Naringenin protects against septic cardiomyopathy in mice by targeting HIF-1α.

Myocardial dysfunction is a prevalent complication of sepsis (septic cardiomyopathy) with a high mortality rate and limited therapeutic options. Naringenin, a natural flavonoid compound with anti-inflammatory and antioxidant properties, holds promise as a potential treatment for sepsis-induced myocardial dysfunction. This study investigated the pharmacological effects of naringenin on septic cardiomyopathy. In vivo and in vitro experiments demonstrated that naringenin improved cardiomyocyte damage. Network pharmacology and database analysis revealed that HIF-1α is a key target protein of naringenin. Elevated expression of HIF-1α was observed in damaged cardiomyocytes, and the HIF-1α inhibitor effectively protected against LPS-induced cardiomyocyte damage. Molecular docking studies confirmed the direct binding between naringenin and HIF-1α protein. Importantly, our findings demonstrated that naringenin did not provide additional attenuation of cardiomyocyte injury on the biases of HIF-1α inhibitor treatment. In conclusion, this study proves that naringenin protects against septic cardiomyopathy through HIF-1α signaling. Naringenin is a promising therapeutic candidate for treating septic cardiomyopathy.

Quercetin and Kaempferol inhibit HMC-1 activation via SOCE/NFATc2 signaling and suppress hippocampal mast cell activation in lipopolysaccharide-induced depressive mice.

OBJECTIVE AND DESIGN: Mast cells (MCs), as the fastest immune responders, play a critical role in the progression of neuroinflammation-related diseases, especially in depression. Quercetin (Que) and kaempferol (Kae), as two major diet-derived flavonoids, inhibit MC activation and exhibit significant antidepressant effect due to their anti-inflammatory capacity. The study aimed to explore the mechanisms of inhibitory effect of Que and Kae on MC activation, and whether Que and Kae suppress hippocampal mast cell activation in LPS-induced depressive mice. SUBJECTS AND TREATMENT: In vitro assays, human mast cells (HMC-1) were pretreated with Que or Kae for 1 h, then stimulated by phorbol 12-myristate 13-acetate (PMA) and 2,5-di-t-butyl-1,4-benzohydroquinone (tBHQ) for 3 h or 12 h. In vivo assays, Que or Kae was administered by oral gavage once daily for 14 days and then lipopolysaccharide (LPS) intraperitoneally injection to induce depressive behaviors. METHODS: The secretion and expression of TNF-α were determined by ELISA and Western blotting. The nuclear factor of activated T cells (NFAT) transcriptional activity was measured in HMC-1 stably expressing NFAT luciferase reporter gene. Nuclear translocation of NFATc2 was detected by nuclear protein extraction and also was fluorescently detected in HMC-1 stably expressing eGFP-NFATc2. We used Ca2+ imaging to evaluate changes of store-operated calcium entry (SOCE) in HMC-1 stably expressing fluorescent Ca2+ indicator jGCamP7s. Molecular docking was used to assess interaction between the Que or Kae and calcium release-activated calcium modulator (ORAI). The  hippocampal mast cell accumulation and activation  were detected by toluidine blue staining and immunohistochemistry with ß-tryptase. RESULTS: In vitro assays of HMC-1 activated by PtBHQ (PMA and tBHQ), Que and Kae significantly decreased expression and secretion of TNF-α. Moreover, NFAT transcriptional activity and nuclear translocation of NFATc2 were remarkably inhibited by Que and Kae. In addition, the Ca2+ influx mediated by SOCE was suppressed by Que, Kae and the YM58483 (ORAI inhibitor), respectively. Importantly, the combination of YM58483 with Que or Kae had no additive effect on the inhibition of SOCE. The molecular docking also showed that Que and Kae both exhibit high binding affinities with ORAI at the same binding site as YM58483. In vivo assays, Que and Kae significantly reversed LPS-induced depression-like behaviors in mice, and inhibited hippocampal mast cell activation  in LPS-induced depressive mice. CONCLUSIONS: Our results indicated that suppression of SOCE/NFATc2 pathway-mediated by ORAI channels may be the mechanism of inhibitory effect of Que and Kae on MC activation, and also suggested Que and Kae may exert the antidepressant effect through suppressing hippocampal mast cell activation.

Real-world experience with Deutetrabenazine management in patients with Huntington's disease using video-based telemedicine.

