Ablation of CD44 attenuates adipogenesis in white adipocytes via the TPH2/5-HT axis to protect mice from high-fat diet induced obesity.

CD44 is a transmembrane protein that plays an essential role in transducing extracellular stimuli into intracellular signaling cascades especially in cancer cells. Recent studies have shown that CD44 contributes to metabolic regulation. However, the effect of CD44 on adipogenesis in white adipose tissue (WAT) remains unclear. Here, the results showed that the expression of CD44 was largely increased in the inguinal and epididymal WAT of obese mice. Ablation or neutralization of CD44 inhibits adipogenesis in cultured adipocytes. CD44 deficient mice are resistant to high-fat diet (HFD) induced obesity and metabolic dysfunction. RNA-seq, together with functional studies, revealed that reduced expression of tryptophan 5-hydroxylase 2 (Tph2) in WAT is responsible for the repressed adipogenesis in the absence of CD44. The application of 5-hydroxytryptamine (5-HT), a product of TPH2, rescues the repressed adipogenesis induced by CD44 neutralization. Moreover, the inhibition of TPH2 by p-chlorophenylalanine (pCPA) recapitulates the beneficial phenotypes observed in CD44 deficient mice. Taken together, these data indicate that CD44 plays a pivotal role in adipogenesis in WAT. In this regard, CD44 and its downstream target TPH2 may hold great therapeutic potential for treating excessive adiposity-related metabolic disorders such as obesity, insulin resistance, and type 2 diabetes.

Cold-inducible lncRNA266 promotes browning and the thermogenic program in white adipose tissue.

Cold-induced nonshivering thermogenesis has contributed to the improvement of several metabolic syndromes caused by obesity. Several long noncoding RNAs (lncRNAs) have been shown to play a role in brown fat biogenesis and thermogenesis. Here we show that the lncRNA lnc266 is induced by cold exposure in inguinal white adipose tissue (iWAT). In vitro functional studies reveal that lnc266 promotes brown adipocyte differentiation and thermogenic gene expression. At room temperature, lnc266 has no effects on white fat browning and systemic energy consumption. However, in a cold environment, lnc266 promotes white fat browning and thermogenic gene expression in obese mice. Moreover, lnc266 increases core body temperature and reduces body weight gain. Mechanistically, lnc266 does not directly regulate Ucp1 expression. Instead, lnc266 sponges miR-16-1-3p and thus abolishes the repression of miR-16-1-3p on Ucp1 expression. As a result, lnc266 promotes preadipocyte differentiation toward brown-like adipocytes and stimulates thermogenic gene expression. Overall, lnc266 is a cold-inducible lncRNA in iWAT, with a key role in white fat browning and the thermogenic program.

Natural medicines-derived carbon dots as novel oral antioxidant administration strategy for ulcerative colitis therapy.

BACKGROUND: Ulcerative colitis (UC) is a chronic intestinal inflammation, resulting in a global healthcare challenge with no real specific medicine. Natural medicines are recognized as a potential clinical alternative therapy, but their applications are limited by poor solubility and low bioavailability. RESULTS: In this work, inspired by the natural medicines of ancient China, novel functional carbon dots derived from Magnetite and Medicated Leaven (MML-CDs) were synthesized by hydrothermal method, and confirmed their ultrasmall nano-size (3.2 ± 0.6 nm) and Fe doped surface structure, thereby with excellent gastrointestinal stability, remarkable capabilities in eliminating ROS, and highly biocompatibility. With no external stimuli, the oral administration of MML-CDs demonstrated obvious alleviation to UC. Further experiments pointed that MML-CDs could improve hemostasis capability, suppress inflammation reactions and oxidative stress, and up-regulate the expression of tight junction proteins. Furthermore, MML-CDs also showed well regulation in the dysbiosis of intestinal flora. CONCLUSION: Overall, above evidence reveals that green-synthesized MML-CDs can significantly alleviate intestinal bleeding, inhibit colon inflammation, and repair colonic barrier damage, further regulating intestinal flora and intestinal inflammation microenvironment. Our findings provide an efficient oral administration of MML-CDs as a novel therapy strategy for ulcerative colitis.

Exosomal miR-673-5p from fibroblasts promotes Schwann cell-mediated peripheral neuron myelination by targeting the TSC2/mTORC1/SREBP2 axis.

