Targeting EFHD2 inhibits interferon-γ signaling and ameliorates non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The precise pathomechanisms underlying the development of non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis [MASH]) remain incompletely understood. In this study, we investigated the potential role of EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, in the pathogenesis of NASH. METHODS: Hepatic EFHD2 expression was characterized in patients with NASH and two diet-induced NASH mouse models. Single-cell RNA sequencing (scRNA-seq) and double-immunohistochemistry were employed to explore EFHD2 expression patterns in NASH livers. The effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma were assessed. Molecular mechanisms underlying EFHD2 function were investigated, while chemical and genetic investigations were performed to assess its potential as a therapeutic target. RESULTS: EFHD2 expression was significantly elevated in hepatic macrophages/monocytes in both patients with NASH and mice. Deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis in NASH. Additionally, it hindered the development of NASH-related hepatocellular carcinoma. Specifically, deletion of myeloid EFHD2 prevented the replacement of TIM4+ resident Kupffer cells by infiltrated monocytes and reversed the decreases in patrolling monocytes and CD4+/CD8+ T cell ratio in NASH. Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of IFNγR2 (interferon-γ receptor-2) onto the plasma membrane. This interaction mediates interferon-γ signaling, which triggers immune and inflammatory responses in macrophages during NASH. Finally, a novel stapled α-helical peptide targeting EFHD2 was shown to be effective in protecting against NASH pathology in mice. CONCLUSION: Our study reveals a pivotal immunomodulatory and inflammatory role of EFHD2 in NASH, underscoring EFHD2 as a promising druggable target for NASH treatment. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH) represents an advanced stage of non-alcoholic fatty liver disease (NAFLD); however, not all patients with NAFLD progress to NASH. A key challenge is identifying the factors that trigger inflammation, which propels the transition from simple fatty liver to NASH. Our research pinpointed EFHD2 as a pivotal driver of NASH, orchestrating the over-activation of interferon-γ signaling within the liver during NASH progression. A stapled peptide designed to target EFHD2 exhibited therapeutic promise in NASH mice. These findings support the potential of EFHD2 as a therapeutic target in NASH.

PRL-3 and MMP9 Expression and Epithelial-Mesenchymal Transition Markers in Circulating Tumor Cells From Patients With Colorectal Cancer: Potential Value in Clinical Practice.

Objective: To evaluate the clinical correlation of epithelial-mesenchymal transition (EMT) with PRL-3 and MMP9 expression in the circulating tumor cells (CTCs) of patients with colorectal cancer (CRC). Materials and Methods: Between January 2016 and December 2018, the EMT phenotype-based subsets of CTCs and the expression levels of PRL-3 and MMP9 in CTCs were identified, and their clinical values in 172 patients were evaluated. The CTCs were isolated, classified, and counted using the CanPatrol™ CTC filtration system. The CTC subsets (epithelial cells, mesenchymal cells and biphenotypic cells), as well as PRL-3 and MMP9 expression, were detected by RNA in situ hybridization. Results: CTCs were detected in 93.0% (160/172) of the included patients with CRC. Positive PRL-3 and MMP9 expression in CTC and M-CTC was found in 75.0% (102/136) and 80.8% (97/120) of the patients, respectively. The proportion of patients with positive PRL-3 and MMP9 expression in M-CTC was significantly associated with distant metastasis (p<0.05). The patients with ≥6 CTCs tended to show poorer progression-free survival (PFS) and overall survival (OS) rates (p=0.016, 0.02, respectively), and the patients with ≥3 M-CTC also showed poor PFS (p=0.0013). Additionally, the patients with positive PRL-3 and MMP9 expression in CTCs had significantly poorer PFS (p=0.0024) and OS (p=0.095) than the patients with negative PRL-3 and MMP9 expression. Multivariate Cox analysis uncovered that positive PRL-3 and MMP9 expression in CTCs may be an independent prognostic factor for worse PFS. Conclusion: EMT phenotypes and CTC numbers can be used as prognostic indicators for metastasis and survival in patients with CRC, and the combination of PRL-3 and MMP9 expression in CTCs is a promising clinical marker for patients with CRC.

