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Introduction: Acute lung injury (ALI) is a lung disease characterized by inflammation and still requires further drug development. Forsythiaside A as the active compound of Forsythiae Fructus has the therapeutic potential for ALI. Objective: To investigate the mechanism of forsythiaside A in treating ALI through PPAR-γ and its conjugate RXR-α based on gut-lung axis. Methods: This study constructed in vitro and in vivo injury models using LPS and TNF-α. Forsythiaside A was used for the drug treatment, and RXR-α inhibitor UVI3003 was used to interfere with PPAR-γ/RXR-α complexes in the cells. HE staining was used for histopathological examination. Serum endotoxin contents were determined using limulus lysate kit. IHC staining and Western blot were conducted to assess the protein expressions. ELISA was applied to examine the content of pro-inflammatory cytokines in the cell supernatants. The protein interactions were analyzed via CO-IP. Results: In vivo results showed that forsythiaside A regulated PPAR-γ/RXR-α and inhibited TLR4/MAPK/NF-κB and MLCK/MLC2 signal pathways, thus inhibiting inflammation and epithelial barrier damages of lung and colon in ALI mice induced by intratracheal LPS. PPAR-γ/RXR-α were promoted by forsythiaside A in lungs, whereas inhibited by forsythiaside A in colons. Additionally, in vitro results showed that forsythiaside A suppressed inflammation and epithelial barrier damages in macrophages and lung/colon epithelial cells, by manipulating PPAR-γ/RXR-α to suppress the LPS- and TNF-α-induced activation of TLR4/MAPK/NF-κB and NF-κB/MLCK/MLC2 signal pathways. Moreover, further mechanism study indicated that forsythiaside A showed a cell-specific regulatory effect on PPAR-γ/RXR-α complex. Specifically, the PPAR-γ/RXR-α protein interactions were promoted by forsythiaside A in LPS-induced macrophages RAW264.7 and TNF-α-induced lung epithelial cells A549, but inhibited by forsythiaside A in TNF-α-induced colon epithelial cells SW620. Conclusion: In the treatment of ALI, Forsythiaside A inhibited inflammation and epithelial barrier damages of lung and colon through its regulation on PPAR-γ/RXR-α complex.

Abstract Exosomes are extracellular vesicles with the diameter of 30 ~ 150 nm, and are widely involved in intercellular communication, disease diagnosis and drug delivery carriers for targeted disease therapy. Therapeutic application of exosomes as drug carriers is limited due to the lack of sources and methods for obtaining adequate exosomes. Milk contains abundant exosomes, several studies have shown that milk-derived exosomes play crucial roles in preventing and treating intestinal diseases. In this review, we summarized the biogenesis, secretion and structure, current novel methods used for the extraction and identification of exosomes, as well as discussed the role of milk-derived exosomes in treating intestinal diseases, such as inflammatory bowel disease, necrotizing enterocolitis, colorectal cancer, and intestinal ischemia and reperfusion injury by regulating intestinal immune homeostasis, restoring gut microbiota composition and improving intestinal structure and integrity, alleviating conditions such as oxidative stress, cell apoptosis and inflammation, and reducing mitochondrial reactive oxygen species (ROS) and lysosome accumulation in both humans and animals. In addition, we discussed future prospects for the standardization of milk exosome production platform to obtain higher concentration and purity, and complete exosomes derived from milk. Several in vivo clinical studies are needed to establish milk-derived exosomes as an effective and efficient drug delivery system, and promote its application in the treatment of various diseases in both humans and animals.

Abstract Liver fibrosis could be the last hope for treating liver cancer and remodeling of the hepatic microenvironment has emerged as a strategy to promote the ablation of liver fibrosis. In recent years, especially with the rapid development of nanomedicine, hepatic microenvironment therapy has been widely researched in studies concerning liver cancer and fibrosis. In this comprehensive review, we summarized recent advances in nano therapy-based remodeling of the hepatic microenvironment. Firstly, we discussed novel strategies for regulatory immune suppression caused by capillarization of liver sinusoidal endothelial cells (LSECs) and macrophage polarization. Furthermore, metabolic reprogramming and extracellular matrix (ECM) deposition are caused by the activation of hepatic stellate cells (HSCs). In addition, recent advances in ROS, hypoxia, and impaired vascular remodeling in the hepatic fibrotic microenvironment due to ECM deposition have also been summarized. Finally, emerging nanotherapeutic approaches based on correlated signals were discussed in this review. We have proposed novel strategies such as engineered nanotherapeutics targeting antigen-presenting cells (APCs) or direct targeting T cells in liver fibrotic immunotherapy to be used in preventing liver fibrosis. In summary, this comprehensive review illustrated the opportunities in drug targeting and nanomedicine, and the current challenges to be addressed. Graphical Abstract