Peripheral myelination is a complicated process, wherein Schwann cells (SCs) promote the formation of the myelin sheath around the axons of peripheral neurons. Fibroblasts are the second resident cells in the peripheral nerves; however, the precise function of fibroblasts in SC-mediated myelination has rarely been examined. Here, we show that exosomes derived from fibroblasts boost myelination-related gene expression in SCs. We used exosome sequencing, together with bioinformatic analysis, to demonstrate that exosomal microRNA miR-673-5p is capable of stimulating myelin gene expression in SCs. Subsequent functional studies revealed that miR-673-5p targets the regulator of mechanistic target of the rapamycin (mTOR) complex 1 (mTORC1) tuberous sclerosis complex 2 in SCs, leading to the activation of downstream signaling pathways including mTORC1 and sterol-regulatory element binding protein 2. In vivo experiments further confirmed that miR-673-5p activates the tuberous sclerosis complex 2/mTORC1/sterol-regulatory element binding protein 2 axis, thus promoting the synthesis of cholesterol and related lipids and subsequently accelerating myelin sheath maturation in peripheral nerves. Overall, our findings revealed exosome-mediated cross talk between fibroblasts and SCs that plays a pivotal role in peripheral myelination. We propose that exosomes derived from fibroblasts and miR-673-5p might be useful for promoting peripheral myelination in translational medicine.

Circ_0091537 promotes gefitinib chemoresistance in non-small cell lung cancer by mediating the miR-520h/YAP1 network.

Chemoresistance is the leading cause of poor outcomes of non-small cell lung cancer (NSCLC). Circular RNA (circRNA) plays a vital role in NSCLC resistance progression. Our study aimed to uncover the role of circRNA PDZ domain containing 8 (circ_0091537) in NSCLC with gefitinib resistance. The expression of circ_0091537, microRNA-520h (miR-520h), and Yes-associated protein 1 (YAP1) mRNA were detected using quantitative real-time PCR. Cell viability and cell proliferation were assessed by MTT assay and colony formation assay. Colony formation ability was detected by colony formation assay. Cell cycle distribution and cell apoptosis were determined by flow cytometry assay. Cell migration and cell invasion were detected by transwell assay. The potential relationship between miR-520h and circ_0091537 or YAP1 was verified by dual-luciferase reporter assay. Tumor formation assay in nude mice was performed to test the role of circ_0091537 in vivo . Circ_0091537 and YAP1 were upregulated, while miR-520h was downregulated in gefitinib-resistant NSCLC cells. Circ_0091537 knockdown inhibited gefitinib resistance in NSCLC cells and then inhibited NSCLC cell growth, migration, and invasion. MiR-520h was a target of circ_0091537, and miR-520h inhibition reversed the effects of circ_0091537 knockdown. Moreover, YAP1 was a target of miR-520h, and circ_0091537 competitively combined with miR-520h to enrich YAP1 expression. MiR-520h restoration impaired gefitinib resistance and suppressed NSCLC cell proliferation, migration, and invasion by repressing YAP1. Circ_0091537 overexpression weakened gefitinib sensitivity in vivo to promote tumor growth. Circ_0091537 strengthens gefitinib chemoresistance to promote NSCLC progression by mediating the miR-520h/YAP1 network, suggesting that circ_0091537 may be a key indicator in resistance to treatment of NSCLC.

Comparative experiments of electrical conductivity from whey protein concentrates conventional film and nanofibril film.

We compared the electrical conductivity from two different aggregates of whey protein concentrates (WPC) film: conventional amorphous aggregation at natural pH (pH 6.5) and amyloid fibrils at a low pH (pH 2.0) far away from the isoelectric point. The two types of film fabricated by these solutions with different aggregate structures showed large variations in electrical conductivity and other properties. The WPC fibril film (pH 2.0) exhibited higher electrical conductivity than that of the conventional WPC film (pH 6.5), improved mechanical properties and oil resistance, due to varying morphology, higher surface hydrophobicity and more (absolute value) surface charge of film-forming solutions. The evidence from this study suggests that fibrilized WPC with high-ordered and ß-sheets-rich structures fabricated high electrical conductivity film, which broadens the potential application of fibrils as functional bio-nanomaterials.

