Role of FXR in the development of NAFLD and intervention strategies of small molecules.

Non-alcoholic fatty liver disease (NAFLD) remains a prevailing etiological agent behind hepatocyte diseases like chronic liver disease. The spectrum of processes involved in NAFLD stages includes hepatic steatosis, non-alcoholic fatty liver, and non-alcoholic steatohepatitis (NASH). Without intervention, the progression of NASH can further deteriorate into cirrhosis and ultimately, hepatocellular carcinoma. The cardinal features that characterize NAFLD are insulin resistance, lipogenesis, oxidative stress and inflammation, extracellular matrix deposition and fibrosis. Due to its complex pathogenesis, existing pharmaceutical agents fail to take a curative or ameliorative effect on NAFLD. Consequently, it is imperative to identify novel therapeutic targets and strategies for NAFLD, ideally to improve the aforementioned key features in patients. As an enterohepatic regulator of bile acid homeostasis, lipid metabolism, and inflammation, FarnesoidX receptor (FXR) is an important pharmacological target for the treatment of NAFLD. Manipulating FXR to regulate lipid metabolic signaling pathways is a potential mechanism to mitigate NAFLD. Therefore, elucidating the modulatory character of FXR in regulating lipid metabolism in NAFLD has the potential to yield groundbreaking perspectives for drug design. This review details recent advances in the regulation of lipid depletion in hepatocytes and investigates the pivotal function of FXR in the progress of NAFLD.

Ponicidin-induced conformational changes of HSP90 regulates the MAPK pathway to relieve ulcerative colitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is a recurring chronic intestinal disease that can be debilitating and in severe cases, may further lead to cancer. However, all these treatment techniques still suffer from drug dependence, adverse effects and poor patient compliance. Therefore, there is an urgent need to seek new therapeutic strategies. In traditional Chinese medicine, Rabdosia rubescens (Hemsl.) H.Hara has the effects of clearing heat-toxin and promoting blood circulation to relieve pain, it is wildly used for treating inflammatory diseases such as sore throats and tonsillitis. Ponicidin is an important molecule for the anti-inflammatory effects of Rabdosia rubescens, but it has not been studied in the treatment of colitis. HSP90 is the most critical regulator in the development and progression of inflammatory diseases such as UC. AIM OF THE STUDY: The aim of this study was to explore the anti-inflammatory activity of ponicidin and its mechanism of effect in vitro and in vivo, as well as to identify the target proteins on which ponicidin may interact. MATERIAL AND METHODS: 2.5% (w/v) dextran sulfate sodium (DSS) was used to induce C57BL/6 mice to form an ulcerative colitis model, and then 5 mg/kg and 10 mg/kg ponicidin was given for treatment, while the Rabdosia rubescens extract group and Rabdosia rubescens diterpene extract group were set up for comparison of the efficacy of ponicidin. At the end of modeling and drug administration, mouse colon tissues were taken, and the length of colon was counted, inflammatory factors and inflammatory signaling pathways were detected. RAW264.7 cells were induced to form cell inflammation model with 1 µg/mL Lipopolysaccharide (LPS) for 24 h. 1 µM, 2 µM and 4 µM ponicidin were given at the same time, and after the end of the modeling and administration of the drug, the inflammatory factors and inflammatory signaling pathways were detected by qRT-PCR, western blotting, immunofluorescence and other methods. In vitro, target angling and combined with mass spectrometry were used to search for relevant targets of ponicidin, while isothermal titration calorimetry (ITC), protease degradation experiments and molecular dynamics simulations were used for further confirmation of the mode of action and site of action between ponicidin and target proteins. RESULTS: Ponicidin can alleviate DSS and LPS-induced inflammation by inhibiting the MAPK signaling pathway at the cellular and animal levels. In vitro, we confirmed that ponicidin can interact with the middle domain of HSP90 and induce the conformational changes in the N-terminal domain. CONCLUSION: These innovative efforts identified the molecular target of ponicidin in the treatment of UC and revealed the molecular mechanism of its interaction with HSP90.

Advances in nanomaterials for the diagnosis and treatment of head and neck cancers: A review.

