The adiponectin-derived peptide ALY688 protects against the development of metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the severe form of non-alcoholic fatty liver disease which has a high potential to progress to cirrhosis and hepatocellular carcinoma, yet adequate effective therapies are lacking. Hypoadiponectinemia is causally involved in the pathogenesis of MASH. This study investigated the pharmacological effects of adiponectin replacement therapy with the adiponectin-derived peptide ALY688 (ALY688-SR) in a mouse model of MASH. Human induced pluripotent stem (iPS) cell-derived hepatocytes were used to test cytotoxicity and signaling of unmodified ALY688 in vitro. High-fat diet with low methionine and no added choline (CDAHF) was used to induce MASH and test the effects of ALY688-SR in vivo. Histological MASH activity score (NAS) and fibrosis score were determined to assess the effect of ALY688-SR. Transcriptional characterization of mice through RNA sequencing was performed to indicate potential molecular mechanisms involved. In cultured hepatocytes, ALY688 efficiently induced adiponectin-like signaling, including the AMP-activated protein kinase and p38 mitogen-activated protein kinase pathways, and did not elicit cytotoxicity. Administration of ALY688-SR in mice did not influence body weight but significantly ameliorated CDAHF-induced hepatic steatosis, inflammation, and fibrosis, therefore effectively preventing the development and progression of MASH. Mechanistically, ALY688-SR treatment markedly induced hepatic expression of genes involved in fatty acid oxidation, whereas it significantly suppressed the expression of pro-inflammatory and pro-fibrotic genes as demonstrated by transcriptomic analysis. ALY688-SR may represent an effective approach in MASH treatment. Its mode of action involves inhibition of hepatic steatosis, inflammation, and fibrosis, possibly via canonical adiponectin-mediated signaling.

The effects of fatty acids on psoriasis: A two-sample mendelian randomization study.

BACKGROUND: Some studies indicated an association between fatty acids (FA) and psoriasis. While definitive correlation between FA and psoriasis is still unclear. Therefore, our objective is to ascertain whether fatty acid levels are causally related to psoriasis using a Mendelian randomization approach. METHOD: We investigated the causal relationship between psoriasis and multiple types of FA by mendelian randomization. All data were acquired from Genome-Wide Association Study. We also performed additional analysis to assess the validity of the causal connection. RESULTS: Our mendelian analysis suggests that n-3 fatty acid levels are associated with a lower risk of psoriasis. [IVW, OR/95% CI: 0.998/(0.997, 0.999), p (2.479 × 10-4)] Complementary analyses returned similar results, indicating consistency in our findings. No horizontal pleiotropy was found in our analysis. There was no indication of causal effects from other varieties of FA on psoriasis. CONCLUSION: Our studies found that n-3 FA may lower the likelihood of developing psoriasis. We also need well-designed prospective studies and related large-scale, multicenter RCTs to confirm our findings.

Intradural extramedullary spinal choristoma: A case report.

RATIONALE: A choristoma is a rare and benign neoplasm characterized by the presence of normal tissue in an anomalous anatomical location. In contrast, choristoma tend to occur in other body regions rather than within the spinal canal. Before our findings, only 4 cases of intraspinal choristoma had been recorded. Because its composition is complex and very rare, routine examinations, such as magnetic resonance imaging, are difficult to diagnose, and the possibility of its occurrence is often missed in clinical diagnosis. If there is no specificity in its components, such as in this case, even pathological examinations can only confirm the diagnosis as choristoma after eliminating other possibilities. Therefore, in clinical practice, when encountering patients with intraspinal tumors, it is essential to consider the possibility of choristoma. In this case, the choristoma lack of specific constituent composition sets it apart from previously reported intraspinal choristoma, significantly raising the diagnostic challenge, which offers valuable insights for clinical diagnosis. PATIENT CONCERNS: A female patient aged 48 years was admitted to our medical center due to experiencing persistent lower back pain accompanied by radiating pain in both legs for 5 months. Based on the findings from the neurological physical examination and magnetic resonance imaging, the patient was diagnosed with an intradural space-occupying lesion located at the level of the first lumbar vertebral body. We performed an enhanced magnetic resonance neurography examination to further determine the positional relationship between the occupation and nerves in preparation for surgery. Postoperative pathological biopsy showed that the mass was an intraspinal choristoma. DIAGNOSIS: Intradural extramedullary spinal choristoma. INTERVENTION: Occupied lesion is removed surgically. OUTCOMES: After surgery, all symptoms were significantly relieved, and when the patient was discharged, all symptoms disappeared completely. There was no sign of recurrence after 1 year of follow-up. LESSONS: Intraspinal choristomas are not specific and need to be diagnosed by pathologic examination. Early detection of and intervention for intraspinal tumors can mitigate nerve dysfunction.

