Effects of different natural products in patients with non-alcoholic fatty liver disease-A network meta-analysis of randomized controlled trials.

Due to a scarcity of appropriate therapeutic approaches capable of ameliorating or eliminating non-alcoholic fatty liver disease (NAFLD), many researchers have come to focus on natural products based on traditional medicine that can be utilized to successfully treat NAFLD. In this study, we aimed to evaluate the effects exerted by seven natural products (curcumin, silymarin, resveratrol, artichoke leaf extract, berberine, catechins, and naringenin) on patients with NAFLD. For this purpose, PubMed, Embase, Cochrane Library, and Web of Science, were searched for randomized controlled trials (RCTs) exclusively. The selected studies were evaluated for methodological quality via the Cochrane bias risk assessment tool, and data analysis software was used to analyze the data accordingly. The RCTs from the earliest available date until September 2022 were collected. This process resulted in 37 RCTs with a total sample size of 2509 patients being included. The results of the network meta-analysis showed that artichoke leaf extract confers a relative advantage in reducing the aspartate aminotransferase (AST) levels (SUCRA: 99.1%), alanine aminotransferase (ALT) levels (SUCRA: 88.2%) and low-density lipoprotein cholesterol (LDL-C) levels (SUCRA: 88.9%). Naringenin conferred an advantage in reducing triglyceride (TG) levels (SUCRA: 97.3%), total cholesterol (TC) levels (SUCRA: 73.9%), and improving high-density lipoprotein cholesterol (HDL-C) levels (SUCRA: 74.9%). High-density catechins significantly reduced body mass index (BMI) levels (SUCRA: 98.5%) compared with the placebo. The Ranking Plot of the Network indicated that artichoke leaf extract and naringenin performed better than the other natural products in facilitating patient recovery. Therefore, we propose that artichoke leaf extract and naringenin may exert a better therapeutic effect on NAFLD. This study may help guide clinicians and lead to further detailed studies.

Non-contrast assessment of blood-brain barrier permeability to water in mice: An arterial spin labeling study at cerebral veins.

Blood-brain barrier (BBB) plays a critical role in protecting the brain from toxins and pathogens. However, in vivo tools to assess BBB permeability are scarce and often require the use of exogenous contrast agents. In this study, we aimed to develop a non-contrast arterial-spin-labeling (ASL) based MRI technique to estimate BBB permeability to water in mice. By determining the relative fraction of labeled water spins that were exchanged into the brain tissue as opposed to those that remained in the cerebral veins, we estimated indices of global BBB permeability to water including water extraction fraction (E) and permeability surface-area product (PS). First, using multiple post-labeling delay ASL experiments, we estimated the bolus arrival time (BAT) of the labeled spins to reach the great vein of Galen (VG) to be 691.2 ± 14.5 ms (N = 5). Next, we investigated the dependence of the VG ASL signal on labeling duration and identified an optimal imaging protocol with a labeling duration of 1200 ms and a PLD of 100 ms. Quantitative E and PS values in wild-type mice were found to be 59.9 ± 3.2% and 260.9 ± 18.9 ml/100 g/min, respectively. In contrast, mice with Huntington's disease (HD) revealed a significantly higher E (69.7 ± 2.4%, P = 0.026) and PS (318.1 ± 17.1 ml/100 g/min, P = 0.040), suggesting BBB breakdown in this mouse model. Reproducibility studies revealed a coefficient-of-variation (CoV) of 4.9 ± 1.7% and 6.1 ± 1.2% for E and PS, respectively. The proposed method may open new avenues for preclinical research on pathophysiological mechanisms of brain diseases and therapeutic trials in animal models.

Solid-State Nanopore Array: Manufacturing and Applications.