BACKGROUND: Huntington's disease (HD) is a rare progressive neurological disorder, and telemedicine has the potential to improve the quality of care for patients with HD. Deutetrabenazine (DTBZ) can reduce chorea symptoms in HD; however, there is limited experience with this medication in Asian countries. METHODS: Retrospective and prospective studies were employed to explore the feasibility and reliability of a video-based telemedicine system for HD patient care. Reliability was demonstrated through consistency between selected-item scores (SIS) and total motor scores (TMS) and the agreement of scores obtained from hospital and home videos. Finally, a single-centre real-world DTBZ management study was conducted based on the telemedicine system to explore the efficacy of DTBZ in patients with HD. RESULTS: There were 77 patients included in the retrospective study, and a strong correlation was found between SIS and TMS (r = 0.911, P < 0.0001), indicating good representativeness. There were 32 patients enrolled in the prospective study. The reliability was further confirmed, indicated by correlations between SIS and TMS (r = 0.964, P < 0.0001) and consistency of SIS derived from the in-person and virtual visits (r = 0.969, P < 0.0001). There were 17 patients included in the DTBZ study with a mean 1.41 (95% confidence interval, 0.37-2.46) improvement in chorea score and reported treatment success. CONCLUSIONS: A video-based telemedicine system is a feasible and reliable option for HD patient care. It may also be used for drug management as a supplementary tool for clinical visits.

Analysis of pollutant dispersion patterns in rivers under different rainfall based on an integrated water-land model.

In the context of rapid urban expansion, the interaction between humanity and nature has become more prominent. Urban land and rivers often exist as distinct entities with limited material exchange. However, during rainfall, these two systems interconnect, resulting in the transfer of land-derived pollutants into rivers. Such transfer significantly increases river pollutant levels, adversely affecting water quality. Therefore, developing a water quality simulation and prediction model is crucial. This model should effectively illustrate pollutant movement and dispersion during rain events. This study proposes a comprehensive model that merges the Storm Water Management Model (SWMM) with the Environmental Fluid Dynamics Code (EFDC). This integrated model assesses the spread and dispersion of pollutants, including Ammonia Nitrogen (NH3-N), Total Phosphorus (TP), Total Nitrogen (TN), and Chemical Oxygen Demand (COD), within urban water cycles for various rainfall conditions, thus offering critical theoretical support for managing the water environment. The application of this model under different rainfall intensities (light, moderate and heavy) provides vital insights. During light rainfall, the river's natural purification process can sustain surface water quality at Class IV. Moderate rainfall causes accumulation of pollutants, reducing water quality to Class V. Conversely, heavy rainfall rapidly increases pollutant concentrations due to higher inflow, pushing the river to a degraded Class V status, which is beyond its natural purification capacity, necessitating engineering solutions to reattain Class IV quality. Furthermore, pollutant accumulation in downstream river sections is more influenced by flow rate than by rainfall intensity. In summary, the SWMM-EFDC integrated model proves highly effective in predicting river water quality, thereby significantly aiding urban water pollution control.

KCOSS: an ultra-fast k-mer counter for assembled genome analysis.

MOTIVATION: The k-mer frequency in whole genome sequences provides researchers with an insightful perspective on genomic complexity, comparative genomics, metagenomics and phylogeny. The current k-mer counting tools are typically slow, and they require large memory and hard disk for assembled genome analysis. RESULTS: We propose a novel and ultra-fast k-mer counting algorithm, KCOSS, to fulfill k-mer counting mainly for assembled genomes with segmented Bloom filter, lock-free queue, lock-free thread pool and cuckoo hash table. We optimize running time and memory consumption by recycling memory blocks, merging multiple consecutive first-occurrence k-mers into C-read, and writing a set of C-reads to disk asynchronously. KCOSS was comparatively tested with Jellyfish2, CHTKC and KMC3 on seven assembled genomes and three sequencing datasets in running time, memory consumption, and hard disk occupation. The experimental results show that KCOSS counts k-mer with less memory and disk while having a shorter running time on assembled genomes. KCOSS can be used to calculate the k-mer frequency not only for assembled genomes but also for sequencing data. AVAILABILITYAND IMPLEMENTATION: The KCOSS software is implemented in C++. It is freely available on GitHub: https://github.com/kcoss-2021/KCOSS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Integrated analysis of FKBP1A/SLC3A2 axis in everolimus inducing ferroptosis of breast cancer and anti-proliferation of T lymphocyte.

