Chrysanthemum morifolium Ramat extract and probiotics combination ameliorates metabolic disorders through regulating gut microbiota and PPARα subcellular localization.

BACKGROUND: Chrysanthemum morifolium Ramat, a traditional Chinese medicine, has the effects on liver clearing, vision improving, and anti-inflammation. C. morifolium and probiotics have been individually studied for their beneficial effects on metabolic diseases. However, the underlying molecular mechanisms were not completely elucidated. This study aims to elucidate the potential molecular mechanisms of C. morifolium and probiotics combination (CP) on alleviating nonalcoholic fatty liver disease (NAFLD) and the dysregulation of glucose metabolism in high-fat diet (HFD)-fed mice. METHODS: The therapeutic effect of CP on metabolism was evaluated by liver histology and serum biochemical analysis, as well as glucose tolerance test. The impact of CP on gut microbiota was analyzed by 16S rRNA sequencing and fecal microbiota transplantation. Hepatic transcriptomic analysis was performed with the key genes and proteins validated by RT-qPCR and western blotting. In addition, whole body Pparα knockout (Pparα-/-) mice were used to confirm the CP-mediated pathway. RESULTS: CP supplementation ameliorated metabolic disorders by reducing body weight and hepatic steatosis, and improving glucose intolerance and insulin resistance in HFD fed mice. CP intervention mitigated the HFD-induced gut microbiota dysbiosis, which contributed at least in part, to the beneficial effect of improving glucose metabolism. In addition, hepatic transcriptomic analysis showed that CP modulated the expression of genes associated with lipid metabolism. CP downregulated the mRNA level of lipid droplet-binding proteins, such as Cidea and Cidec in the liver, leading to more substrates for fatty acid oxidation (FAO). Meanwhile, the expression of CPT1α, the rate-limiting enzyme of FAO, was significantly increased upon CP treatment. Mechanistically, though CP didn't affect the total PPARα level, it promoted the nuclear localization of PPARα, which contributed to the reduced expression of Cidea and Cidec, and increased expression of CPT1α, leading to activated FAO. Moreover, whole body PPARα deficiency abolished the anti-NAFLD effect of CP, suggesting the importance of PPARα in CP-mediated beneficial effect. CONCLUSION: This study revealed the hypoglycemic and hepatoprotective effect of CP by regulating gut microbiota composition and PPARα subcellular localization, highlighting its potential for therapeutic candidate for metabolic disorders.

Astragalus polysaccharides attenuate chemotherapy-induced immune injury by modulating gut microbiota and polyunsaturated fatty acid metabolism.

BACKGROUND: The damage of chemotherapy drugs to immune function and intestinal mucosa is a common side effect during chemotherapy. Astragalus polysaccharides (APS) exhibit immunomodulatory properties and are recognized for preserving the integrity of the human intestinal barrier. Nevertheless, their application and mechanisms of action in chemotherapy-induced immune damage and intestinal barrier disruption remain insufficiently explored. PURPOSE: This study delved into investigating how APS mitigates chemotherapy-induced immune dysfunction and intestinal mucosal injury, while also providing deeper insights into the underlying mechanisms. METHODS: In a chemotherapy mice model induced by 5-fluorouracil (5-Fu), the assessment of APS's efficacy encompassed evaluations of immune organ weight, body weight, colon length, and histopathology. The regulation of different immune cells in spleen was detected by flow cytometry. 16S rRNA gene sequencings, ex vivo microbiome assay, fecal microbiota transplantation (FMT), and targeted metabolomics analysis were applied to explore the mechanisms of APS effected on chemotherapy-induced mice. RESULTS: APS ameliorated chemotherapy-induced damage to immune organs and regulated immune cell differentiation disorders, including CD4+T, CD8+T, CD19+B, F4/80+CD11B+ macrophages. APS also alleviated colon shortening and upregulated the expression of intestinal barrier proteins. Furthermore, APS significantly restored structure of gut microbiota following chemotherapy intervention. Ex vivo microbiome assays further demonstrated the capacity of APS to improve 5-Fu-induced microbiota growth inhibition and compositional change. FMT demonstrated that the regulation of gut microbiota by APS could promote the recovery of immune functions and alleviate shortening of the colon length. Remarkably, APS significantly ameliorated the imbalance of linoleic acid (LA) and α-linolenic acid in polyunsaturated fatty acid (PUFA) metabolism. Further in vitro experiments showed that LA could promote splenic lymphocyte proliferation. In addition, both LA and DGLA down-regulated the secretion of NO and partially up-regulated the percentage of F4/80+CD11B+CD206+ cells. CONCLUSION: APS can effectively ameliorate chemotherapy-induced immune damage and intestinal mucosal disruption by regulating the composition of the gut microbiota and further restoring PUFA metabolism. These findings indicate that APS can serve as an adjuvant to improve the side effects such as intestinal and immune damage caused by chemotherapy.