Nanopore brings extraordinary properties for a variety of potential applications in various industrial sectors. Since manufacturing of solid-state nanopore is first reported in 2001, solid-state nanopore has become a hot topic in the recent years. An increasing number of manufacturing methods have been reported, with continuously decreased sizes from hundreds of nanometers at the beginning to ≈1 nm until recently. To enable more robust, sensitive, and reliable devices required by the industry, researchers have started to explore the possible methods to manufacture nanopore array which presents unprecedented challenges on the fabrication efficiency, accuracy and repeatability, applicable materials, and cost. As a result, the exploration of fabrication of nanopore array is still in the fledging period with various bottlenecks. In this article, a wide range of methods of manufacturing nanopores are summarized along with their achievable morphologies, sizes, inner structures for characterizing the main features, based on which the manufacturing of nanopore array is further addressed. To give a more specific idea on the potential applications of nanopore array, some representative practices are introduced such as DNA/RNA sequencing, energy conversion and storage, water desalination, nanosensors, nanoreactors, and dialysis.

Nemo-like kinase reduces mutant huntingtin levels and mitigates Huntington's disease.

Nemo-like kinase (NLK), an evolutionarily conserved serine/threonine kinase, is highly expressed in the brain, but its function in the adult brain remains not well understood. In this study, we identify NLK as an interactor of huntingtin protein (HTT). We report that NLK levels are significantly decreased in HD human brain and HD models. Importantly, overexpression of NLK in the striatum attenuates brain atrophy, preserves striatal DARPP32 levels and reduces mutant HTT (mHTT) aggregation in HD mice. In contrast, genetic reduction of NLK exacerbates brain atrophy and loss of DARPP32 in HD mice. Moreover, we demonstrate that NLK lowers mHTT levels in a kinase activity-dependent manner, while having no significant effect on normal HTT protein levels in mouse striatal cells, human cells and HD mouse models. The NLK-mediated lowering of mHTT is associated with enhanced phosphorylation of mHTT. Phosphorylation defective mutation of serine at amino acid 120 (S120) abolishes the mHTT-lowering effect of NLK, suggesting that S120 phosphorylation is an important step in the NLK-mediated lowering of mHTT. A further mechanistic study suggests that NLK promotes mHTT ubiquitination and degradation via the proteasome pathway. Taken together, our results indicate a protective role of NLK in HD and reveal a new molecular target to reduce mHTT levels.

Age-dependent cerebrospinal fluid-tissue water exchange detected by magnetization transfer indirect spin labeling MRI.

PURPOSE: A non-invasive magnetization transfer indirect spin labeling (MISL) MRI method is developed to quantify the water exchange between cerebrospinal fluid (CSF) and other tissues in the brain and to examine the age-dependence of water exchange. METHOD: In the pulsed MISL, we implemented a short selective pulse followed by a post-labeling delay before an MRI acquisition with a long echo time; in the continuous MISL, a train of saturation pulses was applied. MISL signal (∆Z) was obtained by the subtraction of the label MRI at -3.5 ppm from the control MRI at 200 ppm. CSF was extracted from the mouse ventricles for the MISL optimization and validation. Comparison between wild type (WT) and aquaporin-4 knockout (AQP4-/- ) mice was performed to examine the contributions of CSF water exchange, whereas its age-dependence was investigated by comparing the adult and young WT mice. RESULTS: The pulsed MISL method observed that the MISL signal reached the maximum at 1.5 s. The continuous MISL method showed the highest MISL signal in the fourth ventricle (∆Z = 13.5% ± 1.4%), whereas the third ventricle and the lateral ventricles had similar MISL ∆Z values (∆Z = 12.0% ± 1.8%). Additionally, significantly lower ∆Z (9.3%-18.7% reduction) was found in all ventricles for the adult mice than those of the young mice (p < 0.02). For the AQP4-/- mice, the ∆Z values were 5.9%-8.3% smaller than those of the age-matched WT mice in the lateral and fourth ventricles, but were not significant. CONCLUSION: The MISL method has a great potential to study CSF water exchange with the surrounding tissues in brain.