A Case of Transcatheter Aortic Valve Replacement for the Treatment of Severe Aortic Stenosis with Multiple Organ Dysfunction.

A 77-year-old woman with extremely high risk of mortality due to severe aortic stenosis (AS) and multiple organ failure was admitted to the affiliated hospital of Jiangsu University. She did not receive regular treatment since being diagnosed with AS 17 months previously. Frequent breakout of acute left heart failure after admission, with a low ostium of the left coronary artery showed by computed tomography, the patient underwent transcatheter aortic valve replacement (TAVR). Though cardiac conduction system abnormalities and a short-term elevation of pulmonary arterial pressure occurred in this patient after TAVR, she eventually recovered and her quality of life improved significantly. As the population adapted to TAVR keeps expanding, we believe this operation will play a more important role in the treatment of AS patients.

[Advances on terpenoids from genus Syringa].

Syringa plants are of important value in ornamental, economic and medical fields. The terpenoids in Syringa plants mainly include iridoids, sesquiterpenoids, and triterpenoids, most showing activities such as cardioprotective, neuroprotective, hypoglycemic, anti-flu virus, anti-bacterial, anti-inflammatory, and anti-oxidation effects. Among the above active compounds, sesquiterpenoids have attracted increasing attention. In this review, the phytochemical and pharmacological activities of Syringa terpenoids were summarized in order to provide an overview for further research and development of Syringa plants.

[Phytochemical and pharmacological progress on genus Syringa].

The genus Syringa, belonging to the family Oleaceae, are distributed naturally in the European and Asian regions.This genus is composed of more than 20 species worldwide, among which about 16 species including 10 endemic ones are discovered in China.The Syringa sp.are extensively used as herbal medicine and ornamental aspects, such as the roots and stems of S. pinnatifolia, which is one of the typical Mongolian folk medicines in China for the treatment of cardiovascular and pulmonary symptoms. As a continuous research following the previous summary in 2015, the present reriew describes the phytochemical and pharmacological progress of the genus, which hopes to provide a valuable reference to its research, development and clinic application.

Salidroside ameliorates Adriamycin nephropathy in mice by inhibiting ß-catenin activity.

Salidroside is a major phenylethanoid glycoside in Rhodiola rosea L., a traditional Chinese medicine, with multiple biological activities. It has been shown that salidroside possesses protective effects for alleviating diabetic renal dysfunction, contrast-induced-nephropathy and other kidney diseases. However, the involved molecular mechanism was still not understood well. Herein, we examined the protective effects of salidroside in mice with Adriamycin (ADR)-induced nephropathy and the underlying molecular mechanism. The results showed that salidroside treatment ameliorates proteinuria; improves expressions of nephrin and podocin; and reduces kidney fibrosis and glomerulosclerosis induced by ADR. Mechanistically, ADR induces a robust accumulation of ß-catenin in the nucleus and stimulates its downstream target gene expression. The application of salidroside largely abolishes the nuclear translocation of ß-catenin and thus inhibits its activity. Furthermore, the activation of ß-catenin almost completely counteracts the protective roles of salidroside in ADR-injured podocytes. Taken together, our data indicate that salidroside ameliorates proteinuria, renal fibrosis and podocyte injury in ADR nephropathy, which may rely on inhibition of ß-catenin signalling pathway.

Application of optimized waveforms for enhancing high-harmonic yields in a three-color laser-field synthesizer.

We apply the optimization method suggested by Jin et al. [Nat. Commun.5, 4003 (2014)24873949] to a three-color laser-field synthesizer in a recent experiment by Burger et al. [Opt. Express25(25), 31130 (2017)29245790] for efficient high-order harmonic generation (HHG). With the experimental laser parameters being precisely tuned according to those returned by the genetic optimization, the three-color waveform composed by a 790-nm laser with its second and third harmonic fields, can enhance the macroscopic HHG yields by one to two orders with only 80% pulse energy compared to the fundamental single-color field. We check that this enhancement can be realized for He or Ne gas at both low and high gas pressures. The optimized waveform enables the short-trajectory emissions dominant to facilitate the buildup of the harmonic field, which is revealed by analyzing the behaviors of electron trajectories and the time-frequency pictures of the single-atom and macroscopic HHG. We also optimize the two-color waveform consisting of the fundamental laser and its third harmonic field for the flexible choice in the experiment. This study provides with a practical route to implement the optimization technique in the experiment for the high-flux harmonic generation from the extreme ultraviolet to the X-rays.