Nanomaterials (NMs) have increasingly been used for the diagnosis and treatment of head and neck cancers (HNCs) over the past decade. HNCs can easily infiltrate surrounding tissues and form distant metastases, meaning that most patients with HNC are diagnosed at an advanced stage and often have a poor prognosis. Since NMs can be used to deliver various agents, including imaging agents, drugs, genes, vaccines, radiosensitisers, and photosensitisers, they play a crucial role in the development of novel technologies for the diagnosis and treatment of HNCs. Indeed, NMs have been reported to enhance delivery efficiency and improve the prognosis of patients with HNC by allowing targeted delivery, controlled release, responses to stimuli, and the delivery of multiple agents. In this review, we consider recent advances in NMs that could be used to improve the diagnosis, treatment, and prognosis of patients with HNC and the potential for future research.

Salvianolic acid B suppresses hepatic fibrosis by inhibiting ceramide glucosyltransferase in hepatic stellate cells.

UDP-glucose ceramide glucosyltransferase (UGCG) is the first key enzyme in glycosphingolipid (GSL) metabolism that produces glucosylceramide (GlcCer). Increased UGCG synthesis is associated with cell proliferation, invasion and multidrug resistance in human cancers. In this study we investigated the role of UGCG in the pathogenesis of hepatic fibrosis. We first found that UGCG was over-expressed in fibrotic livers and activated hepatic stellate cells (HSCs). In human HSC-LX2 cells, inhibition of UGCG with PDMP or knockdown of UGCG suppressed the expression of the biomarkers of HSC activation (α-SMA and collagen I). Furthermore, pretreatment with PDMP (40 µM) impaired lysosomal homeostasis and blocked the process of autophagy, leading to activation of retinoic acid signaling pathway and accumulation of lipid droplets. After exploring the structure and key catalytic residues of UGCG in the activation of HSCs, we conducted virtual screening, molecular interaction and molecular docking experiments, and demonstrated salvianolic acid B (SAB) from the traditional Chinese medicine Salvia miltiorrhiza as an UGCG inhibitor with an IC50 value of 159 µM. In CCl4-induced mouse liver fibrosis, intraperitoneal administration of SAB (30 mg · kg-1 · d-1, for 4 weeks) significantly alleviated hepatic fibrogenesis by inhibiting the activation of HSCs and collagen deposition. In addition, SAB displayed better anti-inflammatory effects in CCl4-induced liver fibrosis. These results suggest that UGCG may represent a therapeutic target for liver fibrosis; SAB could act as an inhibitor of UGCG, which is expected to be a candidate drug for the treatment of liver fibrosis.

Covalent Immobilization of Natural Biomolecules on Chitin Nanocrystals.

As a highly crystalline and renewable natural polymer nanomaterial, chitin nanocrystals (ChNCs) have attracted intense interest in the biomedical field. The structure of a ChNC is composed of an acetylglucosamine unit containing two hydroxyl groups and an acetyl group. The acetyl group can be converted to the active amino group through deacetylation, which is under the condition of maintaining the rod-like morphology and high crystalline property and is beneficial for the following modification and potential application. We investigated the relationship between different treatments and varied crystallinities of the modified ChNC, which obtained surface amino groups and aldehyde groups and retained high crystallinity. The natural biomolecules were covalently immobilized on the surface of the ChNC. The etherification was performed based on the hydroxyl groups. Based on the amino groups and the aldehyde groups, the carboxyamine and Knoevenagel condensation reactions were realized on ChNCs. Finally, natural biomolecule-modified ChNCs showed no or low cytotoxicity, antibacterial properties, and high antioxidant properties, which extended their potential biomedical applications.

Relationship between chronic hypoxia and seizure susceptibility.

Chronic hypobaric hypoxia in high-altitude areas is closely related to the occurrence of many neurological diseases. Among these diseases, epilepsy is a common disease of the nervous system that is difficult to diagnose and treat, with a long treatment cycle. As of 2019, there were more than 70 million epilepsy patients worldwide, including 10 million in China. Studies have shown that chronic hypoxia promotes the occurrence and development of epilepsy, and elucidation of the relationship between chronic hypoxia and epilepsy is important for studying the pathogenesis of epilepsy and exploring the potential characteristics of epilepsy and new drug targets for epilepsy. In this article, we review the factors that may cause increased seizure susceptibility in chronic hypoxia and consider the potential relationship between chronic hypobaric hypoxia and seizure susceptibility in high-altitude areas and prospects surrounding related research in the future.

In-situ growth of robust superlubricated nano-skin on electrospun nanofibers for post-operative adhesion prevention.