Huntingtin silencing delays onset and slows progression of Huntington's disease: a biomarker study.

Huntington's disease is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the huntingtin (HTT) gene, coding for pathological mutant HTT protein (mHTT). Because of its gain-of-function mechanism and monogenic aetiology, strategies to lower HTT are being actively investigated as disease-modifying therapies. Most approaches are currently targeted at the manifest stage, where clinical outcomes are used to evaluate the effectiveness of therapy. However, as almost 50% of striatal volume has been lost at the time of onset of clinical manifest, it would be preferable to begin therapy in the premanifest period. An unmet challenge is how to evaluate therapeutic efficacy before the presence of clinical symptoms as outcome measures. To address this, we aim to develop non-invasive sensitive biomarkers that provide insight into therapeutic efficacy in the premanifest stage of Huntington's disease. In this study, we mapped the temporal trajectories of arteriolar cerebral blood volumes (CBVa) using inflow-based vascular-space-occupancy (iVASO) MRI in the heterozygous zQ175 mice, a full-length mHTT expressing and slowly progressing model with a premanifest period as in human Huntington's disease. Significantly elevated CBVa was evident in premanifest zQ175 mice prior to motor deficits and striatal atrophy, recapitulating altered CBVa in human premanifest Huntington's disease. CRISPR/Cas9-mediated non-allele-specific HTT silencing in striatal neurons restored altered CBVa in premanifest zQ175 mice, delayed onset of striatal atrophy, and slowed the progression of motor phenotype and brain pathology. This study-for the first time-shows that a non-invasive functional MRI measure detects therapeutic efficacy in the premanifest stage and demonstrates long-term benefits of a non-allele-selective HTT silencing treatment introduced in the premanifest Huntington's disease.

Mutant G2019S-LRRK2 Induces Abnormalities in Arteriolar Cerebral Blood Volume in Mouse Brains: An MRI Study.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease and the most common movement disorder characterized by motor impairments resulting from midbrain dopamine neuron loss. Abnormalities in small pial arteries and arterioles, which are the primary pathways of local delivery of nutrients and oxygen in brain tissue, have been reported in many neurodegenerative diseases including PD. Mutations in LRRK2 cause genetic PD and contribute to sporadic PD. The most common PD-linked mutation LRRK2 G2019S contributes 20-47% of genetic forms of PD in Caucasian populations. The human LRRK2 G2019S transgenic mouse model displays PD-like movement impairment and was used to identify novel LRRK2 inhibitors, which provides a useful model for studying microvascular abnormalities in PD. OBJECTIVES: To investigate abnormalities in arteriolar cerebral blood volume (CBVa) in various brain regions using the inflow-based vascular-space occupancy (iVASO) MRI technique in LRRK2 mouse models of PD. METHODS: Anatomical and iVASO MRI scans were performed in 5 female and 7 male nontransgenic (nTg), 3 female and 4 male wild-type (WT) LRRK2, and 5 female and 7 male G2019S-LRRK2 mice of 9 months of age. CBVa was calculated and compared in the substantia nigra (SN), olfactory cortex, and prefrontal cortex. RESULTS: Compared to nTg mice, G2019S-LRRK2 mice showed decreased CBVa in the SN, but increased CBVa in the olfactory and prefrontal cortex in both male and female groups, whereas WT-LRRK2 mice showed no change in CBVa in the SN (male and female), the olfactory (female), and prefrontal (female) cortex, but a slight increase in CBVa in the olfactory and prefrontal cortex in the male group only. CONCLUSIONS: Alterations in the blood volume of small arteries and arterioles (CBVa) were detected in the G2019S-LRRK2 mouse model of PD. The opposite changes in CBVa in the SN and the cortex indicate that PD pathology may have differential effects in different brain regions. Our results suggest the potential value of CBVa as a marker for clinical PD studies.

[Astragaloside IV regulates STAT1/IκB/NF-κB signaling pathway to inhibit activation of BV-2 cells].