Activation of hepatic adenosine A1 receptor ameliorates MASH via inhibiting SREBPs maturation.

Metabolic (dysfunction)-associated steatohepatitis (MASH) is the advanced stage of metabolic (dysfunction)-associated fatty liver disease (MAFLD) lacking approved clinical drugs. Adenosine A1 receptor (A1R), belonging to the G-protein-coupled receptors (GPCRs) superfamily, is mainly distributed in the central nervous system and major peripheral organs with wide-ranging physiological functions; however, the exact role of hepatic A1R in MAFLD remains unclear. Here, we report that liver-specific depletion of A1R aggravates while overexpression attenuates diet-induced metabolic-associated fatty liver (MAFL)/MASH in mice. Mechanistically, activation of hepatic A1R promotes the competitive binding of sterol-regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) to sequestosome 1 (SQSTM1), rather than protein kinase A (PKA) leading to SCAP degradation in lysosomes. Reduced SCAP hinders SREBP1c/2 maturation and thus suppresses de novo lipogenesis and inflammation. Higher hepatic A1R expression is observed in patients with MAFL/MASH and high-fat diet (HFD)-fed mice, which is supposed to be a physiologically adaptive response because A1R agonists attenuate MAFL/MASH in an A1R-dependent manner. These results highlight that hepatic A1R is a potential target for MAFL/MASH therapy.

High Fat Diet and High Sucrose Intake Divergently Induce Dysregulation of Glucose Homeostasis through Distinct Gut Microbiota-Derived Bile Acid Metabolism in Mice.

A high calorie diet such as excessive fat and sucrose intake is always accompanied by impaired glucose homeostasis such as T2DM (type 2 diabetes mellitus). However, it remains unclear how fat and sucrose individually affect host glucose metabolism. In this study, mice were fed with high fat diet (HFD) or 30% sucrose in drinking water (HSD) for 24 weeks, and glucose metabolism, gut microbiota composition, as well as bile acid (BA) profile were investigated. In addition, the functional changes of HFD or HSD-induced gut microbiota were further verified by fecal microbiota transplantation (FMT) and ex vivo culture of gut bacteria with BAs. Our results showed that both HFD and HSD caused dysregulated lipid metabolism, while HFD feeding had a more severe effect on impaired glucose homeostasis, accompanied by reduced hyocholic acid (HCA) levels in all studied tissues. Meanwhile, HFD had a more dramatic influence on composition and function of gut microbiota based on α diversity indices, ß diversity analysis, as well as the abundance of secondary BA producers than HSD. In addition, the phenotypes of impaired glucose homeostasis and less formation of HCA caused by HFD can be transferred to recipient mice by FMT. Ex vivo culture with gut bacteria and BAs revealed HFD-altered gut bacteria produced less HCA than HSD, which might closely associate with reduced relative abundance of C7 epimerase-coding bacteria g_norank/unclassified_f_Eggerthellaceae and bile salt hydrolase-producing bacteria Lactobacillus and Bifidobacterium in HFD group. Our findings revealed that the divergent effects of different high-calorie diets on glucose metabolism may be due to the gut microbiota-mediated generation and metabolism of BAs, highlighting the importance of dietary management in T2DM.

Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling.

Nonalcoholic fatty liver disease (NAFLD) is usually characterized with disrupted bile acid (BA) homeostasis. However, the exact role of certain BA in NAFLD is poorly understood. Here we show levels of serum hyodeoxycholic acid (HDCA) decrease in both NAFLD patients and mice, as well as in liver and intestinal contents of NAFLD mice compared to their healthy counterparts. Serum HDCA is also inversely correlated with NAFLD severity. Dietary HDCA supplementation ameliorates diet-induced NAFLD in male wild type mice by activating fatty acid oxidation in hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent way because the anti-NAFLD effect of HDCA is abolished in hepatocyte-specific Pparα knockout mice. Mechanistically, HDCA facilitates nuclear localization of PPARα by directly interacting with RAN protein. This interaction disrupts the formation of RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer. Our results demonstrate the therapeutic potential of HDCA for NAFLD and provide new insights of BAs on regulating fatty acid metabolism.

Gut microbiota remodeling improves natural aging-related disorders through Akkermansia muciniphila and its derived acetic acid.