It is a great challenge to achieve robustly bonded, fully covered, and nanoscaled coating on the surface of electrospun nanofibers. Herein, we develop a controllable, facile, and versatile strategy to in-situ grow superlubricated nano-skin (SLNS) on the single electrospun nanofiber. Specifically, zwitterionic polymer chains are generated from the nanofiber subsurface in an inside-out way, which consequently form a robust network interpenetrating with the polymeric chains of the nanofiber matrix. The nanofibers with SLNS are superlubricated with the coefficient of friction (COF) lower than 0.025, which is about 16-fold of reduction than the original nanofibers. The time-COF plot is very stable after 12, 000 cycles of friction test, and no abrasion is observed. Additionally, the developed nanofibrous membranes possess favorable tensile property and biocompatibility. Furthermore, the nanofibrous membranes with SLNS achieve prevention of post-operative adhesion, which is confirmed in both rat tendon adhesion model and abdominal adhesion model. Compared with clinically-used antiadhesive membranes such as Interceed and DK-film, our nanofibrous membranes are not only more effective but also have the advantage of lower production cost. Therefore, this study demonstrates a potential of the superlubricated nanofibrous membranes in-situ grown based on a SLNS strategy for achieving prevention of post-operative adhesion in clinics.

Unraveling of Advances in 3D-Printed Polymer-Based Bone Scaffolds.

The repair of large-area irregular bone defects is one of the complex problems in orthopedic clinical treatment. The bone repair scaffolds currently studied include electrospun membrane, hydrogel, bone cement, 3D printed bone tissue scaffolds, etc., among which 3D printed polymer-based scaffolds Bone scaffolds are the most promising for clinical applications. This is because 3D printing is modeled based on the im-aging results of actual bone defects so that the printed scaffolds can perfectly fit the bone defect, and the printed components can be adjusted to promote Osteogenesis. This review introduces a variety of 3D printing technologies and bone healing processes, reviews previous studies on the characteristics of commonly used natural or synthetic polymers, and clinical applications of 3D printed bone tissue scaffolds, analyzes and elaborates the characteristics of ideal bone tissue scaffolds, from t he progress of 3D printing bone tissue scaffolds were summarized in many aspects. The challenges and potential prospects in this direction were discussed.

Altered Dynamic Functional Connectivity in Subcortical Ischemic Vascular Disease With Cognitive Impairment.

Subcortical ischemic vascular disease (SIVD) can cause cognitive impairment and affect the static functional connectivity of resting functional magnetic resonance imaging (fMRI). Numerous previous studies have demonstrated that functional connectivities (FCs) fluctuate dynamically over time. However, little is known about the impact of cognitive impairment on brain dynamic functional connectivity (DFC) in SIVD patients with MCI. In the present study, the DFC analysis method was applied to the resting functional magnetic resonance imaging (fMRI) data of 37 SIVD controls (SIVD-Control) without cognitive impairment, 34 SIVD patients with amnestic MCI (SIVD-aMCI) and 30 SIVD patients with nonamnestic MCI (SIVD-naMCI). The results indicated that the cognitive impairment of SIVD mainly reduced the mean dwell time of State 3 with overall strong positive connections. The reduction degree of SIVD-aMCI was larger than that of SIVD-naMCI. The memory/execution function impairment of SIVD also changed the relationship between the mean dwell time of State 3 and the behavioral performance of the memory/execution task from significant to non-significant correlation. Moreover, SIVD-aMCI showed significantly lower system segregation of FC states than SIVD-Control and SIVD-naMCI. The system segregation of State 5 with overall weak connections was significantly positive correlated with the memory performance. The results may suggest that the mean dwell time of State 3 and the system segregation of State 5 may be used as important neural measures of cognitive impairments of SIVD.

Bio-inspired Flexible Lateral Line Sensor Based on P(VDF-TrFE)/BTO Nanofiber Mat for Hydrodynamic Perception.

Fish and some amphibians can perform a variety of behaviors in confined and harsh environments by employing an extraordinary mechanosensory organ, the lateral line system (LLS). Inspired by the form-function of the LLS, a hydrodynamic artificial velocity sensor (HAVS) was presented in this paper. The sensors featured a polarized poly (vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE)]/barium titanate (BTO) electrospinning nanofiber mat as the sensing layer, a polyimide (PI) film with arrays of circular cavities as the substrate, and a poly(methyl methacrylate) (PMMA) pillar as the cilium. The P(VDF-TrFE)/BTO electrospinning nanofiber mat demonstrated enhanced crystallinity and piezoelectricity compared with the pure P(VDF-TrFE) nanofiber mat. A dipole source was employed to characterize the sensing performance of the fabricated HAVS. The HAVS achieved a velocity detection limit of 0.23 mm/s, superior to the conventional nanofiber mat-based flow sensor. In addition, directivity was feasible for the HAVS, which was in accordance with the simulation results. The proposed bio-inspired flexible lateral line sensor with hydrodynamic perception ability shows promising applications in underwater robotics for real-time flow analysis.