OBJECTIVE: The study was aimed to investigate the inhibitory effect and mechanism of astragaloside IV (ASI) on the activation of microglial cells. METHOD: After pre-incubated with ASI for 2 h, microglial cells BV-2 were stimulated with interferon-γ (IFN-γ) for 1. 5 h and 24 h, respectively. Secretion of nitric oxide (NO) in the medium was measured by Griess method. Production of tumor necrosis factor alpha (TNF-α) was detected by ELISA approach. Cellular gene expressions of CD11b, TNF-α, interleukin 1ß (IL-1ß) and induced nitric oxide synthase (iNOS) were examined by quantitative-PCR analysis. Total and phosphorylation of STAT1, IκB and NF-κB was analyzed by Western blot method. RESULT: ASI could significantly inhibit the increased secretion of TNF-α and NO from BV-2 cells upon IFN-γ stimulation (P < 0.001). Further study showed that ASI significantly down-regulated gene expression of IL-1ß and TNF-α (P < 0.01, P < 0.05) and exhibited a trend to reduce that of iNOS. IFN-γ and ASI have no obvious effect on gene expression of CD11b. Moreover, ASI inhibited the phosphorylation of STAT1, IκB and NF-κB elicited by IFN-γ stimulation. CONCLUSION: ASI could restrain microglial activation through interfering STAT1/IκB/NF-κB signaling pathway, reducing gene expres- sion of IL-1ß and TNF-α, and thus inhibiting the production of proinflammatory mediators such as NO and TNF-α.

Astragalosides from Radix Astragali benefits experimental autoimmune encephalomyelitis in C57BL /6 mice at multiple levels.

BACKGROUND: Radix Astragali is famous for its beneficial effect on inflammation associated diseases. This study was to assess the efficacy of astragalosides (AST) extracted from Radix Astragali, on the progression of experimental autoimmune encephalomyelitis (EAE), and explore its possible underlying molecular mechanisms. METHODS: EAE was induced by subcutaneous immunization of MOG35-55. Infiltration of inflammatory cells was examined by HE staining. ROS level was detected by measuring infiltrated hydroethidine. Leakage of blood brain barrier (BBB) was assessed using Evan's blue dye extravasation method. Levels of inflammatory cytokines were measured using ELISA kits. Activities of total-SOD, GSH-Px, and iNOS and MDA concentration were measured using biochemical analytic kits. Gene expression was detected using real-time PCR method. Protein expression was assayed using western blotting approach. RESULTS: AST administration attenuated the progression of EAE in mice remarkably. Further studies manifested that AST treatment inhibited infiltration of inflammatory cells, lessened ROS production and decreased BBB leakage. In peripheral immune-systems, AST up-regulated mRNA expression of transcriptional factors T-bet and Foxp3 but decreased that of RORγt to modulate T cell differentiation. In CNS, AST stopped BBB leakage, reduced ROS production by up-regulation of T-SOD, and reduced neuroinflammation by inhibition of iNOS and other inflammatory cytokines. Moreover, AST inhibited production of p53 and phosphorylation of tau by modulation of the Bcl-2/Bax ratio. CONCLUSIONS: AST orchestrated multiple pathways, including immuno-regulation, anti-oxidative stress, anti-neuroinflammation and anti-neuroapoptosis involved in the MS pathogenesis, to prevent the deterioration of EAE, which paves the way for the application of it in clinical prevention/therapy of MS.

Mechanism of Action and Related Natural Regulators of Nrf2 in Nonalcoholic Fatty Liver Disease.