[Ultrasound and MRI features of malignant fibrous histiocytoma of soft tissue].

OBJECTIVE: To investigate ultrasound and MRI features of malignant fibrous histiocytoma (MFH) of soft tissue. METHODS: Ultrasound, MRI images and pathological data of 12 patients with malignant fibrous histiocytoma in soft tissue confirmed by operation and pathology were analyzed from January 2012 to August 2018, inlcuding 7 males and 5 females, aged from 36 to 69 years old with an average age of 53 years old; the courses of disease ranged from 4 to 49 months with an average of 28 months. Clinical manifestations were soft tissue masses and pain in the affected limbs. Ultrasound, MRI and contrast-enhanced examination were performed before operation. The lesions, morphology, echo/signal characteristics, color flow signals and enhancement features were observed and compared with pathology. RESULTS: In 12 patients with MFH, 9 patients were primary lesions and 3 patients were recurrent lesions after operation. There were 7 cases of bilateral thighs, 2 cases of calves, 1 case of upper arm, 1 case of buttocks and 1 case of posterior peritoneum. The size ranged from 5.1 to 17.1 cm with an average of 8.7 cm. Ultrasound feature showed lobulated or agglomerate, and focused on low echo; 5 cases had capsule and with clear border; 7 cases were unclear boundary with surrounding tissues; and 6 cases with irregular echo-free. The blood flow signals were around the CDFI, and the internal blood flow signals were different. MRI feature showed lobulated, agglomerate or irregular shape, T1WI showed slightly lower signal or equal signal, T2WI showed high signal and DWI signal increased. Six patients manifested mixed signal inside, 7 patients manifested low signal separation inside, 5 patients with false envelope, and 9 patients manifested infiltration and growth with peripheral edema. T1WI showed uneven strengthening after enhancement. Immunohistochemical expression of Vim, CD68 were positive. CONCLUSIONS: The age, location and imaging features of soft tissue MFH are characteristic. The diagnosis of MFH should be considered when irregular mass occurred in soft tissues of limbs at middle-aged and old people. Echo and signal are homogeneous or mixed. Separation, necrosis and cystic degeneration could be seen in the mass. When the blood flow signals are abundant and solid components are obviously enhanced, the diagnosis of MFH should be considered.

Grape seed proanthocyanidin extract alleviates high-fat diet induced testicular toxicity in rats.

The present study aimed to investigate the protective effects of grape seed proanthocyanidin extract (GSPE) on high-fat diet (HFD) induced testicular damage, oxidative stress, and apoptotic germ cell death. Male rats (n = 40) were randomly divided into four groups: the control group (treated with physiological saline), HFD group, HFD + GSPE (100 mg kg-1) group and HFD + GSPE (300 mg kg-1) group. Compared with the HFD group the rats of the GSPE-treated group showed improved serum testosterone levels, sperm quality and histological appearance of the testis tissue. Significant elevation of antioxidant enzyme (SOD, GSH, and GSH-Px) activities and remarkable reduction in MDA were also observed by GSPE administration, indicating that GSPE can decrease testicular oxidative stress. Finally, a significant reduction in spermatogenic cell apoptosis was detected by TUNEL assay. In summary, these results indicated that GSPE can suppress testicular dysfunction and this effect may be attributed to its antioxidant and anti-apoptotic properties. The current study indicates that GSPE can be considered a promising candidate for use as a drug or a food supplement to alleviate HFD-induced testicular dysfunction.

The protective effects of vitamin C on apoptosis, DNA damage and proteome of pufferfish (Takifugu obscurus) under low temperature stress.

