Osteoporosis treatment: current drugs and future developments.

Osteoporosis is a common systemic metabolic disease characterized by a decrease in bone density and bone mass, destruction of bone tissue microstructure, and increased bone fragility leading to fracture susceptibility. Pharmacological treatment of osteoporosis is the focus of current research, and anti-osteoporosis drugs usually play a role in inhibiting bone resorption, promoting bone formation, and having a dual role. However, most of the drugs have the disadvantages of single target and high toxic and side effects. There are many types of traditional Chinese medicines (TCM), from a wide range of sources and mostly plants. Herbal plants have unique advantages in regulating the relationship between osteoporosis and the immune system, acupuncture therapy has significant therapeutic effects in combination with medicine for osteoporosis. The target cells and specific molecular mechanisms of TCM in preventing and treating osteoporosis have not been fully elucidated. At present, there is a lack of comprehensive understanding of the pathological mechanism of the disease. Therefore, a better understanding of the pathological signaling pathways and key molecules involved in the pathogenesis of osteoporosis is crucial for the design of therapeutic targets and drug development. In this paper, we review the development and current status of anti-osteoporosis drugs currently in clinical application and under development to provide relevant basis and reference for drug prevention and treatment of osteoporosis, with the aim of promoting pharmacological research and new drug development.

The Protection of Astragalus Polysaccharide in BALB/C Mice during Brucella melitensis M5 Infection.

INTRODUCTION: Brucellosis is an important zoonosis worldwide, affecting humans and animals. There are no specific medicines available to treat brucellosis. Astragalus polysaccharide (APS) is derived from Astragalus membranaceus and exhibits impressive bioactivity, including anti-aging, anti-tumor, and immunomodulatory functions. METHODS: Mice were intraperitoneally inoculated with Brucella melitensis M5 and then treated with APS intraperitoneally injection daily for 7 d. RESULTS: Compared to the M5-infected group, the lower bacteria loads in the APS-treated groups were proved, especially at the acute stage of infection. APS treatment relieved splenomegaly, excess expressions of several pro-inflammatory cytokines (including CXCL1, IFN-γ, IL-1ß, IL-2, IL-12p70, and TNF-α). The raised level of IL-4 was observed in APS-treated mice. APS contributed to raising the ratio of M1 macrophage and reducing the ratio of M2 macrophage in the blood. DISCUSSION: The present study provides some evidence on the potential application of APS in controlling and treating brucellosis and should be further explored.

Direct Synthesis for Benzofuro[3,2-d]pyrimidin-2-Amines via One-Pot Cascade [4 + 2] Annulation/Aromatization between Benzofuran-Derived Azadienes and Carbodiimide Anions.

The chemoselective [4+2] annulation/aromatization reactions between benzofuran-derived azadienes and N-Ts cyanamides are developed, affording a convenient method for synthesizing benzofuro[3,2-d]pyrimidin-2-amines under mild conditions. Herein, N-Ts cyanamides selectively participated in reactions absolutely via carbodiimide anion intermediates and the corresponding cyanamide anion intermediates derived products were not observed. The proposed chemoselective stepwise reaction mechanism was well supported by DFT calculations.

miR-331-depleted exosomes derived from injured endometrial epithelial cells promote macrophage activation during endometritis.

Exosomes are natural carriers of biological macromolecules that are involved in the pathogenesis of a wide variety of inflammatory diseases. The purpose of this study was to investigate the role of exosomes derived from injured endometrial epithelial cells (EECs) in the development of endometritis. We isolated exosomes derived from LPS-injured EECs and identified these exosomes as proinflammatory mediators that can be internalized by macrophages and thus induce proinflammatory macrophage activation. We further found that miR-331 expression was sharply downregulated in exosomes derived from LPS-injured EECs and that macrophages treated with these exosomes also presented a lower level of miR-331. Importantly, the pathogenic role of exosomal miR-331 in promoting endometrial inflammation was revealed by the ability of adoptively transferred EECs-derived exosomes to cause macrophage activation, and this was reversed by miR-331 overexpression. Mechanistically, overexpression of miR-331 in macrophages mitigated NF-κB p65 phosphorylation by inhibiting the Notch1/IKKα pathway, which in turn curbed macrophage activation. In vivo assays further unveiled that miR-331 expression is negatively correlated with proinflammatory macrophage activation and that miR-331 upregulation markedly slowed disease progression in mice with endometritis. The exosome/miR-331/Notch1 axis plays a critical pathological role in endometrial inflammation, representing a new therapeutic target for endometritis.