With the acceleration of people's pace of life, non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the world, which greatly threatens people's health and safety. Therefore, there is still an urgent need for higher-quality research and treatment in this area. Nuclear factor Red-2-related factor 2 (Nrf2), as a key transcription factor in the regulation of oxidative stress, plays an important role in inducing the body's antioxidant response. Although there are no approved drugs targeting Nrf2 to treat NAFLD so far, it is still of great significance to target Nrf2 to alleviate NAFLD. In recent years, studies have reported that many natural products treat NAFLD by acting on Nrf2 or Nrf2 pathways. This article reviews the role of Nrf2 in the pathogenesis of NAFLD and summarizes the currently reported natural products targeting Nrf2 or Nrf2 pathway for the treatment of NAFLD, which provides new ideas for the development of new NAFLD-related drugs.

Diosgenin attenuates metabolic-associated fatty liver disease through the hepatic NLRP3 inflammasome-dependent signaling pathway.

Metabolic-associated fatty liver disease (MAFLD) is one of the most common liver diseases worldwide; however, its pathogenesis and treatment methods have not been perfected. NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) is a promising therapeutic target for MAFLD. Diosgenin (DG) is a natural compound that was identified in a traditional Chinese herbal medicine, which has pharmacological effects, such as anti-inflammatory, antioxidant, hepatoprotective, and hypolipidemic activities. In this study, we examined the effects and molecular mechanisms of DG on MAFLD in vitro and in vivo. We established a rat model by administering a high-fat diet (HFD). We also generated an in vitro MAFLD model by treating HepG2 cells with free fatty acids (FFAs). The results indicated that DG attenuated lipid accumulation and liver injury in both in vitro and in vivo models. DG downregulated the expression of NLRP3, apoptosis-associated speckle-like protein (ASC), cysteinyl aspartate specific proteinase-1 (caspase-1), gasdermin D (GSDMD), GSDMD-n, and interleukin-1ß (IL-1ß). In addition, we silenced and overexpressed NLRP3 in vitro to determine the effects of DG on antiMAFLD. Silencing NLRP3 enhanced the effect of DG on the treatment of MAFLD, whereas NLRP3 overexpression reversed its beneficial effects. Taken together, the results show that DG has a favorable effect on attenuating MAFLD through the hepatic NLRP3 inflammasome-dependent signaling pathway. DG represents a natural NLRP3 inhibitor for the MAFLD treatment.

Diosgenin attenuates nonalcoholic hepatic steatosis through the hepatic SIRT1/PGC-1α pathway.

The prevalence of nonalcoholic fatty liver disease (NAFLD) has been increasing worldwide in recent years, causing severe economic and social burdens. Therefore, the lack of currently approved drugs for anti-NAFLD has gradually gained attention. SIRT1, as a member of the sirtuins family, is now the most widely studied in the pathophysiology of many metabolic diseases, and has great potential for preventing and treating NAFLD. Natural products such as Diosgenin (DG) have the potential to be developed as clinical drugs for the treatment of NAFLD due to their excellent multi-target therapeutic effects. In this study, we found that DG can activate the SIRT1/PGC-1α pathway and upregulate the expression of its downstream targets nuclear respiratory factor 1 (NRF1), complex IV (COX IV), mitofusin-2 (MFN2), and PPARα (perox-isome proliferator-activated receptor α) in SD rats induced by high-fat diet (HFD) and HepG2 cells caused by free fatty acids (FFAs, sodium oleate: sodium palmitate = 2:1). Conversely, the levels of dynamin-related protein 1 (DRP1) and inflammatory factors, including NF-κB p65, IL6, and TNFα, were downregulated both in vitro and in vivo. This improved mitochondrial dysfunction, fatty acid oxidation (FAO), lipid accumulation, steatosis, oxidative stress, and hepatocyte inflammation. Subsequently, we applied SIRT1 inhibitor EX527 and SIRT1 agonist SRT1720 to confirm further the necessity of activating SIRT1 for DG to exert therapeutic effects on NAFLD. In summary, these results further demonstrate the potential therapeutic role of DG as a SIRT1 natural agonist for NAFLD. (Graphical Abstracts).