The aim of this study was to investigate the protective effects of vitamin C on apoptosis, DNA damage and proteome of pufferfish under low temperature stress. Six diets were formulated to contain 2.60, 48.90, 95.50, 189.83, 382.40, 779.53mg/kg vitamin C. After 8-week feeding trial, fish were exposed to low temperature challenge. The results showed that pufferfish receiving vitamin C diet exhibited a significant decrease in ROS production (48.9-189.83mg/kg vitamin C diet groups), cytoplasmic free-Ca2+ concentration (48.9-779.53mg/kg vitamin C diet groups), apoptotic cell ratio (95.5-779.53mg/kg vitamin C diet groups) and DNA damage (189.83-779.53mg/kg vitamin C diet groups) under low temperature stress in comparison with those of control. We also investigated the alteration in protein expression under low temperature stress by a comparative proteomic analysis. The results demonstrated that 24 protein spots showed significantly differential expression in the cold-stress-treated group compared with those of the control group, and 5 protein spots were successfully identified. Furthermore, comparative proteomic analysis revealed that vitamin C could increase expressed proteins related to energy metabolism, immune responses and cytoskeleton. These findings would be helpful to understand the protective effects of vitamin C against cold stress.

Vascular risk factors aggravate the progression of Parkinson's disease: a five-year follow-up study in Chinese patients.

OBJECTIVE: Some studies have found that vascular risk factors were related to an increased risk of Parkinson's disease. In order to investigate the comorbidities of the vascular risk factors with PD and their impact on PD progression, we launched a five-year follow-up study in 247 outpatients with probable PD. METHODS: The incidence of vascular risk factors including hypertension, diabetes, hypercholesterolemia, hyperhomocysteinemia and carotid atherosclerotic plaque analyzed. The Hoen and Yahr score with and without vascular risk factors were compared at initial and at final evaluation. RESULTS: Multiple regression analysis showed that age, hypertension and hyperhomocysteinemia were significant variables that are associated with the Hoen and Yahr scales. Younger patients with hypertension or hyperhomocysteinemia showed a greater increasing in the Hoen and Yahr score. There were no significant correlations among the Hoen and Yahr score with sex, initial of the Hoen and Yahr score, diabetes, hypercholesterolemia or carotid atherosclerotic plaque. CONCLUSION: The vascular risk factors are common comorbidities of PD. Younger, more educated patients are more likely to have quicker dyskinesia decline. In addition, hypertension and hyperhomocysteinemia may aggravate the progression of PD. The prevention and treatment of hypertension and hyperhomocysteinemia are important for PD patients.

Determination of dobutamine hydrochloride by enzymatic catalytic spectrofluorimetry.

A highly sensitive and simple spectrofluorimetric method for the determination of dobutamine hydrochloride based on its inhibitory effect on the hemoglobin-catalyzed reaction of H2 O2 and l-tyrosine was developed. The relationship between the concentration of dobutamine hydrochloride and the fluorescence quenching (ΔF) of the system is linear under the optimal experimental conditions. The calibration graph is linear in the range 2.00 × 10(-7) to 3.00 × 10(-6) g/mL with a limit of detection of 4.83 × 10(-9) g/mL. This method can be used for the determination of dobutamine hydrochloride in its pharmaceutical formulations and in urine with satisfactory results.

The importance of the solids loading on confirming the dielectric nanosize dependence of BaTiO3 powders by slurry method.

The dielectric nanosize dependence of BaTiO3 powders was investigated by the slurry method, where two series of BaTiO3 slurries with 10 vol% and 30 vol% solids loadings were prepared as model samples. Applying the Bruggeman-Hanai equation, the high-frequency limiting permittivity (ε(h)) of the slurries was extracted from the dielectric spectra. The ε(h) of the 10 vol% slurry showed abnormal size independence in the range from 100 nm to 700 nm, and the ε(h) of the 30 vol% slurry exhibited good agreement with the previous prediction. Through analysing quantitatively the response of ε(h) to the changing permittivity of the powders under different solids loading, it was found that the ε h of the slurry with lower solids loading is more inclined to be interfered by the systematic and random errors. Furthermore, a high permittivity value was found in the BaTiO3 powders with 50 nm particle size.