Development and validation of a nomogram predictive model for cognitive impairment in cerebral small vessel disease: a comprehensive retrospective analysis.

Background: Cerebral small vessel disease (CSVD) is a common neurodegenerative condition in the elderly, closely associated with cognitive impairment. Early identification of individuals with CSVD who are at a higher risk of developing cognitive impairment is crucial for timely intervention and improving patient outcomes. Objective: The aim of this study is to construct a predictive model utilizing LASSO regression and binary logistic regression, with the objective of precisely forecasting the risk of cognitive impairment in patients with CSVD. Methods: The study utilized LASSO regression for feature selection and logistic regression for model construction in a cohort of CSVD patients. The model's validity was assessed through calibration curves and decision curve analysis (DCA). Results: A nomogram was developed to predict cognitive impairment, incorporating hypertension, CSVD burden, apolipoprotein A1 (ApoA1) levels, and age. The model exhibited high accuracy with AUC values of 0.866 and 0.852 for the training and validation sets, respectively. Calibration curves confirmed the model's reliability, and DCA highlighted its clinical utility. The model's sensitivity and specificity were 75.3 and 79.7% for the training set, and 76.9 and 74.0% for the validation set. Conclusion: This study successfully demonstrates the application of machine learning in developing a reliable predictive model for cognitive impairment in CSVD. The model's high accuracy and robust predictive capability provide a crucial tool for the early detection and intervention of cognitive impairment in patients with CSVD, potentially improving outcomes for this specific condition.

P7C3 suppresses astrocytic senescence to protect dopaminergic neurons: Implication in the mouse model of Parkinson's disease.

AIMS: Astrocytic senescence is inextricably linked to aging and neurodegenerative disorders, including Parkinson's disease (PD). P7C3 is a small, neuroprotective aminopropyl carbazole compound that exhibits anti-inflammatory properties. However, the effects of P7C3 on astrocytic senescence in PD remain to be elucidated. METHODS: An in vitro, long culture-induced, replicative senescence cell model and a 1-methyl-4-phenylpyridinium (MPP+)/rotenone-induced premature senescence cell model were used to investigate the effects of P7C3 on astrocytic senescence. An in vivo, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse PD model was used to study the role of P7C3 in astrocytic senescence. Immunoblotting, real-time quantitative RT-PCR (qPCR), immunofluorescence, subcellular fractionation assays, and immunohistochemistry were utilized to confirm the effects of P7C3 on astrocytic senescence and elucidate its underlying mechanisms. RESULTS: This study determined that P7C3 suppressed the senescence-associated secretory phenotype (SASP) in both cell models, as demonstrated by the reduction in the critical senescence marker p16 and proinflammatory factors (IL-6, IL-1ß, CXCL10, and MMP9) and increased laminB1 levels, implying that P7C3 inhibited replicative astrocytic senescence and MPP+/rotenone-induced premature astrocytic senescence, Most importantly, we demonstrated that P7C3 prevented the death of dopamine (DA) neurons and reduced the behavioral deficits in the MPTP-induced mouse model of PD, which is accompanied by a decrease in senescent astrocytes in the substantia nigra compacta (SNc). Mechanistically, P7C3 promoted Nrf2/Sirt3-mediated mitophagy and reduced mitochondrial reactive oxygen species (mitoROS) generation, which contributed to the suppression of astrocytic senescence. Furthermore, Sirt3 deficiency obviously abolished the inhibitory effects of P7C3 on astrocytic senescence. CONCLUSION: This study revealed that P7C3 inhibited astrocytic senescence via increased Nrf2/Sirt3-mediated mitophagy and suppression of mitoROS, which further protected against DA neuronal loss. These observations provide a prospective theoretical basis for P7C3 in the treatment of age-associated neurodegenerative diseases, such as PD.