The Role of JAK/STAT Signaling Pathway and Its Downstream Influencing Factors in the Treatment of Atherosclerosis.

Atherosclerosis is now widely considered to be a chronic inflammatory disease, with increasing evidence suggesting that lipid alone is not the main factor contributing to its development. Rather, atherosclerotic plaques contain a significant amount of inflammatory cells, characterized by the accumulation of monocytes and lymphocytes on the vessel wall. This suggests that inflammation may play a crucial role in the occurrence and progression of atherosclerosis. As research deepens, other pathological factors have also been found to influence the development of the disease. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a recently discovered target of inflammation that has gained attention in recent years. Numerous studies have provided evidence for the causal role of this pathway in atherosclerosis, and its downstream signaling factors play a significant role in this process. This brief review aims to explore the crucial role of the JAK/STAT pathway and its representative downstream signaling factors in the development of atherosclerosis. It provides a new theoretical basis for clinically affecting the development of atherosclerosis by interfering with the JAK/STAT signaling pathway.

Zone of flow: A new finding on the characteristics of airflow within the zone of influence during air sparging in aquifers.

Air sparging (AS) is a popular technology for the in-situ remediation of groundwater contaminated by volatile organic compounds. The scope of the zone within which injected air exists, i.e., zone of influence (ZOI) and the airflow characteristics within ZOI are of great interest. However, few studies have shed light on the scope of the zone within which air flows, namely, the zone of flow (ZOF) and its relation with the scope of ZOI. This study focuses on the ZOF characteristics and its relation with ZOI based on quantitative observations of ZOF and ZOI using a quasi-2D transparent flow chamber. The relative transmission intensity obtained by the light transmission method presents a rapid and continuous increasing near the ZOI boundary, providing a criterion for the quantitative determination of ZOI. An integral airflow flux approach is proposed to determine the scope of ZOF based on the airflow flux distributions through aquifers. The ZOF radius decreases with the growth of particle sizes of aquifers; while it increases first and then keeps constant with the increase of sparging pressure. The ZOF radius is around 0.55- 0.82 times of the ZOI radius, which depends on air flow patterns related to particle diameters dp, that is, 0.55- 0.62 for channel flow (dp < 1- 2 mm), while 0.75- 0.82 for bubble flow (dp > 2- 3 mm). The experimental results show that the sparged air is entrapped with little flowing inside ZOI regions that are outside the ZOF, which should be considered carefully in the design of AS.

Association between gastroesophageal reflux disease and stroke: a bidirectional Mendelian randomization study.

Objective: Some previous studies have suggested a potential link between stroke and gastroesophageal reflux disease (GERD). We used a two-sample bidirectional Mendelian randomization (MR) method to explore the causal relationship between stroke and GERD. Design: Summary-level data derived from the published genome-wide association studies (GWAS) were employed for analyses. Single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for stroke (n = 446,696) and its common subtypes ischemic stroke (IS) (n = 440,328), large vessel stroke (LVS) (n = 410,484), small vessel stroke (SVS) (n = 198,048), and cardioembolic stroke (CES) (n = 413,304) were obtained from the MEGASTROKE consortium. The data on intracerebral hemorrhage (ICH) (n = 721,135) come from the UK Biobank. Instrumental variables (IVs) for lacunar stroke (LS) (n = 474,348) and GERD (n = 602,604) were screened from publicly available genetic summary data. The inverse variance weighted (IVW) method was used as the main MR method. Pleiotropy was detected by the MR-Egger intercept test, MR pleiotropy residual sum and outlier, and leave-one-out analysis. Cochran Q statistics were used as supplements to detect pleiotropy. Results: We found that GERD can causally increase the risk of stroke [IVW odds ratio (OR): 1.22, 95% confidence interval (CI): 1.13-1.32, p = 1.16 × 10-6] and its common subtypes IS (OR: 1.19, 95% CI: 1.10-1.30, p = 3.22 × 10-5), LVS (OR: 1.49, 95% CI: 1.21-1.84, p = 1.47 × 10-4), and LS (OR: 1.20, 95% CI: 1.001-1.44, p = 0.048). Several important risk factors for stroke have also been implicated in the above causal relationship, including type 2 diabetes, sleep apnea syndrome, high body mass index, high waist-to-hip ratio, and elevated serum triglyceride levels. In reverse MR analysis, we found that overall stroke (OR: 1.09, 95% CI: 1.004-1.19, p = 0.039) and IS (OR: 1.10, 95% CI: 1.03-1.17, p = 0.007) have the causal potential to enhance GERD risk. Conclusion: This MR study provides evidence supporting a causal relationship between GERD and stroke and some of its common subtypes. We need to further explore the interconnected mechanisms between these two common diseases to better prevent and treat them.