Active underwater descattering and image recovery.

Underwater imaging is a promising but challenging topic due to the scattering particles in water, which result in serious light attenuation. Therefore, underwater images suffer from low-contrast and low-resolution issues. In this study, in order to recover high-quality underwater images, the point spread functions (PSFs) are estimated by a slant-edge method. The experiment modulates the illumination source to deal with backscattering and the imager to take two images in orthogonally polarized states. This imaging method benefits the satisfactory edge extraction. The PSF estimation is performed based on the extracted slant edge to enable recovery of the image. In addition, the modulation transfer function (MTF) is introduced to evaluate the resolution variation with the spatial frequencies. It manifests considerable resolution enhancement in the recovered images. Moreover, the proposed underwater image recovery method also reduces the effect from the scattering as an effective compensation to the polarization imaging approach.

Low cost, high performance white-light fiber-optic hydrophone system with a trackable working point.

A working-point trackable fiber-optic hydrophone with high acoustic resolution is proposed and experimentally demonstrated. The sensor is based on a polydimethylsiloxane (PDMS) cavity molded at the end of a single-mode fiber, acting as a low-finesse Fabry-Perot (FP) interferometer. The working point tracking is achieved by using a low cost white-light interferometric system with a simple tunable FP filter. By real-time adjusting the optical path difference of the FP filter, the sensor working point can be kept at its highest sensitivity point. This helps address the sensor working point drift due to hydrostatic pressure, water absorption, and/or temperature changes. It is demonstrated that the sensor system has a high resolution with a minimum detectable acoustic pressure of 148 Pa and superior stability compared to a system using a tunable laser.

Model-free robust motion control for biological optical microscopy using time-delay estimation with an adaptive RBFNN compensator.

The field of large numerical aperture microscopy has witnessed significant advancements in spatial and temporal resolution, as well as improvements in optical microscope imaging quality. However, these advancements have concurrently raised the demand for enhanced precision, extended range, and increased load-bearing capacity in objective motion carrier (OMC). To address this challenge, this study introduces an innovative OMC that employs a ball screw mechanism as its primary driving component. Furthermore, a robust nonlinear motion control strategy has been developed, which integrates fast nonsingular terminal sliding mode, experimental estimation techniques, and adaptive radial basis neural network, to mitigate the impact of nonlinear friction within the ball screw mechanism on motion precision. The stability of the closed-loop control system has been rigorously demonstrated through Lyapunov theory. Compared with other enhanced sliding mode control strategies, the maximum error and root mean square error of this controller are improved by 33% and 34% respectively. The implementation of the novel OMC has enabled the establishment of a high-resolution bio-optical microscope, which has proven its effectiveness in the microscopic imaging of retinal organoids.

Early life malnutrition and risk of T2DM adulthood: evidence from the lower socioeconomic status of northwest Chinese population.

Objective: This study aimed to explore whether famine exposure during early life are associated with a high risk of Type 2 Diabetes Mellitus (T2DM) in adulthood and the role of socioeconomic status (SES) on this effect. Materials and methods: We conducted a secondary data analysis based on data from a cross-sectional survey, collected 3,355 participants born between January 1, 1941 and December 31, 1966. Participants were categorized into four groups based on their date of birth, unexposed (individuals born in 1963-1966), infant exposed (individuals born in 1959-1962), childhood exposed (individuals born in 1949-1958), and adolescent exposed (born in 1941-1948). The association of famine exposure with T2DM risk in adults and conducted separately in plain area and mountain area was assessed using logistics regression model. Result: 22.35% of participants were diagnosed with T2DM, of which 43.47% were from the childhood famine-exposed group, representing the highest proportion among all subgroups (p < 0.001). Participants exposed to famine during childhood and adolescence from the lower SES mountain areas showed a significantly higher prevalence of T2DM in adulthood than those from the plain areas (p < 0.001). The adolescence stage exposed famine will increase the risk of T2DM in the mountain area (OR 2.46, 95% CI 1.61, 3.77). Conclusion: No strong evidence demonstrates that exposure to famine during the early life stage increases the risk of developing T2DM in adulthood. However, populations with lower SES are likely to be exposed to more risk factors for T2DM.