Accumulating evidence indicates gut microbiota contributes to aging-related disorders. However, the exact mechanism underlying gut dysbiosis-related pathophysiological changes during aging remains largely unclear. In the current study, we first performed gut microbiota remodeling on old mice by fecal microbiota transplantation (FMT) from young mice, and then characterized the bacteria signature that was specifically altered by FMT. Our results revealed that FMT significantly improved natural aging-related systemic disorders, particularly exerted hepatoprotective effects, and improved glucose sensitivity, hepatosplenomegaly, inflammaging, antioxidative capacity and intestinal barrier. Moreover, FMT particularly increased the abundance of fecal A.muciniphila, which was almost nondetectable in old mice. Interestingly, A.muciniphila supplementation also exerted similar benefits with FMT on old mice. Notably, targeted metabolomics on short chain fatty acids (SCFAs) revealed that only acetic acid was consistently reversed by FMT. Then, acetic acid intervention exerted beneficial actions on both Caenorhabditis elegans and natural aging mice. In conclusion, our current study demonstrated that gut microbiota remodeling improved natural aging-related disorders through A.muciniphila and its derived acetic acid, suggesting that interventions with potent stimulative capacity on A. muciniphila growth and production of acetic acid was alternative and effective way to maintain healthy aging. DATA AVAILABILITY STATEMENT: The data of RNAseq and 16 S rRNA gene sequencing can be accessed in NCBI with the accession number PRJNA848996 and PRJNA849355.

3D-printed facet-attached optical elements for beam shaping in optical phased arrays.

We demonstrate an optical phased-array equipped with a 3D-printed facet-attached element for shaping and deflection of the emitted beam. The beam shaper combines freeform refractive surfaces with total-internal-reflection mirrors and is in-situ printed to edge-emitting waveguide facets using high-resolution multi-photon lithography, thereby ensuring precise alignment with respect to on-chip waveguide structures. In a proof-of-concept experiment, we achieve a grating-lobe free steering range of ±30∘ and a full-width-half-maximum beam divergence of approximately 2∘. The concept opens an attractive alternative to currently used grating structures and is applicable to a wide range of integration platforms.

[Comparative study on short and long-term intervention impacts of six Chinese herbs with cold or heat property on lipid and energy metabolism in mice].

This study selected three typical Chinese herbs with cold property(Rhei Radix et Rhizoma, Scutellariae Radix, and Coptidis Rhizoma) and another three with heat property(Cinnamomi Cortex, Zingiberris Rhizoma, and Aconiti Lateralis Radix Praeparata) to observe their regulatory effects on metabolism in animal organism, especially on lipid and energy metabolism in mice after a short-(7 d) and long-term(35 d) intervention. The mRNA expression levels of lipid metabolism genes in epididymal adipose tissue and liver were determined by real-time PCR. The oxygen consumption, carbon dioxide production, and energy consumption were detected by metabolic system. After the short-term intervention, the Chinese herbs with heat property significantly reduced epididymal adipose tissue index and elevated the expression levels of acetyl-CoA carboxylase(ACC), lipoprotein lipase(LPL), and carnitine-palmityl transferase 1(CPT-1) in liver and epididymal adipose tissues. However, those with cold property promoted the expression of above-mentioned genes in epididymal adipose tissue. After the long-term intervention, cold and heat Chinese herbs had no significant effect on epididymal adipose tissue index of animals, while cold Chinese herbs could increase carbon dioxide production and energy consumption and reduce activity. These findings demonstrated that the short-term intervention effects of cold and heat Chinese herbs on animal metabolism were significantly stronger than the long-term intervention effects. Specifically, the short-term intervention with cold Chinese herbs enhanced the lipid metabolism in epididymal adipose tissue, while the heat Chinese herbs promoted lipid metabolism in epididymal adipose tissue and liver. The long-term intervention with cold and heat Chinese herbs resulted in no obvious change in lipid level, but long-term intervention with cold Chinese herbs accelerated energy consumption of the body. This study preliminarily observed the effects of cold and heat Chinese herbs on normal animal physiology from lipid and energy metabolism, which would provide reference for explaining the biological basis of Chinese herbs with cold or heat property based on biological response.

Hybrid external-cavity lasers (ECL) using photonic wire bonds as coupling elements.

Combining semiconductor optical amplifiers (SOA) on direct-bandgap III-V substrates with low-loss silicon or silicon-nitride photonic integrated circuits (PIC) has been key to chip-scale external-cavity lasers (ECL) that offer wideband tunability along with small optical linewidths. However, fabrication of such devices still relies on technologically demanding monolithic integration of heterogeneous material systems or requires costly high-precision package-level assembly, often based on active alignment, to achieve low-loss coupling between the SOA and the external feedback circuits. In this paper, we demonstrate a novel class of hybrid ECL that overcome these limitations by exploiting 3D-printed photonic wire bonds as intra-cavity coupling elements. Photonic wire bonds can be written in-situ in a fully automated process with shapes adapted to the mode-field sizes and the positions of the chips at both ends, thereby providing low-loss coupling even in presence of limited placement accuracy. In a proof-of-concept experiment, we use an InP-based reflective SOA (RSOA) along with a silicon photonic external feedback circuit and demonstrate a single-mode tuning range from 1515 to 1565 nm along with side mode suppression ratios above 40 dB and intrinsic linewidths down to 105 kHz. Our approach combines the scalability advantages of monolithic integration with the performance and flexibility of hybrid multi-chip assemblies and may thus open a path towards integrated ECL on a wide variety of integration platforms.