Fluorescent Pdots Facilitate High-Resolution Mapping of the Intact Meningeal Vascular Network and Eye-Brain Connections.

Meningeal vascular network is significant in neurology and neurosurgery. However, high-resolution imaging of intact meningeal vascular network is lacking. In this work, we develop a practical experimental method to ensure that the intact meninges are morphologically unfolded and fixed in an agarose gel. With the help of high-brightness polymer dots (Pdots) as probe, macroscopic and detailed imaging of the vascular network on the intact dorsal meninges can be performed. Meningeal vessels are symmetrically distributed along the superior sagittal sinus, and the distribution of meningeal vessels had a certain degree of hierarchy. The meninges are thicker blood vessels and capillary networks from the outside to the inside. Moreover, the diameter of the capillaries is 3.96 ± 0.89 µm. Interestingly, meningeal primo vessels in the central nervous system of mice is imaged with the diameter of 4.18 ± 1.18 µm, which has not been reported previously. It is worth mentioning that we found that orthotopic xenografts of brain tumors caused the appearance of corneal neovascularization and morphological changes in optic nerve microvessels. In conclusion, our work provides an effective Pdots-based imaging method for follow-up research on meningeal vascular-related diseases, and illustrates that the eye can serve as a window for the prevention and diagnosis of brain diseases.

Identification of a Rye Spring Mutant Derived from a Winter Rye Variety by High-Altitude Environment Screening Using RNA Sequencing Technology.

Wintergrazer-70 and Ganyin No1 are high-yield forage varieties suitable for cultivation in high-altitude areas of Tibet (4300 m above sea level). Ganyin No1 was developed from Wintergrazer-70, with the latter serving as its parent variety. Ganyin No1 was identified as a spring variety, and subsequent RNA sequencing was conducted. RNA sequencing analysis identified 4 differentially expressed genes related to vernalization and 28 genes related to photoperiod regulation. The Sc7296g5-i1G3 gene is related to the flowering inhibition of rye, which may be related to the phenotypic difference in the Ganyin No1 variety in winter and spring. This finding provides valuable insights for future research on Ganyin No1, especially in addressing feed shortages in Tibet during winter and spring.

Characterization of the novel HLA-C*06:376N allele by Pacific Biosciences HiFi sequencing in a Chinese individual.

HLA-C*06:376N differs from HLA-C*06:02:01:01 by seven nucleotide changes in exon 2, intron 2, and exon 3.

Low-phase-noise microwave generation with a free-running dual-pumped Si3N4 soliton microcomb.

Microwave signals can be generated by photodetecting the repetition frequencies of the soliton microcombs. In comparison to other methods, the dual-pumped method allows for the stable generation of the soliton microcombs even with resonators having lower Q-factors. However, introducing an additional pump laser may affect the phase noise of the generated microwave signals when using these dual-pumped soliton microcombs. Here, we investigate the factors that could influence the phase noise of microwave signals generated with dual-pumped soliton microcombs, including the polarization, amplitude noise, and phase noise of the two pumps. We demonstrate a 25.25 (12.63) GHz microwave with phase noise reaching -112(-118) dBc/Hz at a 10 kHz offset frequency, surpassing the performance of previous reports on microwave generation using free-running Si3N4 soliton microcombs, even those generated with higher Q microresonators. We analyze the noise floor of the generated microwave signals and establish a phase noise simulation model to study the limiting factors in our system. Our work highlights the potential of generating low-phase-noise microwave signals using free-running dual-pumped soliton microcombs.

Effects of Alginic Acid on the Porcine Granulosa Cells and Maturation of Porcine Oocytes.

