine, and increased glycerophosphocholine, suggesting disruption in choline metabolism due to GPCPD1 deficiency. Treatment with citicoline significantly improved motor performance, upregulated anti‐apoptotic Bcl2 expression, and reduced oxidative stress marker malondialdehyde in both brain regions. Metabolomic analysis revealed partial restoration of disrupted metabolic patterns in the striatum and cortex following citicoline treatment. These findings strongly suggest the role of GPCPD1 deficiency in choline metabolism dysregulation in HD. The therapeutic potential of citicoline in R6/2 mice highlights the choline metabolic pathway as a promising target for future HD therapies. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is characterized by progressive involuntary chorea movements and cognitive decline. Recent research indicates that metabolic disturbance may play a role in its pathogenesis. Bile acids, produced during cholesterol metabolism in the liver, have been linked to neurodegenerative conditions. This study investigated variations in plasma bile acid profiles among individuals with HD. Plasma levels of 16 primary and secondary bile acids and their conjugates were analyzed in 20 healthy controls and 33 HD patients, including 24 with symptoms (symHD) and 9 carriers in the presymptomatic stage (preHD). HD patients exhibited significantly higher levels of glycochenodeoxycholic acid (GCDCA) and glycoursodeoxycholic acid (GUDCA) compared to healthy controls. Conversely, isolithocholic acid levels were notably lower in the HD group. Neurotoxic bile acids (glycocholic acid (GCA) + glycodeoxycholic acid (GDCA) + GCDCA) were elevated in symHD patients, while levels of neuroprotective bile acids (ursodeoxycholic acid (UDCA) + GUDCA + tauroursodeoxycholic acid (TUDCA)) were higher in preHD carriers, indicating a compensatory response to early neuronal damage. These results underscore the importance of changes in plasma bile acid profiles in HD and their potential involvement in disease mechanisms. The identified bile acids (GCDCA, GUDCA, and isolithocholic acid) could potentially serve as markers to distinguish between HD stages and healthy individuals. Nonetheless, further research is warranted to fully understand the clinical implications of these findings and their potential as diagnostic or therapeutic tools for HD. [ABSTRACT FROM AUTHOR]

1,8‐Diazabicyclo[5.4.0]undec‐7‐ene (DBU) catalyzed Michael addition reactions between α,β‐unsaturated esters and benzophenone‐imines of glycine esters have been realized in THF at room temperature by using LiBr as an additive, effectively enabling the glutamation of phenols, thiophenols, secondary amines and imides. 3‐Substituted glutamic acid esters were obtained in excellent yields and diastereoselectivities (up to quantitative yield and >20 : 1 dr). These glutamic acid esters were readily converted into their corresponding pyroglutamic acid esters in high yields through acidic hydrolysis followed by lactamization. [ABSTRACT FROM AUTHOR]