Synergistic induction of mitotic pyroptosis and tumor remission by inhibiting proteasome and WEE family kinases.

Mitotic catastrophe (MC), which occurs under dysregulated mitosis, represents a fascinating tactic to specifically eradicate tumor cells. Whether pyroptosis can be a death form of MC remains unknown. Proteasome-mediated protein degradation is crucial for M-phase. Bortezomib (BTZ), which inhibits the 20S catalytic particle of proteasome, is approved to treat multiple myeloma and mantle cell lymphoma, but not solid tumors due to primary resistance. To date, whether and how proteasome inhibitor affected the fates of cells in M-phase remains unexplored. Here, we show that BTZ treatment, or silencing of PSMC5, a subunit of 19S regulatory particle of proteasome, causes G2- and M-phase arrest, multi-polar spindle formation, and consequent caspase-3/GSDME-mediated pyroptosis in M-phase (designated as mitotic pyroptosis). Further investigations reveal that inhibitor of WEE1/PKMYT1 (PD0166285), but not inhibitor of ATR, CHK1 or CHK2, abrogates the BTZ-induced G2-phase arrest, thus exacerbates the BTZ-induced mitotic arrest and pyroptosis. Combined BTZ and PD0166285 treatment (named BP-Combo) selectively kills various types of solid tumor cells, and significantly lessens the IC50 of both BTZ and PD0166285 compared to BTZ or PD0166285 monotreatment. Studies using various mouse models show that BP-Combo has much stronger inhibition on tumor growth and metastasis than BTZ or PD0166285 monotreatment, and no obvious toxicity is observed in BP-Combo-treated mice. These findings disclose the effect of proteasome inhibitors in inducing pyroptosis in M-phase, characterize pyroptosis as a new death form of mitotic catastrophe, and identify dual inhibition of proteasome and WEE family kinases as a promising anti-cancer strategy to selectively kill solid tumor cells.

Bariatric arterial embolization slows gastric emptying and improves postprandial glycaemia in obese dogs with impaired glucose tolerance.

AIM: To evaluate the effects of bariatric arterial embolization (BAE) on gastric emptying of, and the glycaemic response to, an oral glucose load in an obese canine model with impaired glucose tolerance. METHODS: Eleven male dogs were fed a high-fat, high-fructose diet for 7 weeks before receiving BAE, which involved selective embolization of the left gastric artery (n = 5; 14.9 ± 0.8 kg), or the sham (n = 6; 12.6 ± 0.8 kg) procedure. Postprocedural body weight was measured weekly for 4 weeks. Prior to and at 4 weeks postprocedure, a glucose solution containing 13C-acetate was administered orally for evaluation of the gastric half-emptying time (T50) and the glycaemic response. The relationship between the changes in the blood glucose area under the curve over the first 60 minutes (AUC0-60min) and the T50 was also assessed. RESULTS: At 4 weeks postprocedure, BAE reduced body weight (BAE vs. the sham procedure: -5.7% ± 0.9% vs. 3.5% ± 0.9%, P < .001), slowed gastric emptying (T50 at baseline vs. postprocedure: 75.5 ± 2.0 vs. 82.5 ± 1.8 minutes, P = .021 in the BAE group; 73.8 ± 1.8 vs. 74.3 ± 1.9 minutes in the sham group) and lowered the glycaemic response to oral glucose (AUC0-60min at baseline vs. postprocedure: 99.2 ± 13.7 vs. 67.6 ± 9.8 mmol·min/L, P = .043 in the BAE group; 100.2 ± 13.4 vs. 103.9 ± 14.6 mmol·min/L in the sham group). The change in the glucose AUC0-60min correlated inversely with that of the T50 (r = -0.711; P = .014). CONCLUSIONS: In a canine model with impaired glucose tolerance, BAE, while reducing body weight, slowed gastric emptying and attenuated the glycaemic response to an oral glucose load.

GutUDB: A comprehensive multiomics database for intestinal diseases.