SCOPE: Alginic acid (AA) from brown algae is a marine organic compound. There is extensive use of AA in the food industry and healthcare, suggesting a high probability of AA exposure. The present study investigates the effects of AA on porcine ovarian granulosa cells (GCs) and oocytes to explore its mechanism in female reproduction because of its adverse effects on reproduction. METHODS AND RESULTS: The study adds 20 µM AA to the porcine primary ovarian GCs medium and porcine oocyte in vitro maturation (IVM) medium. Estrogen and progesterone levels are downregulated in GCs. Reactive oxygen species are excessive, and the antioxidant capacity declines. Then mitochondria-mediated apoptosis pathway is involved in GCs apoptosis. In addition, scores of autophagosomes are found in the experimental cells. Furthermore, AA significantly inhibits the proliferation of GCs around cumulus-oocyte complexes (COCs) accompanied by abnormal spindle assembly, chromosome arrangement disorder, and aberrant cortical granules distribution in oocytes, leading to a decreased oocyte maturation rate. CONCLUSION: These findings suggest that 20 µM AA is toxic to sow reproduction by interfering with estrogen production, oxidative stress, mitochondria-mediated apoptosis, autophagy in GCs of sows, and oocyte maturation.

Long non-coding RNA FENDRR suppresses cancer-associated fibroblasts and serves as a prognostic indicator in colorectal cancer.

Genetically abnormal fibroblasts are notably more prevalent in colorectal cancer (CRC) than in adjacent normal tissue, emphasizing their significance in driving the heterogeneity of the tumor microenvironment. Functioning as a significant regulatory gene in the context of fibrosis, FOXF1 adjacent non-coding developmental regulatory RNA (FENDRR) has exhibited abnormal expression in colorectal cancer and interstitial localization in our experiments. However, current research on the role of FENDRR in cancer has focused solely on its impact on cancer cells. Its crucial role in the tumor stroma is yet to be explored. The goal of this study was to understand the relationship between atypical FENDRR expression, its distinct localization, and genetically abnormal fibroblasts in CRC. We aimed to establish the function of FENDRR within the stromal compartment of patients through bioinformatics. Our study confirmed that FENDRR suppresses cancer-associated fibroblasts by inhibiting their activation and collagen generation in CRC. Furthermore, our findings suggest that low FENDRR expression indicates a poor prognosis. Therefore, we propose that FENDRR is a promising therapeutic target for future studies in CRC.

Clinical effects of 3D printing-assisted posterolateral incision in the treatment of ankle fractures involving the posterior malleolus.

Objective: To explore the clinical outcomes of a 3D printing-assisted posterolateral approach for the treatment of ankle fractures involving the posterior malleolus. Methods: A total of 51 patients with ankle fractures involving the posterior malleolus admitted to our hospital from January 2018 to December 2019 were selected. The patients were divided into 3D printing group (28 cases) and control group (23 cases). 3D printing was performed for ankle fractures, followed by printing of a solid model and simulation of the operation on the 3D model. The operation was then performed according to the preoperative plan, including open reduction and internal fixation via the posterolateral approach with the patient in the prone position. Routine x-ray and CT examinations of the ankle joint were performed, and ankle function was evaluated using the American Foot and Ankle Surgery Association (AOFAS) ankle-hindfoot score. Results: All patients underwent x-ray and CT examinations. All fractures healed clinically, without loss of reduction or failure of internal fixation. Good clinical effects were achieved in both groups of patients. The operation time, intraoperative blood loss and intraoperative fluoroscopy frequency in the 3D printing group were significantly less than those in the control group (p < 0.05). There was no significant difference between the two groups in the anatomical reduction rate of fractures or the incidence of surgical complications (p > 0.05). Conclusion: The 3D printing-assisted posterolateral approach is effective in the treatment of ankle fractures involving the posterior malleolus. The approach can be well planned before the operation, is simple to perform, yields good fracture reduction and fixation, and has good prospects for clinical application.

Asymmetric rhodium-catalyzed click cycloaddition to access C-N axially chiral N-triazolyl indoles.

The copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is regarded as a prime example of "click chemistry", but the asymmetric click cycloaddition of internal alkynes still remains challenging. A new asymmetric Rh-catalyzed click cycloaddition of N-alkynylindoles with azides was developed, providing atroposelective access to C-N axially chiral triazolyl indoles, a new type of heterobiaryl, with excellent yields and enantioselectivity. This asymmetric approach is efficient, mild, robust and atom-economic, and features very broad substrate scope with easily available Tol-BINAP ligands.