In this paper, a novel nested concentric circle anti-resonant hollow-core fiber with double-layer cladding structure and an outer cladding ring is proposed. By optimizing the structural parameter of the novel fiber, its confinement loss reaches 0.0001 dB/km at the wavelength of 1.55 μm, which is one or two orders of magnitude lower than the conventional fiber loss, and the ratio of the lowest high-order mode loss to fundational mode loss also reaches a maximum of 60,000. In the range of 1.14–1.78 μm, its loss is less than 0.005 dB/km, indicating that its bandwidth is also wide. Its surface scattering loss is 0.0017 dB/km, and the bending loss is 0.0011 dB/km. Furthermore, we discuss the effect of the movement of the nested concentric circles and the rotation of the cladding structure on the fiber properties. Consequently, we believe that the designed fiber will lay a theoretical foundation for the fabrication and application of new hollow-core fibers.

Quercetin, a naturally non-toxic flavonoid within the safe dose range with antioxidant, anti-apoptotic and anti-inflammatory properties, plays an important role in the treatment of aging-related diseases. Sirtuin 1 (SIRT1), a member of NAD+-dependent deacetylase enzyme family, is extensively explored as a potential therapeutic target for attenuating aging-induced disorders. SIRT1 possess beneficial effects against aging-related diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Depression, Osteoporosis, Myocardial ischemia (M/I) and reperfusion (MI/R), Atherosclerosis (AS), and Diabetes. Previous studies have reported that aging increases tissue susceptibility, whereas, SIRT1 regulates cellular senescence and multiple aging-related cellular processes, including SIRT1/Keap1/Nrf2/HO-1 and SIRTI/PI3K/Akt/GSK-3β mediated oxidative stress, SIRT1/NF-κB and SIRT1/NLRP3 regulated inflammatory response, SIRT1/PGC1α/eIF2α/ATF4/CHOP and SIRT1/PKD1/CREB controlled phosphorylation, SIRT1-PINK1-Parkin mediated mitochondrial damage, SIRT1/FoxO mediated autophagy, and SIRT1/FoxG1/CREB/BDNF/Trkβ-catenin mediated neuroprotective effects. In this review, we summarized the role of SIRT1 in the improvement of the attenuation effect of quercetin on aging-related diseases and the relationship between relevant signaling pathways regulated by SIRT1. Moreover, the functional regulation of quercetin in aging-related markers such as oxidative stress, inflammatory response, mitochondrial function, autophagy and apoptosis through SIRT1 was discussed. Finally, the prospects of an extracellular vesicles (EVs) as quercetin loading and delivery, and SIRT1-mediated EVs as signal carriers for treating aging-related diseases, as well as discussed the ferroptosis alleviation effects of quercetin to protect against aging-related disease via activating SIRT1. Generally, SIRT1 may serve as a promising therapeutic target in the treatment of aging-related diseases via inhibiting oxidative stress, reducing inflammatory responses, and restoring mitochondrial dysfunction.

Hydroxy amino acids (HAAs) are of unique value in the chemical and pharmaceutical industry with antiviral, antifungal, antibacterial, and anticancer properties. At present, the hydroxylated amino acids most studied are tryptophan, lysine, aspartic acid, leucine, proline, etc., and some of their derivatives. The hydroxylation of amino acids is inextricably linked to the catalysis of various biological enzymes, such as tryptophan hydroxylase, L-pipecolic acid trans-4-hydroxylase, lysine hydroxylase, etc. Hydroxylase conspicuously increases the variety of amino acid derivatives. For the manufacture of HAAs, the high regioselectivity biocatalytic synthesis approach is favored over chemical synthesis. Nowadays, the widely used method is to transcribe the hydroxylation pathway of various amino acids, including various catalytic enzymes, into Corynebacterium glutamicum or Escherichia coli for heterologous expression and then produce hydroxyamino acids. In this paper, we systematically reviewed the biosynthetic hydroxylation of aliphatic, heterocyclic, and aromatic amino acids and introduced the basic research and application of HAAs.