Background: Solute Carrier Family 3 Member 2 (SLC3A2) is a member of the solute carrier family that plays pivotal roles in regulation of intracellular calcium levels and transports L-type amino acids. However, there are insufficient scientific researches on the prognostic and immunological roles of SLC3A2 in breast cancer (BC) and whether everolimus regulates novel SLC3A2 related molecular mechanism in the immuno-oncology context of the tumor microenvironment (TME), therefore, we see a necessity to conduct the current in silico and biological experimental study. Methods: Using diverse online databases, we investigated the role of SLC3A2 in therapy response, clinicopathological characteristics, tumor immune infiltration, genetic alteration, methylation and single cell sequencing in BC. WB, Co-IP, cell proliferation assay, Edu staining, ROS and GSH assay and in vivo tumor xenograft assays were performed to verify FKBP1A/SLC3A2 axis in everolimus inducing ferroptosis of breast cancer. Co-cultures and IL-9 ELISA were performed to demonstrate the T lymphocyte function. Results: We demonstrated that SLC3A2 was aberrantly expressed among various BC cohorts. Our results also suggested that SLC3A2 expression was associated with chemotherapeutic outcome in BC patients. Our results further indicated that SLC3A2 was associated with tumor infiltration of cytotoxic T cell but not other immune cells among BC TME. The alterations in SLC3A2 gene had a significant correlation to relapse free survival and contributed a significant impact on BC tumor mutational burden. Finally, SLC3A2 was illustrated to be expressed in diverse BC cellular populations at single cell level, and negatively linked to angiogenesis, inflammation and quiescence, but positively correlated with other functional phenotypes. Noteworthily, everolimus (a targeted therapy drug for BC) related protein, FK506-binding protein 1A (FKBP1A) was found to bind with SLC3A2, and negatively regulated SLC3A2 expression during the processes of everolimus inducing ferroptosis of BC cells and promoting anti-proliferation of Th9 lymphocytes. Conclusions: Altogether, our study strongly implies that SLC3A2 is an immuno-oncogenic factor and FKBP1A/SLC3A2 axis would provide insights for a novel immunotherapy approach for the treatment of BC in the context of TME.

[Plasma components of Danzhi Xiaoyao Formula and its mechanism of action in treating perimenopausal depression based on UPLC-Q-TOF-MS~E integrated with network pharmacology].

In this study, ultra-performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS~E) was used to analyze the plasma components of Danzhi Xiaoyao Formula after oral administration. Forty-nine plasma components were found in the serum of rats by comparing the compound extract, drug-containing serum, and blank serum. Components, such as 6-hydroxycoumarin, poricoic acid F, deoxoglabrolide, 30-norhederagenin, kanzonol R, 3',6'-di-O-galloylpaeoniflorin, 16α-hydroxytrametenolic acid, 16-deoxyporicoic acid B, 3-O-acetyl-16α-hydroxytrametenolic acid, and 16α,25-dihydroxydehydroeburiconic acid, were first found in rat serum. Behavioral tests, including the tail suspension test, novel object recognition test, and novelty-suppressed feeding test, were conducted for behavioral analysis. It was confirmed that this formula had therapeutic effects on perimenopausal depression. Furthermore, in combination with the network pharmacology method, 53 core targets including MAPK1, HRAS, AKT1, EGFR, and ESR1 were screened, and these targets participated in 165 signaling pathways, including PI3K-AKT, AMPK, VEGFA, MAPK, and HIF-1. In summary, the potential effects of Danzhi Xiaoyao Formula in treating perimenopausal depression are associated with mechanisms in accelerating inflammation repair, improving neuroplasticity, affecting neurotransmitters, regulating estrogen levels, and promoting new blood vessel formation.

Ratiometric fluorescence sensor for sensitive detection of inorganic phosphate in environmental samples.

Fast, simple, and low-cost on-site visualized detection of inorganic phosphate (Pi) is in great demand since phosphate is the major reason of eutrophication. In this work, a ratiometric fluorescent probe composed by green carbon dots (GCDs) and red carbon dots (RCDs) has been established for high-sensitivity and selective sensing of Pi. A trend of color change from red to green is observed for the detection of Pi under ultraviolet light and the detection limit is 0.09 µM in the range of 0 to 55 µM. Fluorescent test paper prepared from the probe solution was successfully applied to semi-quantitative visual detection of Pi in real-world water and soil samples, which shows great real-world application potentials.