Immune-check blocking combination multiple cytokines shown curative potential in mice tumor model.

OBJECTIVE: In order to ensure the stable transcription of target genes, we constructed a eukaryotic high expression vector carrying an immune-check inhibitor PD-1v and a variety of cytokines, and studied their effects on activating immune response to inhibit tumor growth. METHODS: A novel eukaryotic expression plasmid vector named pT7AMPCE containing T7RNA polymerase, T7 promoter, internal ribosome entry site (IRES), and poly A tailing signal was constructed by T4 DNA ligase, on which homologous recombination was used to clone and construct the vector carrying PD-1v, IL-2/15, IL-12, GM-CSF, and GFP. In vitro transfection of CT26 cells was performed, and the protein expression of PD-1v, IL-12 and GM-CSF was detected by Western blot and ELISA after 48 h. Mice were subcutaneously inoculated with CT26-IRFP tumor cells in the rib abdomen, and the tumor tissues were injected with PD-1v, IL-2/15, IL-12, and GM-CSF recombinant plasmids for treatment during the experimental period. The efficacy of the treatment was evaluated by assay tumor size and survival time of tumor-bearing mice during the experiment. Expression levels of IFN-γ, TNF, IL-4, IL-2, and IL-5 in mouse blood were measured using the CBA method. Tumor tissues were extracted and immune cell infiltration in tumor tissues was detected by HE staining and the IHC method. RESULTS: The recombinant plasmids carrying PD-1v, IL-2/15, IL-12, and GM-CSF were successfully constructed, and the Western blot and ELISA results showed that PD-1v, IL-12, and GM-CSF were expressed in the supernatant of CT26 cells 48 h after in vitro cell transfection. The combined application of PD-1v, IL-2/15, IL-12, and GM-CSF recombinant plasmids significantly inhibited tumor growth in mice, and the tumor growth rate was significantly lower than that in the blank control group and GFP plasmid control group (p < 0.05). Cytometric bead array data suggested that the combination of PD-1v and various cytokines can effectively activate immune cells. HE and IHC analysis revealed plenty of immune cell infiltrates in the tumor tissue, and a large proportion of tumor cells showed the necrotic phenotype in the combination treatment group. CONCLUSION: The combination of immune check blockade and multiple cytokine therapy can significantly activate the body's immune response and inhibit tumor growth.

Topological Photonic Lattice for Uniform Beam Splitting, Robust Routing, and Sensitive Far-Field Steering.

Far-field optical beam steering is a fast-growing technology for communications, spatial ranging, and detections. Nonmechanical optical phased arrays based on straight waveguides have been studied recently, where the beam emission angle to the propagation axis can be scanned by conveniently tuning the wavelength. However, the dispersion of the waveguide limits the wavelength sensitivity of beam steering and the deliberately created emitters inevitably introduce in-line backscattering on-chip. To overcome these limitations, here, we report a robust and back-reflection-free topological photonic integrated circuit, where different functionalities, such as beam splitting, routing, and far-field steering, are defined by strategic arrangements of lattices with different topological modulations simply controlled by a single lattice deformation parameter. Benefiting from the robust topological scheme, an extra band flattening is applied to achieve far-field steering with high wavelength sensitivity.

One-Step Synthesis of Self-Stratification Core-Shell Latex for Antimicrobial Coating.