Wireless and Opto-Stimulated Flexible Implants: Artificial Retina Constructed by Ferroelectric BiFeO3-BaTiO3/P(VDF-TrFE) Composites.

The degeneration of retinal photoreceptors is one of the primary causes of blindness, and the implantation of retinal prostheses offers hope for vision restoration in individuals who are completely blind. Flexible bioelectronic devices present a promising avenue for the next generation of retinal prostheses owing to their soft mechanical properties and tissue friendliness. In this study, we developed flexible composite films of ferroelectric BiFeO3-BaTiO3 (BFO-BTO) particles synthesized by the hydrothermal method and ferroelectric poly(vinyldene difluoride-trifluoroethylene) (P(VDF-TrFE)) polymer and investigated their applications in artificial retinas. Owing to the coupling of the photothermal effect of BFO-BTO particles and the pyroelectric effect of the P(VDF-TrFE) polymer, the composite films demonstrate a strong photoelectric response (a maximum peak-to-peak photovoltage > 80 V under blue light of 100 mW/cm2) in a wide wavelength range of light (from visible to infrared) with the inherent flexibility and ease of preparation, making it an attractive candidate for artificial retinal applications. Experimental results showed that blind rats implanted with artificial retinas of the composites display light-responsive behavior, showcasing the effectiveness of vision restoration. This study demonstrates a novel approach for employing ferroelectric materials in vision restoration and offers insights into future artificial retina design.

Clinical laboratory characteristics and gene mutation spectrum of Ph-negative MPN patients with atypical variants of JAK2, MPL, or CALR.

OBJECTIVE: To evaluate the incidence, clinical laboratory characteristics, and gene mutation spectrum of Ph-negative MPN patients with atypical variants of JAK2, MPL, or CALR. METHODS: We collected a total of 359 Ph-negative MPN patients with classical mutations in driver genes JAK2, MPL, or CALR, and divided them into two groups based on whether they had additional atypical variants of driver genes JAK2, MPL, or CALR: 304 patients without atypical variants of driver genes and 55 patients with atypical variants of driver genes. We analyzed the relevant characteristics of these patients. RESULTS: This study included 359 patients with Ph-negative MPNs with JAK2, MPL, or CALR classical mutations and found that 55 (15%) patients had atypical variants of JAK2, MPL, or CALR. Among them, 28 cases (51%) were male, and 27 (49%) were female, with a median age of 64 years (range, 21-83). The age of ET patients with atypical variants was higher than that of ET patients without atypical variants [70 (28-80) vs. 61 (19-82), p = 0.03]. The incidence of classical MPL mutations in ET patients with atypical variants was higher than in ET patients without atypical variants [13.3% (2/15) vs. 0% (0/95), p = 0.02]. The number of gene mutations in patients with atypical variants of driver genes PV, ET, and Overt-PMF is more than in patients without atypical variants of PV, ET, and Overt-PMF [PV: 3 (2-6) vs. 2 (1-7), p < 0.001; ET: 4 (2-8) vs. 2 (1-7), p < 0.05; Overt-PMF: 5 (2-9) vs. 3 (1-8), p < 0.001]. The incidence of SH2B3 and ASXL1 mutations were higher in MPN patients with atypical variants than in those without atypical variants (SH2B3: 16% vs. 6%, p < 0.01; ASXL1: 24% vs. 13%, p < 0.05). CONCLUSION: These data indicate that classical mutations of JAK2, MPL, and CALR may not be completely mutually exclusive with atypical variants of JAK2, MPL, and CALR. In this study, 30 different atypical variants of JAK2, MPL, and CALR were identified, JAK2 G127D being the most common (42%, 23/55). Interestingly, JAK2 G127D only co-occurred with JAK2V617F mutation. The incidence of atypical variants of JAK2 in Ph-negative MPNs was much higher than that of the atypical variants of MPL and CALR. The significance of these atypical variants will be further studied in the future.

Overexpression of Arabidopsis acyl-CoA binding protein ACBP3 promotes starvation-induced and age-dependent leaf senescence.