A Research on the Sharing Platform of Wild Bird Data in Yunnan Province Based on Blockchain and Interstellar File System.

Sharing scientific data is an effective means to rationally exploit scientific data and is vital to promote the development of the industrial chain and improve the level of science and technology. In recent years, the popularity of the open data platform has increased, but problems remain, including imperfect system architecture, unsound privacy and security, and non-standardized interaction data. To address these problems, the blockchain's decentralization, smart contracts, distributed storage, and other features can be used as the core technology for open data systems. This paper addresses the problems of opening, allocation-right confirmation, sharing, and rational use of wild-bird data from Yunnan Province, China. A data storage model is proposed based on the blockchain and interstellar file system and is applied to wild-bird data to overcome the mutual distrust between ornithology institutions in the collaborative processing and data storage of bird data. The model provides secure storage and secure access control of bird data in the cloud, thereby ensuring the decentralized and secure storage of wild-bird data for multiple research institutions.

Analysis of the influence of vibrations on the imaging quality of an integrated TDICCD aerial camera.

Taking the area CCD optical system as a whole, the analysis methods of the influence of vibrations on its imaging quality have been relatively mature. However, external vibrations will cause different vibrations of optical components inside the opto-mechanical structure. The existing methods are not suitable for analyzing optical components with different vibrations and TDICCD imaging. This paper studies the influence of vibrations on the imaging quality of the integrated TDICCD aerial camera. The relationship between the vibration responses of structures and the imaging quality is established by mathematical models. First, a vibration beam trajectory model of the integrated TDICCD aerial camera is established for the first time using geometric optics and ray tracing. The deviations of the optical axis caused by vibrations in the object plane can be obtained. Then, this paper establishes a TDICCD vibration modulation transfer function model based on statistical moments. The vibration MTF of pixels of each column in the complex two-dimensional moving image captured by the TDICCD can be obtained through this model. Furthermore, a simulation imaging model of the integrated TDICCD aerial camera is established. The influence of vibrations on the imaging quality can be directly obtained through images. Finally, the accuracy of the models established in this paper is verified by multiple tests. The results show that the imaging quality of the integrated TDICCD aerial camera decreases rapidly with the increase of the acceleration excitation.

Application of Mobile Stroke Unit in Prehospital Thrombolysis of Acute Stroke: Experience from China.

BACKGROUND AND PURPOSE: Most patients cannot receive intravenous thrombolytic therapy in the early stage of stroke onset, and the application of mobile stroke unit (MSU) in prehospital intravenous thrombolytic therapy of acute stroke may change this situation. The first MSU in China was put into use in 2017. Herein, we aimed to explore the preliminary experience of MSU in prehospital thrombolysis of acute stroke. METHODS: Patients who received prehospital intravenous thrombolytic therapy using MSU were classified to the MSU thrombolysis group, and the control group consisted of stroke patients admitted by regular ambulances, who were transferred to hospital for intravenous thrombolytic therapy. The feasibility, safety, and duration of procedures were compared. RESULTS: There were 14 patients received prehospital intravenous thrombolysis on the MSU, and 24 patients underwent intravenous thrombolysis in the emergency center, who were transferred by the ordinary ambulance during the same period. The median call-to-needle time was 59.5 min in the MSU thrombolysis group, while it was 89 min in the control group; the difference between the 2 groups was statistically significant (p = 0.001). The median time from onset to thrombolysis was 70 and 102.5 min, respectively, in the 2 groups (p = 0.002). The percentages of good clinical outcome (modified Rankin Scale score ≤ 2) at 90-day follow-up were 79 and 67%, respectively (p = 0.488). The rate of symptomatic intracranial hemorrhage and mortality during the perioperative period did not differ significantly between 2 groups. CONCLUSION: Despite the small sample size, our preliminary experience of the application of MSU in the prehospital thrombosis therapy seems to indicate a significant reduction in time from call to needle, the efficacy of MSU in the treatment of acute stroke needs further experiment and larger sample size to confirm.

Two-dimensional vibration actuated polishing of small surfaces by generating random-like Lissajous trajectories.