Herein, we describe a one-step method for synthesizing cationic acrylate-based core-shell latex (CACS latex), which is used to prepare architectural coatings with excellent antimicrobial properties. Firstly, a polymerizable water-soluble quaternary ammonium salt (QAS-BN) was synthesized using 2-(Dimethylamine) ethyl methacrylate (DMAEMA) and benzyl bromide by the Hoffman alkylation reaction. Then QAS-BN, butyl acrylate (BA), methyl methacrylate (MMA), and vinyltriethoxysilane (VTES) as reactants and 2,2'-azobis(2-methylpropionamidine) dihydrochloride (AIBA) as a water-soluble initiator were used to synthesize the CACS latex. The effect of the QAS-BN dosage on the properties of the emulsion and latex film was systematically investigated. The TGA results showed that using QAS-BN reduced the latex film's initial degradation temperature but improved its thermal stability. In the transmission electron microscopy (TEM) photographs, the self-stratification of latex particles with a high dosage of QAS-BN was observed, forming a core-shell structure of latex particles. The DSC, TGA, XPS, SEM, and performance tests confirmed the core-shell structure of the latex particles. The relationship between the formation of the core-shell structure and the content of QAS-BN was proved. The formation of the core-shell structure was due to the preferential reaction of water-soluble monomers in the aqueous phase, which led to the aggregation of hydrophilic groups, resulting in the formation of soft-core and hard-shell latex particles. However, the water resistance of the films formed by CACS latex was greatly reduced. We introduced a p-chloromethyl styrene and n-hexane diamine (p-CMS/EDA) crosslinking system, effectively improving the water resistance in this study. Finally, the antimicrobial coating was prepared with a CACS emulsion of 7 wt.% QAS-BN and 2 wt.% p-CMS/EDA. The antibacterial activity rates of this antimicrobial coating against E. coli and S. aureus were 99.99%. The antiviral activity rates against H3N2, HCoV-229E, and EV71 were 99.4%, 99.2%, and 97.9%, respectively. This study provides a novel idea for the morphological design of latex particles. A new architectural coating with broad-spectrum antimicrobial properties was obtained, which has important public health and safety applications.

Transcutaneous auricular vagus nerve stimulation reduces cytokine production in sepsis: An open double-blind, sham-controlled, pilot study.

BACKGROUND: Studies have shown that vagus nerve-mediated inflammatory reflex could inhibit cytokine production and inflammation in sepsis animals. OBJECTIVES: This study aimed to explore the efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) on inflammation and disease severity of sepsis patients. METHODS: A randomized, double-blind, sham-controlled pilot study was performed. Twenty sepsis patients were randomly assigned to receive taVNS or sham stimulation for five consecutive days. Stimulation effect was assessed with serum cytokine levels, Acute Physiology and Chronic Health Evaluation (APACHE) Ⅱ score, and Sequential Organ Failure Assessment (SOFA) score at baseline and on Day 3, Day 5, and Day 7. RESULTS: TaVNS was well tolerated in the study population. Patients receiving taVNS experienced significant reductions in serum TNF-α and IL-1ß levels and increases in IL-4 and IL-10 levels. SOFA scores decreased on Day 5 and Day 7 compared with baseline in the taVNS group. However, no changes were found in sham stimulation group. The changes of cytokine from Day 7 to Day 1 were greater with taVNS than sham stimulation. No differences in the APACHE Ⅱ score and SOFA score were observed between the two groups. CONCLUSIONS: TaVNS resulted in significantly lower serum pro-inflammatory cytokines and higher serum anti-inflammatory cytokines in sepsis patients.

Promotion of bone formation and antibacterial properties of titanium coated with porous Si/Ag-doped titanium dioxide.