Diosgenin attenuates nonalcoholic hepatic steatosis through the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and has no approved treatment. The hepatic farnesoid X receptor (FXR) is one of the most promising therapeutic targets for NAFLD. Diosgenin (DG), a natural compound extracted from Chinese herbal medicine, is very effective in preventing metabolic diseases. Our research aims to determine the effects and molecular mechanisms of DG on NAFLD in vivo and in vitro. The effect of DG on hepatic steatosis was evaluated in Sprague‒Dawley (SD) rats induced by a high-fat diet (HFD) and in HepG2 cells exposed to free fatty acids (FFAs, sodium oleate:sodium palmitate = 2:1). DG treatment efficiently managed hepatic lipid deposition in vivo and in vitro. Mechanistically, DG upregulated the expression of FXR and small heterodimer partner (SHP) and downregulated the expression of genes involved in hepatic de novo lipogenesis (DNL), including sterol regulatory element-binding protein 1C (SREBP1C), acetyl-CoA carboxylase 1 (ACC1), and fatty acid synthase (FASN). Moreover, DG promoted the expression of peroxisome proliferator-activated receptor alpha (PPARα), which is related to fatty acid oxidation. In addition, DG inhibited the expression of the CD36 molecule (CD36) related to fatty acid uptake. However, hepatic FXR silencing weakened the regulatory effects of DG on these genes. Collectively, our data show that DG has a good effect on alleviating nonalcoholic hepatic steatosis via the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway. DG promises to be a novel candidate FXR activator that can be utilized to treat NAFLD.

Biological Role and Related Natural Products of SIRT1 in Nonalcoholic Fatty Liver.

Non-alcoholic fatty liver disease(NAFLD) is an umbrella term for a range of diseases ranging from hepatic fat accumulation and steatosis to non-alcoholic steatohepatitis (NASH) in the absence of excessive alcohol consumption and other definite liver damage factors. The incidence of NAFLD has increased significantly in recent years and will continue to grow in the coming decades. NAFLD has become a huge health problem and economic burden. SIRT1 is a member of Sirtuins, a group of highly conserved histone deacetylases regulated by NAD+, and plays a vital role in regulating cholesterol and lipid metabolism, improving oxidative stress, inflammation, and insulin resistance through deacetylating some downstream transcription factors and thus improving NAFLD. Although there are no currently approved drugs for treating NAFLD and some unresolved limitations in developing SIRT1 activators, SIRT1 holds promise as a proper therapeutic target for NAFLD and other metabolic diseases. In recent years, natural products have played an increasingly important role in drug development due to their safety and efficacy. It has been discovered that some natural products may be able to prevent and treat NAFLD by targeting SIRT1 and its related pathways. This paper reviews the mechanism of SIRT1 in the improvement of NALFD and the natural products that regulate NAFLD through SIRT1 and its associated pathways, and discusses the potential of SIRT1 as a therapeutic target for treating NAFLD and the effectiveness of these related natural products as clinical drugs or dietary supplements. These works may provide some new ideas and directions for finding new therapeutic targets for NAFLD and the development of anti-NAFLD drugs with good pharmacodynamic properties.