Constriction canal assisted artificial lateral line system for enhanced hydrodynamic pressure sensing.

With the assistance of mechanosensory lateral line system, fish can perceive minute water motions in complex underwater environments. Inspired by the constriction within canal nearby canal neuromast in fish lateral line system, we proposed a novel canal artificial lateral line (CALL) device with constriction in canal nearby the sensing element. The designed CALL device consisted of a poly(vinylidene fluoride-trifluoroethylene)/polyimide cantilever as the sensing element and a polydimethylsiloxane (PDMS) microfluid canal. Two types of CALL devices, i.e., CALL with straight canal (S-CALL) and CALL with constriction canal (C-CALL), were developed and characterized employing a dipole source. Experimental results showed that the proposed C-CALL device achieved a pressure gradient detection limit of 0.64 Pa m-1, which was much lower than the S-CALL device. It indicates that the constriction in the canal nearby the sensing element could enhance the hydrodynamic pressure sensing performance of the CALL device. In addition, the constriction could modify the frequency response of the CALL device, and the C-CALL device achieved higher voltage output than S-CALL in high-frequency domain.

Improved Piezoelectric Sensing Performance of P(VDF-TrFE) Nanofibers by Utilizing BTO Nanoparticles and Penetrated Electrodes.

Piezoelectric polymers with good flexibility have attracted tremendous attention in wearable sensors and energy harvesters. As the piezoelectricity of polymers such as polyvinylidene fluoride (PVDF) and polyvinylidene fluoride-trifluoroethylene [P(VDF-TrFE)] is lower than that of their ceramic counterparts, various approaches have been employed to improve the piezoelectric output of PVDF-based sensors, such as electrospinning, heat annealing, nanoconfinement, polymer blending, and nanoparticle addition. Here, we report two strategies to improve the piezoelectric sensing performance of polymer-based piezoelectric nanofibers, which include the formation of barium titanate (BTO)/P(VDF-TrFE) composite nanofibers and fabrication of penetrated electrodes to enlarge the interfacial area. BTO/P(VDF-TrFE) nanofibers with a BTO weight fraction of 5 wt % exhibit the maximum ß-phase crystallinity and piezoelectricity. The piezoelectric output of the BTO/P(VDF-TrFE) nanofiber mat is significantly improved compared with that of pristine P(VDF-TrFE), which is confirmed by piezoresponse force microscopy (PFM) and compression loading tests. In order to form the penetrated electrodes, oxygen (O2) plasma treatment is employed, followed by an electroless plating process. The BTO/P(VDF-TrFE) nanofibers with penetrated electrodes demonstrate increased dielectric constants and enhanced piezoelectric outputs. A BTO/P(VDF-TrFE) nanofiber-based sensor with penetrated electrodes is capable of discerning the energy of a free-falling ball as low as 0.6 µJ and sensing the movement of a walking ant.

Continuous glucose monitoring and control in a rotating wall perfused bioreactor.

A glucose control system consisting of a single in-line glucose sensor, concentrated glucose solution, and computer hardware and software were developed. The system was applied to continuously control glucose concentrations of a perfusion medium in a rotating wall perfused vessel (RWPV) bioreactor culturing BHK-21 cells. The custom-made glucose sensor was based on a hydrogen peroxide electrode. The sensor continuously and accurately measured the glucose concentration of GTSF-2 medium in the RWPV bioreactor during cell culture. Three sets of two-point calibrations were applied to the glucose sensor during the 55-day cell culture. The system first controlled the glucose concentration in perfusing medium between 4.2 and 5.6 mM for 36 days and then at different glucose levels for 19 days. A stock solution with a high glucose concentration (266 mM) was used as the glucose injection solution. The standard error of prediction (SEP) for glucose measurement by the sensor, compared to measurement by the Beckman glucose analyzer, was +/-0.4 mM for 55 days.