Implant materials are mainly used to repair and replace defects in human hard tissue (bones and teeth). Titanium (Ti) and Ti alloys are widely used as implant materials because of their good mechanical properties and biocompatibilities, but they do not have the ability to induce new bone formation and have no antibacterial properties. Through surface modification, Ti and its alloys have certain osteogenic and antibacterial properties such that Ti implants can meet clinical needs and ensure integration between Ti implants and bone tissue, and this is currently an active research area. In this study, bioactive Si and Ag were introduced onto a Ti surface by plasma oxidation. The surface morphology, structure, elemental composition and valence, surface roughness, hydrophilicity and other physical and chemical properties of the coating were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), a profiler and a contact angle meter (CA). Adhesion and extensions of osteoblasts on the surface of the material were observed by scanning electron microscopy, and mineralization of osteoblasts on the surface of the material were observed by alizarin red staining. The antibacterial properties of the material were tested by culturing Staphylococcus aureus on the surface of the material. The osteogenic properties of Ti implants with porous Si/Ag TiO2 (TCP-SA) coatings were evaluated with in vivo experiments in rats. The results showed that Si and Ag were successfully introduced onto the Ti surface by plasma oxidation, and doping with Si and Ag did not change the surface morphology of the coating. The osteoblasts showed good adhesion and extension on the surfaces of Si/Ag coated samples, and the porous Si/Ag TiO2 coating promoted cell proliferation and mineralization. The bacterial experiments showed that the porous TiO2 coatings containing Si/Ag had certain antibacterial properties. The animal experiments showed that Si/Ag-coated Ti implants promoted integration between the implants and the surrounding bone. It was concluded that the porous Si/Ag TiO2 coating on the Ti surface had good osteogenic and antibacterial properties and provides an optimal strategy for improving the osteogenic and antibacterial properties of Ti implants.

Synthesis of Benzofuran Derivates via a Gold-Catalyzed Claisen Rearrangement Cascade.

A novel method toward a facile synthesis of diverse benzofuran derivates from easily obtained quinols and alkynyl esters has been reported. A gold-catalyzed intermolecular alkoxylation/Claisen rearrangement/condensation cascade was involved. The introduction of difluorodiphenylsilane as a water-trapping reagent in the reaction leads to a higher yield.

New indication of Chuankezhi injection for steroid-resistant focal segmental glomerulosclerosis and its mechanism of action.

Background: Chuankezhi (CKZ) injection is a traditional Chinese medicine (TCM) injection extracted from Chinese herbs Epimedium sagittatum (Yin Yang Huo) and Morinda officinalis (Bai Ji Tian). Studies have shown that CKZ has a positive effect on improving diabetic nephropathy and regulating immune function. Focal segmental glomerulosclerosis (FSGS) is a kind of refractory nephropathy, which has been confirmed as closely associated with immunity. Whether CKZ is effective against FSGS and how it works warrant further study. This study aimed to verify the efficacy of CKZ in rats with steroid-resistant (SR) FSGS and explore its mechanism of action. Methods: We established an SR FSGS model in male Sprague Dawley (SD) rats by injecting adriamycin into the tail vein. Based on group intervention and comparison, the primary efficacy parameters of FSGS were observed, including general condition, 24-hour urine protein, serum albumin, cholesterol, triglyceride, and renal pathological changes. Network pharmacological analysis and molecular docking were used to predict the mechanism of action of CKZ. Finally, we used quantitative polymerase chain reaction (qPCR) and western blot (WB) to detect messenger RNA (mRNA) expression and protein phosphorylation at specific targets in rat kidney tissue to validate the predicted results. Results: Intramuscular injection of CKZ had a dose-dependent effect in SR FSGS model rats, including lowering urine protein, increasing serum albumin, lowering cholesterol and triglyceride, and treating pathological lesions in the kidney. Network pharmacological analysis and Molecular docking revealed that 5 active components (Icariin, Icariside II, Epimedin C, Icaritin, and Noricaritin) might be the critical components. The findings also revealed that Akt was perhaps the critical target gene, the PI3K-Akt signaling pathway was perhaps the critical pathway, and reversible protein phosphorylation was probably the critical biological process. The qPCR and WB analyses showed that CKZ significantly increased the relative mRNA expression and protein phosphorylation of PI3K and Akt, respectively. Conclusions: This study showed that intramuscular injection of CKZ has a significant therapeutic effect in SR FSGS rats, which may be associated with the activation of PI3K-Akt signaling by CKZ.

CircFAT1 Promotes Lung Adenocarcinoma Progression by Sequestering miR-7 from Repressing IRS2-ERK-mediated CCND1 Expression.