In Arabidopsis thaliana, a family of six genes (ACBP1 to ACBP6) encodes acyl-CoA binding proteins (ACBPs). Investigations on ACBP3 reported here show its upregulation upon dark treatment and in senescing rosettes. Transgenic Arabidopsis overexpressing ACBP3 (ACBP3-OEs) displayed accelerated leaf senescence, whereas an acbp3 T-DNA insertional mutant and ACBP3 RNA interference transgenic Arabidopsis lines were delayed in dark-induced leaf senescence. Acyl-CoA and lipid profiling revealed that the overexpression of ACBP3 led to an increase in acyl-CoA and phosphatidylethanolamine (PE) levels, whereas ACBP3 downregulation reduced PE content. Moreover, significant losses in phosphatidylcholine (PC) and phosphatidylinositol, and gains in phosphatidic acid (PA), lysophospholipids, and oxylipin-containing galactolipids (arabidopsides) were evident in 3-week-old dark-treated and 6-week-old premature senescing ACBP3-OEs. Such accumulation of PA and arabidopsides (A, B, D, E, and G) resulting from lipid peroxidation in ACBP3-OEs likely promoted leaf senescence. The N-terminal signal sequence/transmembrane domain in ACBP3 was shown to be essential in ACBP3-green fluorescent protein targeting and in promoting senescence. Observations that recombinant ACBP3 binds PC, PE, and unsaturated acyl-CoAs in vitro and that ACBP3 overexpression enhances degradation of the autophagy (ATG)-related protein ATG8 and disrupts autophagosome formation suggest a role for ACBP3 as a phospholipid binding protein involved in the regulation of leaf senescence by modulating membrane phospholipid metabolism and ATG8 stability in Arabidopsis. Accelerated senescence in ACBP3-OEs is dependent on salicylic acid but not jasmonic acid signaling.

Recent advances of long non-coding RNAs in control of hepatic gluconeogenesis.

Gluconeogenesis is the main process for endogenous glucose production during prolonged fasting, or certain pathological conditions, which occurs primarily in the liver. Hepatic gluconeogenesis is a biochemical process that is finely controlled by hormones such as insulin and glucagon, and it is of great importance for maintaining normal physiological blood glucose levels. Dysregulated gluconeogenesis induced by obesity is often associated with hyperglycemia, hyperinsulinemia, and type 2 diabetes (T2D). Long noncoding RNAs (lncRNAs) are involved in various cellular events, from gene transcription to protein translation, stability, and function. In recent years, a growing number of evidences has shown that lncRNAs play a key role in hepatic gluconeogenesis and thereby, affect the pathogenesis of T2D. Here we summarized the recent progress in lncRNAs and hepatic gluconeogenesis.

Fibroblast exosomal TFAP2C induced by chitosan oligosaccharides promotes peripheral axon regeneration via the miR-132-5p/CAMKK1 axis.

Chitosan and its degradation product, oligosaccharides, have been shown to facilitate peripheral nerve regeneration. However, the underlying mechanisms are not well understood. In this study, we analyzed the protein expression profiles in sciatic nerves after injury using proteomics. A group of proteins related to exosome packaging and transport is up-regulated by chitosan oligosaccharides (COS), implying that exosomes are involved in COS-induced peripheral nerve regeneration. In fact, exosomes derived from fibroblasts (f-EXOs) treated with COS significantly promoted axon extension and regeneration. Exosomal protein identification and functional studies, revealed that TFAP2C is a key factor in neurite outgrowth induced by COS-f-EXOs. Furthermore, we showed that TFAP2C targets the pri-miRNA-132 gene and represses miR-132-5p expression in dorsal root ganglion neurons. Camkk1 is a downstream substrate of miR-132-5p that positively affects axon extension. In rats, miR-132-5p antagomir stimulates CAMKK1 expression and improves axon regeneration and functional recovery in sciatic nerves after injury. Our data reveal the mechanism for COS in axon regeneration, that is COS induce fibroblasts to produce TFAP2C-enriched EXOs, which are then transferred into axons to promote axon regeneration via miR-132-5p/CAMKK1. Moreover, these results show a new facet of fibroblasts in axon regeneration in peripheral nerves.