Small-surface optical components with complex shapes and high-precision requirements are increasingly needed in the fields of mobile communications, in vivo diagnosis, and other fields. Some scholars have studied and proposed a two-dimensional vibration actuated polishing (2D-VAP) method based on small polishing tools for the preparation of small-surface optical elements. Using the nonresonant 2D-VAP device developed by the author, the frequency and amplitude of 2D-VAP are precisely adjusted to generate a random-like Lissajous polishing trajectory, which can overcome the problem that most of the existing 2D-VAP methods generate a circular or elliptical polishing trajectory at the small polishing tool, resulting in leaving periodic polishing marks on the workpiece surface. The removal function model under the condition of random-like Lissajous polishing motion with a small polishing tool is established. In addition, the removal function verification experiments and surface polishing experiments are carried out. The experimental results show that the measured removal function is in good agreement with that obtained by numerical simulation. Compared with the circular polishing trajectory, the random-like Lissajous polishing trajectory can significantly improve the material removal rate, and there are no obvious periodic polishing marks on the workpiece surface.

Quasi-Heteroface Perovskite Solar Cells.

Perovskite solar cells (PSCs) have attracted unprecedented attention due to their rapidly rising photoelectric conversion efficiency (PCE). In order to further improve the PCE of PSCs, new possible optimization path needs to be found. Here, quasi-heteroface PSCs (QHF-PSCs) is designed by a double-layer perovskite film. Such brand new PSCs have good carrier separation capabilities, effectively suppress the nonradiative recombination of the PSCs, and thus greatly improve the open-circuit voltage and PCE. The root cause of the performance improvement is the benefit from the additional built-in electric field, which is confirmed by measuring the external quantum efficiency under applied electric field and Kelvin probe force microscope. Meanwhile, an intermediate band gap perovskite layer can be obtained simply by combining a wide band gap perovskite layer with a narrow band gap perovskite layer. Tunability of the band gap is obtained by varying the film thicknesses of the narrow and wide band gap layers. This phenomenon is quite different from traditional inorganic solar cells, whose band gap is determined only by the narrowest band gap layer. It is believed that these QHF-PSCs will be an effective strategy to further enhance PCE in PSCs and provide basis to further understand and develop the perovskite materials platform.

Development of a sensitive and specific nanoparticle-assisted PCR assay for detecting HPV-16 and HPV-18 DNA.

Carcinoma precursor lesion caused by persistent infection of human papillomavirus (HPV) types 16 and 18 is known as a principal inducer of cervical cancer. Therefore, rapid and effective detection of HPV-16 and HPV-18 infection at early stage is an important strategy for preventing such disease. In this study, a novel duplex nanoparticle-assisted polymerase chain reaction (nanoPCR) assay was developed to detect both of the two genotypes simultaneously. Two pairs of primers for nanoPCR were designed based on the conserved region within the early 6 (E6) gene of HPV-16 and HPV-18, respectively. After optimizing reaction conditions, the nanoPCR assay displayed 10-fold more sensitive than that of conventional PCR and showed high specificity. The detection limit of nanoPCR was 1.7 × 101 copies/µL for HPV-16, 1.2 × 102 copies/µL for HPV-18, and no cross-reaction was detected after using other viruses or HPV subtypes as templates. Of 209 clinical samples collected from patients, as also confirmed by sequencing, the nanoPCR method gave consistent results with conventional PCR assay: 7 positives for HPV-16, 4 positives for HPV-18, and no co-infection. Here is the first report to introduce a reproducible nanoPCR assay for detecting HPV DNA with high sensitivity and specificity, which may point out a useful diagnostic tool for potential clinical application.

Astrocyte-derived exosomes suppress autophagy and ameliorate neuronal damage in experimental ischemic stroke.

The aim of this study was to investigate the role of astrocyte-derived exosomes (AS-Exo) on neuronal damage in ischemic stroke. We isolated astrocytes from 3- to 4-day-old C57BL/6 mice and astrocytes were identified by GFAP immunostaining. Exosomes were obtained from astrocyte supernatant by overspeed centrifugation. For investigating the effect of AS-Exo on the apoptosis of neurons after oxygen and glucose deprivation (OGD), the exosome labeling and uptake by neurons were observed by confocal laser microscopy, then HT-22 cell vitality and apoptosis were determined by Cell Counting Kit-8 (CCK-8) assay and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, respectively. Tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) in OGD-induced HT-22 was analyzed by Enzyme-linked immunosorbent assay (ELISA). Apoptosis-related protein in HT-22 was analyzed by Western blot. For investigating the effect of AS-Exo on the OGD neurons autophagy, expression of Beclin-1, LC3-I, LC3-II and P62 in OGD-induced HT-22 was analyzed by Western blot. For animal experiments, C57BL/6 mice (6-8 weeks old) models of middle cerebral artery occlusion were used to create permanent focal ischemia. AS-Exo were injected intravenously through the tail vein into ischemic mice at a concentration of 80 µg per 2 ml after 60 min of the ligation operation The results showed that AS-Exo enhanced neurons viability; inhibited OGD-induced apoptosis, inhibited OGD-induced expressions of caspase-3 and Bax and levels of TNF-α, IL-6 and IL-1ß in HT-22 cells. Further findings showed AS-Exo inhibited OGD-induced neurons apoptosis via regulating autophagy. AS-Exo ameliorated neuronal damage through regulating autophagy in vivo. Our data indicate that AS-Exo suppress autophagy and ameliorate neuronal damage in experimental ischemic stroke.