Our understanding of coding gene functions in lung cancer leads to the development of multiple generations of targeted drugs. Noncoding RNAs, including circular RNAs (circRNAs), have been demonstrated to play a vital role in tumorigenesis. Uncovering the functions of circRNAs in tumorigenesis and their underlying regulatory mechanisms may shed new light on the development of novel diagnostic and therapeutic strategies for human cancer. Here we report the important role of circFAT1 in lung adenocarcinoma (LUAD) progression and the potential impact of circFAT1 on LUAD treatment. We found that circFAT1 was one of the top expressed circRNAs in A549 cells by circRNA-seq and was significantly upregulated in human LUAD tissues. Multiple cellular assays with A549 and PC9 LAUD cell lines under both gain-of-function and loss-of-function conditions demonstrated that circFAT1 promoted proliferation of LUAD cells in vitro and in vivo. At molecular level, circFAT1 sequestered miR-7 to upregulate IRS2, which in turn regulated downstream ERK1/2 phosphorylation and CCND1 expression, ultimately promoting tumor progression. In addition, we showed that DDP treatment was much more effective in circFAT1 knockdown tumor cells in vitro and in a xenograft tumor model. Our results indicate that circFAT1 promote tumorigenesis in LUAD through sequestering miR-7, consequently upregulating IRS2-ERK1/2-mediated CCND1 expression, and can be a valuable therapeutic target and an important parameter for precision treatment in LUAD patients.

Metabolism reprogramming signature associated with stromal cells abundance in tumor microenvironment improve prognostic risk classification for gastric cancer.

BACKGROUND: Stromal cells play an important role in the process of tumor progression, but the relationship between stromal cells and metabolic reprogramming is not very clear in gastric cancer (GC). METHODS: Metabolism-related genes associated with stromal cells were identified in The Cancer Genome Atlas (TCGA) and GSE84437 datasets, and the two datasets with 804 GC patients were integrated into a training cohort to establish the prognostic signature. Univariate Cox regression analysis was used to screen for prognosis-related genes. A risk score was constructed by LASSO regression analysis combined with multivariate Cox regression analysis. The patients were classified into groups with high and low risk according to the median value. Two independent cohorts, GSE62254 (n = 300) and GSE15459 (n = 191), were used to externally verify the risk score performance. The CIBERSORT method was applied to quantify the immune cell infiltration of all included samples. RESULTS: A risk score consisting of 24 metabolic genes showed good performance in predicting the overall survival (OS) of GC patients in both the training (TCGA and GSE84437) and testing cohorts (GSE62254 and GSE15459). As the risk score increased, the patients' risk of death increased. The risk score was an independent prognostic indicator in both the training and testing cohorts suggested by the univariate and multivariate Cox regression analyses. The patients were clustered into four subtypes according to the quantification of 22 kinds of immune cell infiltration (ICI). The proportion of ICI Cluster C with the best prognosis in the low-risk group was approximately twice as high as that in the high-risk group, and the risk score of ICI Cluster C was significantly lower than that of the other three subtypes. CONCLUSION: Our study proposed the first scheme for prognostic risk classification of GC from the perspective of tumor stromal cells and metabolic reprogramming, which may contribute to the development of therapeutic strategies for GC.

Aging Promotes Chronic Stress-Induced Depressive-Like Behavior by Activating NLRP1 Inflammasome-Driven Inflammatory Signaling in Mice.

NLRP1 inflammasome has been reported to participate in many neurological disorders. Our previous study has demonstrated that NLRP1 inflammasome is implicated in chronic stress-induced depressive-like behaviors in mice. Age has been reported to be related to depression. Here we examine whether NLRP1 inflammasome is involved in the effect of age on depressive disorder. Two chronic stress stimuli, chronic social defeat stress (CSDS) and repeat social defeat stress (RSDS), were used to establish a depression model in mice of different ages. We found that aged mice exhibited worse depressive-like behaviors and locomotor activity compared to young mice. Interestingly, the expression of hippocampal NLRP1 inflammasome complexes and the levels of the inflammatory cytokines were increased in an age-dependent manner. Also, chronic stress-induced increase in the expression of the hippocampal chemokine C-X-C motif ligand 1 (CXCL1), and its cognate receptor, CXC-motif receptor 2 (CXCR2), was more remarkable in aged mice than that in young mice. Moreover, aged mice exhibited lower hippocampal BDNF levels compared to young mice. Hippocampal Nlrp1a knockdown reduced the levels of pro-inflammatory cytokines and the expression of CXCL1/CXCR2, restored BDNF levels, and alleviated chronic stress-induced depressive-like behaviors in aged mice. Our results suggest that NLRP1 inflammasome-CXCL1/CXCR2-BDNF signaling contributes to the effect of age on chronic stress-induced depressive-like behavior in mice.