The coming of the hyper-aged society in Taiwan prompts us to investigate the relationship between the metabolic status of sarcopenic patients and their most adverse outcome–death. We studied the association between any plasma metabolites and the risk for mortality among older Taiwanese sarcopenic patients. We applied a targeted metabolomic approach to study the plasma metabolites of adults aged ≥65 years, and identified the metabolic signature predictive of the mortality of sarcopenic patients who died within a 5.5-year follow-up period. Thirty-five sarcopenic patients who died within the follow-up period (Dead cohort) had shown a specific plasma metabolic signature, as compared with 54 patients who were alive (Alive cohort). Only 10 of 116 non-sarcopenic individuals died during the same period. After multivariable adjustment, we found that sex, hypertension, tetradecanoyl-carnitine (C14-carnitine), and docosahexaenoic acid (DHA)-containing phosphatidylcholine diacyl (PCaa) C38:6 and C40:6 were important risk factors for the mortality of sarcopenic patients. Low PCaa C38:6 levels and high C14-carnitine levels correlated with an increased mortality risk; this was even the same for those patients with hypertension (HTN). Our findings suggest that plasma PCaa C38:6 and acylcarnitine C14-carnitine, when combined, can be a better early biomarker for evaluating the mortality risk of sarcopenia patients. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) hijacks autophagy for its replication. Nucleos(t)ide analogs (NUCs) treatment suppressed HBV replication and reduced hepatocellular carcinoma (HCC) incidence. However, the use of NUCs in chronic hepatitis B (CHB) patients with normal or minimally elevated serum alanine aminotransferase (ALT) levels is still debated. Animal models are crucial for studying the unanswered issue and evaluating new therapies. MicroRNA‐122 (miR‐122), which regulates fatty acid and cholesterol metabolism, is downregulated during hepatitis and HCC progression. The reciprocal inhibition of miR‐122 with HBV highlights its role in HCC development as a tumor suppressor. By crossbreeding HBV‐transgenic mice with miR‐122 knockout mice, we generated a hybrid mouse model with a high incidence of HCC up to 89% and normal ALT levels before HCC. The model exhibited early‐onset hepatic steatosis, progressive liver fibrosis, and impaired late‐phase autophagy. Metabolomics and microarray analysis identified metabolic signatures, including dysregulation of lipid metabolism, inflammation, genomic instability, the Warburg effect, reduced TCA cycle flux, energy deficiency, and impaired free radical scavenging. Antiviral treatment reduced HCC incidence in hybrid mice by approximately 30–35% compared to untreated mice. This effect was linked to the activation of ER stress‐responsive transcription factor ATF4, clearance of autophagosome cargo p62, and suppression of the CHOP‐mediated apoptosis pathway. In summary, this study suggests that despite minimal ALT elevation, HBV replication can lead to liver injury. Endoplasmic reticulum stress, reduced miR‐122 levels, mitochondrial and metabolic dysfunctions, blocking protective autophagy resulting in p62 accumulation, apoptosis, fibrosis, and HCC. Antiviral may improve the above‐mentioned pathogenesis through HBV suppression. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES The aim of this study was to evaluate the performance of consolidation-to-tumour ratio (CTR) and the radiomic models in two- and three-dimensional modalities for assessing radiological invasiveness in early-stage lung adenocarcinoma. METHODS A retrospective analysis was conducted on patients with early-stage lung adenocarcinoma from Guangdong Provincial People's Hospital and Shenzhen People's Hospital. Manual delineation of pulmonary nodules along the boundary was performed on cross-sectional images to extract radiomic features. Clinicopathological characteristics and radiomic signatures were identified in both cohorts. CTR and radiomic score for every patient were calculated. The performance of CTR and radiomic models were tested and validated in the respective cohorts. RESULTS A total of 818 patients from Guangdong Provincial People's Hospital were included in the primary cohort, while 474 patients from Shenzhen People's Hospital constituted an independent validation cohort. Both CTR and radiomic score were identified as independent factors for predicting pathological invasiveness. CTR in two- and three-dimensional modalities exhibited comparable results with areas under the receiver operating characteristic curves and were demonstrated in the validation cohort (area under the curve: 0.807 vs 0.826, P  =   0.059) Furthermore, both CTR in two- and three-dimensional modalities was able to stratify patients with significant relapse-free survival (P  <   0.000 vs P  <   0.000) and overall survival (P  =   0.003 vs P  =   0.001). The radiomic models in two- and three-dimensional modalities demonstrated favourable discrimination and calibration in independent cohorts (P  =   0.189). CONCLUSIONS Three-dimensional measurement provides no additional clinical benefit compared to two-dimensional. [ABSTRACT FROM AUTHOR]

The incidence of heart failure (HF) is increasing and is associated with a poor prognosis. Moreover, HF often coexists with renal dysfunction and is associated with a worsened outcome. In many experimental studies on cardiac dysfunction, the function of other organs was either not addressed or did not show any decline. Until now, the exact mechanisms for initiating and sustaining this interaction are still unknown. The objective of this study is to use volume overload to induce cardiac hypertrophy and HF in aortocaval fistula (ACF) rat models, and to elucidate how volume overload affects metabolic changes in the kidney, even with normal renal function, in HF. The results showed the metabolic changes between control and ACF rats, including taurine metabolism; purine metabolism; glycine, serine, and threonine metabolism; glycerophospholipid metabolism; and histidine metabolism. Increasing the downstream purine metabolism from inosine to uric acid in the kidneys of ACF rats induced oxidative stress through xanthine oxidase. This result was consistent with HK-2 cells treated with xanthine and xanthine oxidase. Under oxidative stress, taurine accumulation was observed in ACF rats, indicating increased activity of the hypotaurine–taurine pathway as a defense mechanism against oxidative stress in the kidney. Another antioxidant, ascorbic acid 2-sulfate, showed lower levels in ACF rats, indicating that the kidneys experience elevated oxidative stress due to volume overload and HF. In summary, metabolic profiles are more sensitive than clinical parameters in reacting to damage to the kidney in HF. [ABSTRACT FROM AUTHOR]

DBU-catalyzed Michael reactions between tert-butyl 2-((diphenylmethylene) amino)acetate and simple β-substituted α,β-unsaturated esters have been achieved in high yields (up to 95% yield) and diastereoselectivties (up to 99:1 dr) in the presence of 1.0 eq. of LiBr in acetonitrile under room temperature. The Michael adduct can be easily converted into trans-3-substituted pyroglutamic acid ester through in-situ acidic hydrolysis following lactamation. [ABSTRACT FROM AUTHOR]