Thrombosis is a general pathological phenomenon during severe disturbances to homeostasis, which plays an essential role in cardiovascular and cerebrovascular diseases. Leonurine (LEO), isolated from Leonurus japonicus Houtt, showes a crucial role in anticoagulation and vasodilatation. However, the properties and therapeutic mechanisms of this effect have not yet been systematically elucidated. Therefore, the antithrombotic effect of LEO was investigated in this study. Hematoxylin-Eosin staining was used to detect the thrombosis of zebrafish tail. Fluorescence probe was used to detect the reactive oxygen species. The biochemical indexes related to oxidative stress (lactate dehydrogenase, malondialdehyde, superoxide dismutase and glutathione) and vasodilator factor (endothelin-1 and nitric oxide) were analyzed by specific commercial assay kits. Besides, we detected the expression of related genes (fga, fgb, fgg, pkcα, pkcβ, vwf, f2) and proteins (PI3K, phospho-PI3K, Akt, phospho-Akt, ERK, phospho-ERK FIB) related to the anticoagulation and fibrinolytic system by quantitative reverse transcription and western blot. Beyond that, metabolomic analyses were carried out to identify the expressions of metabolites associated with the anti-thrombosis mechanism of LEO. Our in vivo experimental results showed that LEO could improve the oxidative stress injury, abnormal platelet aggregation and coagulation dysfunction induced by adrenalin hydrochloride. Moreover, LEO restored the modulation of amino acids and inositol metabolites which are reported to alleviate the thrombus formation. Collectively, LEO attenuates adrenalin hydrochloride-induced thrombosis partly via modulating oxidative stress, coagulation cascade and platelet activation and amino acid and inositol metabolites.

In the prescription of Traditional Chinese Medicine for lipid metabolism, Polygoni Multiflori Radix Preparata (ZhiHeShouWu, RPMP) was widely used. In recent years, RPMP ethanol extract has been reported for the treatment of non-alcoholic fatty liver disease (NAFLD). However, the role of RPMP ethanol extract in the treatment of NAFLD has not been fully elucidated. Therefore, we examined the optimal therapeutic dose of RPMP ethanol extracts. Afterward, a mouse model of non-alcoholic fatty liver induced by a high-fat diet (HFD) was treated with RPMP ethanol extract to further evaluate the mechanism of action of RPMP ethanol extract treatment. And the serum lipid metabolism indexes and liver function indexes showed that the RPMP ethanol extract in the 1.35 g/kg dose group exhibited better therapeutic effects than the 2.70 g/kg dose group. Meanwhile, RPMP ethanol extract can regulate the biochemical indicators of serum and liver to normal levels, and effectively reduce liver steatosis and lipid deposition. RPMP ethanol extract treatment restored HFD-induced disruption of the compositional structure of the intestinal microbial (IM) and bile acids (BAs) pools. And restore the reduced expression of intestinal barrier-related genes caused by HFD administration, which also effectively regulates the expression of genes related to the metabolism of BAs in mice. Thus, RPMP ethanol extract can effectively improve the abnormal lipid metabolism and hepatic lipid accumulation caused by HFD, which may be related to the regulation of IM composition, maintenance of intestinal barrier function, and normal cholesterol metabolism in the body.

In this paper, we propose a polarization-independent optoelectronic modulator based on the electrical absorption effect of graphene. Firstly, we use the simulation software COMSOL Multiphysics to design the structure, and find via changing the applied voltage on both ends of the graphene that the equivalent refractive index of graphene can be changed, thus changing the light absorption capacity of the modulator. The waveguides in the transverse magnetic (TM) and transverse electric (TE) modes have almost the same extinction coefficient by making a double-layer graphene ridge structure in the center of the silicon-based waveguide, which can achieve approaching modulation depth in the TM and TE modes. At 1550 nm wavelength, the two-dimensional cross-section of the structure is analyzed by the FEM method using COMSOL Multiphysics to obtain the effective refractive index of the structure. The simulation results show that when the distance between the double-layer graphene isolation layer is d = 20 nm, the TE and TM modes can achieve extinction ratios up to 110 dB over the wide communication band by selecting appropriate “ON” and “OFF” switching points. The bandwidth is 173.78 GHz and the insertion loss is only 0.0338 dB.