NAD+ Anabolism Disturbance Causes Glomerular Mesangial Cell Injury in Diabetic Nephropathy.

The homeostasis of NAD+ anabolism is indispensable for maintaining the NAD+ pool. In mammals, the mainly synthetic pathway of NAD+ is the salvage synthesis, a reaction catalyzed by nicotinamide mononucleotide adenylyltransferase (NAMPT) and nicotinamide mononucleotide adenylyltransferase (NMNATs) successively, converting nicotinamide (NAM) to nicotinamide mononucleotide (NMN) and NMN to NAD+, respectively. However, the relationship between NAD+ anabolism disturbance and diabetic nephropathy (DN) remains elusive. Here our study found that the disruption of NAD+ anabolism homeostasis caused an elevation in both oxidative stress and fibronectin expression, along with a decrease in Sirt1 and an increase in both NF-κB P65 expression and acetylation, culminating in extracellular matrix deposition and globular fibrosis in DN. More importantly, through constitutively overexpressing NMNAT1 or NAMPT in human mesangial cells, we revealed NAD+ levels altered inversely with NMN levels in the context of DN and, further, their changes affect Sirt1/NF-κB P65, thus playing a crucial role in the pathogenesis of DN. Accordingly, FK866, a NAMPT inhibitor, and quercetin, a Sirt1 agonist, have favorable effects on the maintenance of NAD+ homeostasis and renal function in db/db mice. Collectively, our findings suggest that NMN accumulation may provide a causal link between NAD+ anabolism disturbance and diabetic nephropathy (DN) as well as a promising therapeutic target for DN treatment.

Oleic acid reduces steroidogenesis by changing the lipid type stored in lipid droplets of ovarian granulosa cells.

BACKGROUND: Oleic acid is an abundant free fatty acid present in livestock that are in a negative energy-balance state, and it may have detrimental effects on female reproduction and fertility. Oleic acid induces lipid accumulation in bovine granulosa cells, which leads to a foam cell-like morphology and reduced steroidogenesis. However, why oleic acid increases lipid accumulation but decreases steroidogenesis remains unclear. This study focused on oleic acid's effects on lipid type and steroidogenesis. RESULTS: Oleic acid increased the lipid accumulation in a concentration-dependent manner and mainly increased the triglyceride level and decreased the cholesterol ester level. Oleic acid also led to a decline in estradiol and progesterone production in porcine granulosa cells in vitro. In addition, oleic acid up-regulated the expression of CD36 and diacylglycerol acyltransferase 2, but down-regulated the expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, scavenger receptor class B member 1 and acetyl-Coenzyme A acetyltransferase 2, as well as steroidogenesis-related genes, including cytochrome P450 family 11 subfamily A member 1, cytochrome P450 family 19 subfamily A member 1 and 3 as well as steroidogenic acute regulatory protein at the mRNA and protein levels. An oleic acid-rich diet also enhanced the triglyceride levels and reduced the cholesterol levels in ovarian tissues of female mice, which resulted in lower estradiol levels than in control-fed mice. Compared with the control, decreases in estrus days and the numbers of antral follicles and corpora lutea, as well as an increase in the numbers of the atretic follicles, were found in the oleic acid-fed female mice. CONCLUSIONS: Oleic acid changed the lipid type stored in lipid droplets of ovarian granulosa cells, and led to a decrease in steroidogenesis. These results improve our understanding of fertility decline in livestock that are in a negative energy-balance state.