An Illustration of FY-3E GNOS-R for Global Soil Moisture Monitoring.

An effective soil moisture retrieval method for FY-3E (Fengyun-3E) GNOS-R (GNSS occultation sounder II-reflectometry) is developed in this paper. Here, the LAGRS model, which is totally oriented for GNOS-R, is employed to estimate vegetation and surface roughness effects on surface reflectivity. Since the LAGRS (land surface GNSS reflection simulator) model is a space-borne GNSS-R (GNSS reflectometry) simulator based on the microwave radiative transfer equation model, the method presented in this paper takes more consideration on the physical scattering properties for retrieval. Ancillary information from SMAP (soil moisture active passive) such as the vegetation water content and the roughness coefficient are investigated for the final algorithm's development. At first, the SR (surface reflectivity) data calculated from GNOS-R is calculated and then calibrated, and then the vegetation roughness factor is achieved and used to eliminate the effects on both factors. After receiving the Fresnel reflectivity, the corresponding soil moisture estimated from this method is retrieved. The results demonstrate good consistency between soil moisture derived from GNOS-R data and SMAP soil moisture, with a correlation coefficient of 0.9599 and a root mean square error of 0.0483 cm3/cm3. This method succeeds in providing soil moisture on a global scale and is based on the previously developed physical LAGRS model. In this way, the great potential of GNOS-R for soil moisture estimation is presented.

Efficacy and safety of upadacitinib for the treatment of moderate-to-severe atopic dermatitis: a systematic review and meta-analysis.

Introduction: Upadacitinib, an oral selective-JAK1 inhibitor, has been used in clinical trials to treat atopic dermatitis (AD). Aim: To evaluate the efficacy and safety of upadacitinib in moderate-to-severe AD. Material and methods: We searched clinical trials from PubMed, Embase, Cochrane Library databases, and Web of Science. All randomized controlled trials (RCTs) of upadacitinib treatment on patients with moderate-to-severe AD were included. A meta-analysis was performed using the fixed- or random-effects models to calculate pooled standard mean differences or relative risks (SMD or RR, respectively). Results: Compared with the placebo group, our meta-analysis revealed that upadacitinib was related to a significant decrease in Eczema Area and Severity Index (EASI) scores, and pruritus numeric rating scale (NRS) scores. A higher response rate in Investigator's Global Assessment (IGA) and EASI-75 were also detected in the upadacitinib group. Although patients treated with upadacitinib experienced a higher incidence of adverse events (AEs), these AEs were mild and tolerated. As for serious adverse events (SAEs), there was no difference between the placebo group and the upadacitinib group. Conclusions: This meta-analysis demonstrated that upadacitinib is a safe and effective treatment for moderate-to-severe AD. Further long-term trials are required for confirmation.

Hsa-let-7c-5p, hsa-miR-130b-3p, and hsa-miR-142-3p as Novel miRNA Biomarkers for Melanoma Progression.

This study aimed to screen miRNA biomarkers for melanoma progression. Raw melanoma data were downloaded from the Gene Expression Omnibus (GSE34460, GSE35579, GSE18509, and GSE24996) and the Cancer Genome Atlas (TCGA). Then, all differentially expressed miRNAs (DEmiRNAs) between benign vs. primary, metastatic vs. benign, and metastatic vs. primary groups were obtained in the GSE34460 and GSE35579 datasets, and the miRNAs related to disease progression were further screened. Then, the miRNA-gene network was constructed, followed by enrichment, survival, and cluster analyses. Differentially expressed genes (DEGs), tumor-infiltrating immune cells, and tumor mutation burden (TMB) between subtypes were analyzed. miRNAs were verified in the GSE18509 and GSE24996 datasets. A total of 132 and 209 DEmiRNAs were obtained in the GSE34460 and GSE35579 datasets, respectively, and 27 DEmiRNAs related to disease progression were screened. hsa-miR-106b-5p, hsa-miR-27b-3p, and hsa-miR-141-3p had a higher degree and were regulated by numerous genes in the miRNA-gene network. Moreover, four miRNAs were associated with prognosis: hsa-let-7c-5p, hsa-miR-130b-3p, hsa-miR-142-3p, and hsa-miR-509-3p. Furthermore, the bidirectional hierarchical clustering of 27 miRNAs was classified into three subtypes, and TMB and four types of immune cells, including activated dendritic cells, naïve CD4 T cells, M1 macrophages, and plasma cells, showed significant differences among the three subtypes. The expression levels of most miRNAs in the GSE18509 and GSE24996 datasets were consistent with those in the training dataset. These miRNAs, including hsa-let-7c-5p, hsa-miR-130b-3p, and hsa-miR-142-3p, and activated dendritic cells, naïve CD4 T cells, M1 macrophages, and plasma cells may play vital roles in the pathogenesis of melanoma.