Interrogation of dynamic glucose-enhanced MRI and fluorescence-based imaging reveals a perturbed glymphatic network in Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder that presents with progressive motor, mental, and cognitive impairment leading to early disability and mortality. The accumulation of mutant huntingtin protein aggregates in neurons is a pathological hallmark of HD. The glymphatic system, a brain-wide perivascular network, facilitates the exchange of interstitial fluid (ISF) and cerebrospinal fluid (CSF), supporting interstitial solute clearance including abnormal proteins from mammalian brains. In this study, we employed dynamic glucose-enhanced (DGE) MRI to measure D-glucose clearance from CSF as a tool to assess CSF clearance capacity to predict glymphatic function in a mouse model of HD. Our results demonstrate significantly diminished CSF clearance efficiency in premanifest zQ175 HD mice. The impairment of CSF clearance of D-glucose, measured by DGE MRI, worsened with disease progression. These DGE MRI findings in compromised glymphatic function in HD mice were further confirmed with fluorescence-based imaging of glymphatic CSF tracer influx, suggesting an impaired glymphatic function in premanifest stage of HD. Moreover, expression of the astroglial water channel aquaporin-4 (AQP4) in the perivascular compartment, a key mediator of glymphatic function, was significantly diminished in both HD mouse brain as well as postmortem human HD brain. Our data, acquired using a clinically translatable MRI approach, indicate a perturbed glymphatic network in the HD brain as early as in the premanifest stage. Further validation of these findings in clinical studies should provide insights into potential of glymphatic clearance as a HD biomarker and for glymphatic functioning as a disease-modifying therapeutic target for HD.

Significant Enhancement of Circular Polarization in Light Emission through Controlling Helical Pitches of Semiconductor Nanohelices.

Circularly polarized light emission (CPLE) can be potentially applied to three-dimensional displays, information storage, and biometry. However, these applications are practically limited by a low purity of circular polarization, i.e., the small optical dissymmetry factor gCPLE. Herein, glancing angle deposition (GLAD) is performed to produce inorganic nanohelices (NHs) to generate CPLE with large gCPLE values. CdSe NHs emit red CPLE with gCPLE = 0.15 at a helical pitch (P) ≈ 570 nm, having a 40-fold amplification of gCPLE compared to that at P ≈ 160 nm. Ceria NHs emit ultraviolet-blue CPLE with gCPLE ≈ 0.06 at P ≈ 830 nm, with a 103-fold amplification compared to that at P ≈ 110 nm. Both the photoluminescence and scattering among the close-packed NHs complicatedly account for the large gCPLE values, as revealed by the numerical simulations. The GLAD-based NH-fabrication platform is devised to generate CPLE with engineerable color and large gCPLE = 10-2-10-1, shedding light on the commercialization of CPLE devices.

An RNA-targeting CRISPR-Cas13d system alleviates disease-related phenotypes in Huntington's disease models.

Huntington's disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by CAG trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Since the reduction of pathogenic mutant HTT messenger RNA is therapeutic, we developed a mutant allele-sensitive CAGEX RNA-targeting CRISPR-Cas13d system (Cas13d-CAGEX) that eliminates toxic CAGEX RNA in fibroblasts derived from patients with HD and induced pluripotent stem cell-derived neurons. We show that intrastriatal delivery of Cas13d-CAGEX via an adeno-associated viral vector selectively reduces mutant HTT mRNA and protein levels in the striatum of heterozygous zQ175 mice, a model of HD. This also led to improved motor coordination, attenuated striatal atrophy and reduction of mutant HTT protein aggregates. These phenotypic improvements lasted for at least eight months without adverse effects and with minimal off-target transcriptomic effects. Taken together, we demonstrate proof of principle of an RNA-targeting CRISPR-Cas13d system as a therapeutic approach for HD, a strategy with implications for the treatment of other dominantly inherited disorders.