Gut Universe Database (GutUDB) provides a comprehensive, systematic, and practical platform for researchers, and is dedicated to the management, analysis, and visualization of knowledge related to intestinal diseases. Based on this database, eight major categories of omics data analyses are carried out to explore the genotype-phenotype characteristics of a certain intestinal disease. The first tool for comprehensive omics data research on intestinal diseases will help each researcher better understand intestinal diseases.

Rapid and Sensitive Quantification of Bacterial Viability Using Ratiometric Fluorescence Sensing.

Bacterial viability assessment plays an important role in food-borne pathogen detection and antimicrobial drug development. Here, we first used GelRed as a DNA-binding stain for a bacterial viability assessment. It was found that live bacteria were able to exclude GelRed, which however could easily penetrate dead ones and be absorbed nonspecifically on the bacterial periplasm. Cations were used to reduce the nonspecific adsorption and greatly increase the red fluorescence ratio of dead to live bacteria. Combined with SYTO 9 (a membrane-permeable dye) for double-staining, a ratiometric fluorescent method was established. Using Escherichia coli O157:H7 as a bacteria model, the ratiometric fluorescent method can probe dead bacteria as low as 0.1%. A linear correlation between the ratiometric fluorescence and the theoretical ratio of dead bacteria was acquired, with a correlation coefficient R2 of 0.97. Advantages in sensitivity, accuracy, and safety of the GelRed/SYTO9-based ratiometric fluorescent method against traditional methods were demonstrated. The established method was successfully applied to the assessment of germicidal efficacy of different heat treatments. It was found that even 50 °C treatment could lead to the death of minor bacteria. The as-developed method has many potential applications in microbial researches, and we believe it could be expanded to the viability assessment of mammalian cells.

The effect of body mass index on stroke prognosis: A systematic review and meta-analysis of 32 cohort studies with 330,353 patients.

BACKGROUND: Many studies have explored the impact of body mass index (BMI) on stroke prognosis, yet findings remain inconsistent. AIMS: The aims of this study were to conduct a systematic review and meta-analyses to summarize the existing evidence on BMI and stroke outcomes. METHODS: PubMed, Web of Science, Embase, The Cochrane Library, CNKI, CBM, Wanfang Database, and VIP Database were systematically searched from inception to 1 January 2023. Cohort studies were included if they reported on a population of patients with stroke, evaluated BMI on stroke outcomes (mortality/recurrence/score of modified Rankin scale (mRs)), and reported original data. Data extraction and quality assessment were independently undertaken by two reviewers. Stata 16.0 software was used for meta-analysis. RESULTS: Thirty-two studies involving 330,353 patients (5 Chinese language articles) were included in the analysis. The proportion of underweight, overweight, and obese patients was 1.85%, 18.2%, and 15.6%, respectively. Compared with normal weight, being underweight was associated with an increased risk of mortality (relative risk (RR) = 1.78, 95% confidence interval (CI) = 1.60-1.96), poor functional outcomes defined as modified Rankin scale ⩾ 3 (RR = 1.33, 95% CI = 1.22-1.45), and stroke recurrence (RR = 1.19, 95% CI = 1.04-1.37). Being overweight but not obese was associated with reduced mortality (RR = 0.81, 95% CI = 0.74-0.89) and better functional outcomes (RR = 0.92, 95% CI = 0.89-0.96), but did not alter the risk of stroke recurrence (RR = 1.03, 95% CI = 0.90-1.17). Obesity was associated with lower risk of mortality (RR = 0.76, 95% CI = 0.72-0.81) and better functional outcomes (RR = 0.89, 95% CI = 0.84-0.94). CONCLUSIONS: Our findings indicate that in patients with stroke, being underweight is associated with an increased risk of mortality, poor functional outcomes, and stroke recurrence. In contrast, being overweight but not obese, or being obese, was associated with a decreased risk of mortality and better functional outcomes. This is consistent with the obesity paradox in stroke, whereby obesity increases stroke risk in the general population but is associated with improved outcome in patients suffering stroke.

Gelatin nanocarriers assembled by a self-immolative cross-linker for targeted cancer therapy.