Berberine attenuates fructose-induced insulin resistance by stimulating the hepatic LKB1/AMPK/PGC1α pathway in mice.

Context: Berberine is an alkaloid that possesses various pharmacologic effects.Objective: To explore the mechanism of berberine to improve insulin sensitivity in fructose-fed mice.Materials and methods: Sixty male ICR mice were randomly divided into 6 groups (10 mice in each group): control, fructose, pioglitazone (10 mg/kg) and berberine (50, 100, and 200 mg/kg). Except for the control group, the mice received 20% fructose drinking for 10 weeks. Pioglitazone and berberine were orally administered once daily during the last 4 weeks. The insulin sensitivity was evaluated using an oral glucose tolerance test (OGTT). The serum levels of fasting glucose and insulin, blood lipids, and hormones were determined. The hepatic AMP and ATP contents were detected using high performance liquid chromatography (HPLC) analysis, and the protein expression was examined by immunoblotting.Results: Berberine significantly reversed the insulin resistance induced by fructose, including lowering fasting insulin levels (from 113.9 to 67.4) and area under the curve (AUC) during OGTT (from 1310 to 1073), decreasing serum leptin (from 0.28 to 0.13) and increasing serum adiponectin levels (from 1.50 to 2.80). Moreover, berberine enhanced the phosphorylation levels of protein kinase B (PKB/AKT; 2.27-fold) and glycogen synthase kinase-3ß (GSK3ß; 2.56-fold), and increased hepatic glycogen content (from 0.19 to 1.65). Furthermore, berberine upregulated the protein expression of peroxisome proliferator activated receptor gamma coactivator 1α (PGC1α; 2.61-fold), phospho-AMP-activated protein kinase (p-AMPK; 1.35-fold) and phospho-liver kinase B1 (p-LKB1; 1.41-fold), whereas it decreased the AMP/ATP ratio (from 4.25 to 1.82).Conclusion: The present study demonstrated the protective effects of berberine against insulin resistance induced by fructose. Our findings may provide an experimental basis for the application of berberine in the treatment of insulin resistance.

Effects of Portulaca Oleracea Extract on Acute Alcoholic Liver Injury of Rats.

The present study was envisaged to investigate the chemical constituents and the intervention effects of Portulaca oleracea extract (POE) on acute alcoholic liver injury of rats. The chemical composition of POE was detected by high performance liquid chromatography (HPLC). Sixty male Wistar rats were divided into 6 groups: Normal control (NC) group, acute alcoholic liver injury model group (ALI), low, medium and high dose of POE (25, 50, 100 mg/kg) groups and bifendate (BF, 3.75 mg/kg) group. Each group was given by intragastrical administration for 7 days. Alcoholic liver injury was induced in the experimental model by administering 50% ethanol at 8 mL/kg and repeated administration after 6 h, for a period of 7 days. The results showed that pretreatment with POE significantly reduced the ethanol-elevated serum level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and triglyceride (TG). The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) in liver were enhanced followed by administration of POE, while the content of nitric oxide (NO) and malondialdehyde (MDA) was found to decrease. Hepatic content of tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) was also reduced by POE treatment. These results indicated that POE could increase the antioxidant capacity and relieve the inflammatory injury of the liver cells induced by ethanol. Meanwhile, in our study, POE reduced the expression of miR-122, acetyl coenzyme A carboxylase (ACC) 1 mRNA and protein and increased the expression of lipoprotein lipase (LPL) mRNA and protein in liver, which indicated that POE could improve the lipid metabolism disorder induced by ethanol. Our findings suggested that POE had protective effects on acute alcoholic liver injury of rats.