Serum Thrombospondin-2 Levels Are Closely Associated With the Severity of Metabolic Syndrome and Metabolic Associated Fatty Liver Disease.

CONTEXT: Metabolic associated fatty liver disease (MAFLD) is the hepatic manifestation of obesity-related metabolic syndrome (MetS). Noninvasive biomarkers for monitoring the progression and severity of these metabolic comorbidities are needed. OBJECTIVES: To investigate the associations of serum thrombospondin-2 (TSP2) with MetS and MAFLD severity, and the potential diagnostic value of serum TSP2 for identifying at-risk metabolic associated steatohepatitis (MASH). METHODS: Blood samples, clinical data, and liver biopsies were collected from consecutively recruited 252 individuals with morbid obesity receiving bariatric surgery. Histopathology samples of liver biopsies were examined in a blinded fashion by 3 independent pathologists. Serum TSP2 levels were measured by enzyme-linked immunosorbent assay. RESULTS: Serum TSP2 levels were significantly elevated in MetS (1.58 [1.07-2.20] ng/mL) compared with non-MetS (1.28 [0.84-1.73] ng/mL; P = .006) in obese patients and positively correlated with increasing number of the MetS components, fasting glucose, glycated hemoglobin, fasting insulin, C-peptide, and homeostatic model assessment of insulin resistance after adjustment of conventional confounders. Serum TSP2 levels differentiated MASH (1.74 [1.32-3.09] ng/mL) from the other non-MASH less severe groups: normal liver (1.41 [1.04-1.63] ng/mL), simple steatosis (1.45 [0.89-1.92] ng/mL), and borderline MASH (1.30 [0.99-2.17] ng/mL) (P < .05). Elevated serum TSP2 was positively associated with the severity of hepatic steatosis, inflammation, fibrosis, and abnormal liver function independent of age, sex and adiposity. Furthermore, high serum TSP2 identified at-risk MASH with area under the operating curve of 0.84 (95% CI 0.70-0.98). CONCLUSION: Serum TSP2 is closely associated with severity and progression of MetS and MAFLD, and is a promising noninvasive biomarker for differentiating MASH from benign steatosis and identifying at-risk MASH patients among individuals with obesity.

A Forward GPS Multipath Simulator Based on the Vegetation Radiative Transfer Equation Model.

Global Navigation Satellite Systems (GNSS) have been widely used in navigation, positioning and timing. Nowadays, the multipath errors may be re-utilized for the remote sensing of geophysical parameters (soil moisture, vegetation and snow depth), i.e., GPS-Multipath Reflectometry (GPS-MR). However, bistatic scattering properties and the relation between GPS observables and geophysical parameters are not clear, e.g., vegetation. In this paper, a new element on bistatic scattering properties of vegetation is incorporated into the traditional GPS-MR model. This new element is the first-order radiative transfer equation model. The new forward GPS multipath simulator is able to explicitly link the vegetation parameters with GPS multipath observables (signal-to-noise-ratio (SNR), code pseudorange and carrier phase observables). The trunk layer and its corresponding scattering mechanisms are ignored since GPS-MR is not suitable for high forest monitoring due to the coherence of direct and reflected signals. Based on this new model, the developed simulator can present how the GPS signals (L1 and L2 carrier frequencies, C/A, P(Y) and L2C modulations) are transmitted (scattered and absorbed) through vegetation medium and received by GPS receivers. Simulation results show that the wheat will decrease the amplitudes of GPS multipath observables (SNR, phase and code), if we increase the vegetation moisture contents or the scatters sizes (stem or leaf). Although the Specular-Ground component dominates the total specular scattering, vegetation covered ground soil moisture has almost no effects on the final multipath signatures. Our simulated results are consistent with previous results for environmental parameter detections by GPS-MR.