With a number of outstanding properties, gelatin is an ideal candidate for assembling nanoplatforms in biomedical applications. Generally, gelatin nanocarriers are cross-linked by aldehydes to improve their stability in water solution. However, aldehydes could cause multiple toxicities and their cross-linking products are uncontrollable. Here, we first used a self-immolative cross-linker to assemble gelatin nanocarriers for the controlled release of drugs and targeted cancer therapy. The cross-linker contains a disulphide bridge and two symmetrical succinimidyl-esters, endowing it with multiple functions: 1) to cross-link the gelatin nanocarriers and thus improve their stability in water; 2) to conjugate the drug and tumor-targeting ligands with nanocarriers through covalent linkage; 3) to redox-responsively degrade the nanocarriers through hydrolysis of disulphide bridge; and 4) to produce traceless drug molecules through self-immolative reaction. Good biocompatibility and controllable drug release were demonstrated by in vitro experiments. Both qualitative and quantitative analyses confirmed the intracellular uptake of the nanocarriers by using doxorubicin (DOX) as a drug model and phenylboronic acid (PBA) as the targeting ligand. In vivo results demonstrated high therapeutic efficiency and low toxic side effects of the DOX loaded nanocarriers against artificial liver tumors.

Deep Learning-Assisted Colorimetric/Electrical Dual-Sensing System for Ultrafast Detection of Hydrogen Sulfide.

This study presents a colorimetric/electrical dual-sensing system (CEDS) for low-power, high-precision, adaptable, and real-time detection of hydrogen sulfide (H2S) gas. The lead acetate/poly(vinyl alcohol) (Pb(Ac)2/PVA) nanofiber film was transferred onto a polyethylene terephthalate (PET) flexible substrate by electrospinning to obtain colorimetric/electrical sensors. The CEDS was constructed to simultaneously record both the visual and electrical response of the sensor, and the improved Manhattan segmentation algorithm and deep neural network (DNN) were used as its intelligent algorithmic aids to achieve quantitative exposure to H2S. By exploring the mechanism of color change and resistance response of the sensor, a dual-sensitivity mechanism explanation model was proposed to verify that the system, as a dual-mode parallel system, can adequately solve the sensor redundancy problem. The results show that the CEDS can achieve a wide detection range of H2S from 0.1-100 ppm and identify the H2S concentration in 4 s at the fastest. The sensor can be stabilized for 180 days with excellent selectivity and a low limit of detection (LOD) to 0.1 ppm of H2S. In addition, the feasibility of the CEDS for measuring H2S levels in underground waterways was validated. This work provides a new method for adaptable, wide range of applications and low-power, high-precision H2S gas detection.

Insufficient secretion of pancreatic FGF21 is the toxicological mechanism and therapeutic target of asparaginase-associated pancreatitis.

Asparaginase-associated pancreatitis (AAP) is a severe and potentially life-threatening drug-induced pancreas targeted toxicity in the combined chemotherapy of acute lymphoblastic leukemia among children and adolescents. The toxicological mechanism of AAP is not yet clear, and there are no effective preventive and treatment measures available clinically. Fibroblast growth factor 21 (FGF21) is a secretory hormone that regulates lipid, glucose, and energy metabolism balance. Acinar tissue is the main source of pancreatic FGF21 protein and plays an important role in maintaining pancreatic metabolic balance. In this study, we found that the decrease of FGF21 in pancreas is closely related to AAP. Pegaspargase (1 IU/g) induces widespread edema and inflammatory infiltration in the pancreas of rats/mice. The specific expression of FGF21 in the acinar tissue of AAP rats was significantly downregulated. Asparaginase caused dysregulation of the ATF4/ATF3/FGF21 axis in acinar tissue or cells, and thus mediated the decrease of FGF21. It greatly activated ATF3 in the acinar, which competed with ATF4 for the Fgf21 promoter, thereby inhibiting the expression of FGF21. Pharmacological replacement of FGF21 (1 mg/kg) or PERK inhibitors (GSK2656157, 25 mg/kg) can significantly mitigate the pancreatic tissue damage and reduce markers of inflammation associated with AAP, representing potential strategies for the prevention and treatment of AAP.