Upregulation of LINC00963 facilitates melanoma progression through miR-608/NACC1 pathway and predicts poor prognosis.

Long noncoding RNAs (lncRNAs) are acknowledged as crucial regulators involved in multiple pathological processes, including cancer. Although some lncRNAs are studied in melanoma, the association between lncRNA and melanoma progression still remains vague. And the function of LINC00963 in melanoma is waiting for investigation. In this study, upregulated level of LINC00963 in melanoma tissues was observed. Notably, we found DNA copy-number-gain of LINC00963 contributes to its high expression. And high expression of LINC00963 predicts poor prognosis in patients with melanoma. Functional investigation indicated that LINC00963 knockdown dramatically suppressed melanoma cell proliferation, migration and invasion. Mechanistically, we found that LINC00963 could interact with miR-608 while miR-608 could target NACC1. Upregulated LINC00963 led to elevated expression of NACC1 through inhibiting miR-608, which consequently promoted melanoma malignant progression. Taken together, our results illustrated that LINC00963-miR-608-NACC1 pathway might be a potential target for melanoma therapy.

The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions.

Antibodies targeting PD-1 have been demonstrated durable anti-cancer activity in certain cancer types. However, the anti-PD-1 antibodies are less or not efficacious in many situations, which might be attributed to co-expression of multiple inhibitory receptors or presence of immunosuppressive cells in the tumor microenvironment. Most of the anti-PD-1 antibodies used in clinical studies are of IgG4 isotype with the S228P mutation (IgG4S228P). The functional impact by the interaction of anti-PD-1 IgG4S228P antibody with Fc gamma receptors (FcγRs) is poorly understood. To assess the effects, we generated a pair of anti-PD-1 antibodies: BGB-A317/IgG4S228P and BGB-A317/IgG4-variant (abbreviated as BGB-A317), with the same variable regions but two different IgG4 Fc-hinge sequences. There was no significant difference between these two antibodies in binding to PD-1. However, BGB-A317/IgG4S228P binds to human FcγRI with high affinity and mediates crosslinking between PD-1 and FcγRI. In contrast, BGB-A317 does neither. Further cell-based assays showed that such crosslinking could reverse the function of an anti-PD-1 antibody from blocking to activating. More importantly, the crosslinking induces FcγRI+ macrophages to phagocytose PD-1+ T cells. In a mouse model transplanted with allogeneic human cancer cells and PBMCs, BGB-A317 showed significant tumor growth inhibition, whereas BGB-A317/IgG4S228P had no such inhibition. Immunohistochemistry study revealed an inverse correlation between FcγRI+ murine macrophage infiltration and the density of CD8+PD-1+ human T cells within tumors in the BGB-A317/IgG4S228P-treated group. These evidences suggested that FcγRI+ binding and crosslinking had negative impact on the anti-PD-1 antibody-mediated anti-cancer activity.

Curcumin reverses the depressive-like behavior and insulin resistance induced by chronic mild stress.

Increasing evidence has demonstrated that patients with depression have a higher risk of developing type 2 diabetes. Insulin resistance has been identified as the key mechanism linking depression and diabetes. The present study established a rat model of depression complicated by insulin resistance using a 12-week exposure to chronic mild stress (CMS) and investigated the therapeutic effects of curcumin. Sucrose intake tests were used to evaluate depressive-like behaviors, and oral glucose tolerance tests (OGTT) and intraperitoneal insulin tolerance tests (IPITT) were performed to evaluate insulin sensitivity. Serum parameters were detected using commercial kits. Real-time quantitative PCR was used to examine mRNA expression. CMS rats exhibited reduced sucrose consumption, increased serum glucose, insulin, triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), non-esterified fatty acid (NEFA), glucagon, leptin, and corticosterone levels, as well as impaired insulin sensitivity. Curcumin upregulated the phosphorylation of insulin receptor substrate (IRS)-1 and protein kinase B (Akt) in the liver, enhanced insulin sensitivity, and reversed the metabolic abnormalities and depressive-like behaviors mentioned above. Moreover, curcumin increased the hepatic glycogen content by inhibiting glycogen synthase kinase (GSK)-3ß and prevented gluconeogenesis by inhibiting phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase). These results suggest that curcumin not only exerted antidepressant-like effects, but also reversed the insulin resistance and metabolic abnormalities induced by CMS. These data may provide evidence to support the potential use of curcumin against depression and/or metabolic disorders.