Glucotoxicity inhibits cAMP-protein kinase A-potentiated glucose-stimulated insulin secretion in pancreatic ß-cells.

BACKGROUND: The effect of incretin is markedly blunted in patients with type 2 diabetes (T2D), and this reduced effect of incretin is correlated with a diminished insulintropic potency of glucagon-like peptide-1 (GLP-1). We reported recently that GLP-1 potentiates glucose-stimulated insulin secretion (GSIS) mainly via activation of the cAMP-protein kinase A (PKA) signaling pathway in INS-1E cells under hyperglycemic conditions. In the present study, we further explored whether glucotoxicity impairs cAMP-PKA-mediated effects and its relevance to the reduced insulinotropic action of GLP-1 in hyperglycemia. METHODS: Mouse islets and INS-1E cells were cultured in 30 mmol/L glucose for 72 h. The effects of glucotoxicity on cAMP-PKA-linked pathways and its insulinotropic action were then evaluated. RESULTS: Chronic exposure of INS-1E cells and primary mouse islets to 30 mmol/L glucose almost abolished GSIS. The cAMP-elevating agent forskolin produced an approximate 1.9-fold increase in GSIS, significantly lower than that observed with 5.5 mmol/L glucose (~3.3-fold). Moreover, 72 h culture in the presence of 30 mmol/L glucose reduced forskolin-stimulated cAMP accumulation in ß-cells. Notably, glucotoxicity reduced the expression and activity of PKA, as well as PKA-mediated effects. In contrast, glucotoxicity had no effect on the expression of Epac2, another cAMP effector. CONCLUSIONS: Glucotoxicity-induced reductions in PKA and its signaling account, at least in part, for the decreased incretin effect under conditions of glucotoxicity.

Glucagon-like peptide 1 stimulates insulin secretion via inhibiting RhoA/ROCK signaling and disassembling glucotoxicity-induced stress fibers.

Chronic hyperglycemia leads to pancreatic ß-cell dysfunction characterized by diminished glucose-stimulated insulin secretion (GSIS), but the precise cellular processes involved are largely unknown. Here we show that pancreatic ß-cells chronically exposed to a high glucose level displayed substantially increased amounts of stress fibers compared with ß-cells cultured at a low glucose level. ß-Cells at high glucose were refractory to glucose-induced actin cytoskeleton remodeling and insulin secretion. Importantly, F-actin depolymerization by either cytochalasin B or latrunculin B restored glucotoxicity-diminished GSIS. The effects of glucotoxicity on increasing stress fibers and reducing GSIS were reversed by Y-27632, a Rho-associated kinase (ROCK)-specific inhibitor, which caused actin depolymerization and enhanced GSIS. Notably, glucagon-like peptide-1-(7-36) amide (GLP-1), a peptide hormone that stimulates GSIS at both normal and hyperglycemic conditions, also reversed glucotoxicity-induced increase of stress fibers and reduction of GSIS. In addition, GLP-1 inhibited glucotoxicity-induced activation of RhoA/ROCK and thereby resulted in actin depolymerization and potentiation of GSIS. Furthermore, this effect of GLP-1 was mimicked by cAMP-increasing agents forskolin and 3-isobutyl-1-methylxanthine as well as the protein kinase A agonist 6-Bnz-cAMP-AM whereas it was abolished by the protein kinase A inhibitor Rp-Adenosine 3',5'-cyclic monophosphorothioate triethylammonium salt. To establish a clinical relevance of our findings, we examined the association of genetic variants of RhoA/ROCK with metabolic traits in homeostasis model assessment index of insulin resistance. Several single-nucleotide polymorphisms in and around RHOA were associated with elevated fasting insulin and homeostasis model assessment index of insulin resistance, suggesting a possible role in metabolic dysregulation. Collectively these findings unravel a novel mechanism whereby GLP-1 potentiates glucotoxicity-diminished GSIS by depolymerizing F-actin cytoskeleton via protein kinase A-mediated inhibition of the RhoA-ROCK signaling pathway.