In Situ Growth 3D GDY-NCNTs Nanocomposites for High-Performance Supercapacitors.

New binary carbon composites (GDY-NCNTs and GDY-CNTs) with a three-dimensional porous structure, which are synthesized by an in situ growth method, are adopted in this article. The GDY-NCNTs composites exhibit excellent specific capacitance performance (679 F g-1, 2 mV s-1, 139% increase compared to GDY-CNTs) and good cycling stability (with a capacity retention rate of up to 116% after 10000 cycles). The three-dimensional porous structure not only promotes ion transfer and increases the effective specific surface area to improve its specific capacitance performance but also adapts to the volume expansion and contraction during the charging and discharging process to improve its cycling stability. The presence of nitrogen doping in the carbon nanotubes of GDY-NCNTs increases the surface defects of the composites, provides more electrochemical points, and improves the surface wettability of the composites, further improving the electrochemical performance of the composites.

Vestibular-evoked myogenic potential abnormalities in Parkinson's disease with freezing of gait.

BACKGROUND: Vestibular dysfunction is closely associated with the pathophysiology of Parkinson's disease (PD) accompanied by freezing of gait (FOG); however, evidence supporting this clinical association is lacking. Vestibular-evoked myogenic potentials (VEMPs) have been widely acknowledged as a crucial electrophysiological parameter in the clinical evaluation of vestibular function. OBJECTIVE: The present study investigated the possible correlation of FOG occurrence with VEMP observations in patients diagnosed with PD. METHODS: Altogether, 95 idiopathic PD patients were recruited into the present cross-sectional study. All patients underwent motor and non-motor assessments using serial scales. In addition, the electrophysiological vestibular evaluation was conducted, which included cervical (cVEMP) and ocular VEMP (oVEMP) assessments. Furthermore, the correlations of bilateral c/oVEMP absence with clinical phenotypes, especially FOG, among the PD patients were analyzed. RESULTS: Among the 95 patients with PD, 44 (46.3%) had bilateral oVEMP absence and 23 (24.2%) had bilateral cVEMP absence, respectively. The proportions of patients with bilateral oVEMP absence (77.8% vs 30.9%, p = 0.004) and bilateral cVEMP absence (44.4% vs 19.5%, p = 0.035) were higher in the patient group exhibiting FOG than in the group without FOG. Following the adjustment of confounding variables, bilateral oVEMP absence (OR = 8.544, p = 0.007), rather than bilateral cVEMP absence, was shown to independently predict FOG occurrence in patients with PD. CONCLUSION: The close correlation between bilateral oVEMP absence and FOG in PD patients sheds new light on the possible role of central vestibular/upper brainstem dysfunction in FOG development in patients with PD.

Preparation, structural characterization, biological activity, and nutritional applications of oligosaccharides.

Oligosaccharides are low-molecular-weight carbohydrates between monosaccharides and polysaccharides. They can be extracted directly from natural products by physicochemical methods or obtained by chemical synthesis or enzymatic reaction. Oligosaccharides have important physicochemical and physiological properties. Their research and production involve many disciplines such as medicine, chemical industry, and biology. Functional oligosaccharides, as an excellent functional food base, can be used as dietary fibrer and prebiotics to enrich the diet; improve the microecology of the gut; exert antitumour, anti-inflammatory, antioxidant, and lipid-lowering properties. Therefore, the industrial applications of oligosaccharides have increased rapidly in the past few years. It has great prospects in the field of food and medicinal chemistry. This review summarized the preparation, structural features and biological activities of oligosaccharides, with particular emphasis on the application of functional oligosaccharides in the food industry and human nutritional health. It aims to inform further research and development of oligosaccharides and food chemistry.

Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice.

Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GCase) are responsible for Gaucher disease (GD) and are considered the strongest genetic risk factor for Parkinson's disease (PD) and Lewy body dementia (LBD). GCase deficiency leads to extensive accumulation of glucosylceramides (GCs) in cells and contributes to the neuropathology of GD, PD, and LBD by triggering chronic neuroinflammation. Here, we investigated the mechanisms by which GC accumulation induces neuroinflammation. We found that GC accumulation within microglia induced by pharmacological inhibition of GCase triggered STING-dependent inflammation, which contributed to neuronal loss both in vitro and in vivo. GC accumulation in microglia induced mitochondrial DNA (mtDNA) leakage to the cytosol to trigger STING-dependent inflammation. Rapamycin, a compound that promotes lysosomal activity, improved mitochondrial function, thereby decreasing STING signaling. Furthermore, lysosomal damage caused by GC accumulation led to defects in the degradation of activated STING, further exacerbating inflammation mediated by microglia. Thus, limiting STING activity may be a strategy to suppress neuroinflammation caused by GCase deficiency.

Effect of high NEFA concentration on lipid metabolism disorders in hepatocytes based on lipidomics.

Introduction: High concentrations of nonesterified fatty acids (NEFA) is the key of characteristic of fatty liver in dairy cows. Therefore, the aim of this study was to investigate the effect of high concentration of NEFA on lipid metabolism in hepatocytes through the lipidomic approach and molecular biology techniques. Methods: Stimulate AML-12 cells with different concentrations of NEFA, observe the cellular lipid accumulation, and select 0.6 mM NEFA stimulation concentration for subsequent experiments. Collect cells for lipidomics analysis. Results: High concentration of NEFA (0.6-2.4 mM) significantly reduced the cell viability in a concentration-dependent manner, indicating that high concentrations of NEFA have lipotoxicity on hepatocytes. In addition, NEFA promoted triglycerides (TAG) accumulation, increased the mRNA expression of the lipogenic molecules SREBP1c and FASN, and decreased the mRNA expression of lipolytic molecules CPT1A and HSL in hepatocytes. Mechanistically, high concentration of NEFA induced lipid metabolism disorders in hepatocytes by regulating metabolic pathways such as glycerol phospholipid metabolism, glycosyl phosphatidylinositol anchored biosynthesis, triglyceride metabolism, sphingolipid metabolism, and inositol phosphate metabolism. Discussion: High concentration of NEFA is lipotoxic to cells, promoting lipid accumulation. LPE (18:2), LPE (18:3), LPE (18:1) via glycerophospholipid metabolism, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, glycerolipid metabolism, sphingolipid metabolism, and inositol phosphate metabolism, indicating their potential regulation role in the pathogenesis of fatty liver.

The Synergistic Effect Study of Lipopolysaccharide (LPS) and A53T-α-Synuclein: Intranasal LPS Exposure on the A53T-α-Synuclein Transgenic Mouse Model of Parkinson's Disease.

Aging and interactions between genetic and environmental factors are believed to be involved the chronic development of Parkinson's disease (PD). Among PD patients, abnormally aggregated α-synuclein is a major component of the Lewy body. Generally, the intranasal route is believed to be a gate way to the brain, and it assists environmental neurotoxins in entering the brain and is related to anosmia during early PD. The current study applies the chronic intranasal application of lipopolysaccharides (LPS) in 4-, 8-, 12- and 16-month-old A53T-α-synuclein (A53T-α-Syn) transgenic C57BL/6 mice at 2-day intervals for a 2-month period, for evaluating the behavioral, pathological, and biochemical changes and microglial activation in these animals. According to our results, after intranasal administration of LPS, A53T-α-Syn mice showed severe progressive anosmia, hypokinesia, selective dopaminergic (DAergic) neuronal losses, decreased striatal dopamine (DA) level, and enhanced α-synuclein accumulation within the substantia nigra (SN) in an age-dependent way. In addition, we found obvious NF-кB activation, Nurr1 inhibition, IL-1ß, and TNF-α generation within the microglia of the SN. Conversely, the wild-type (WT) mice showed mild, whereas A53T-α-Syn mice had moderate PD-like changes among the old mice. This study demonstrated the synergistic effect of intranasal LPS and α-synuclein burden on PD development. Its underlying mechanism may be associated with Nurr1 inhibition within microglia and the amplification of CNS neuroinflammation. The mice with multiple factors, including aging, neuroinflammation, and α-synuclein mutation, have played a significant role in enhancing our understanding of how inflammation and α-synuclein mutation contribute to the neurodegeneration observed in PD.