Combination of Fushengong decoction with Western medicine on patients with chronic renal failure: An observational study.

Chronic renal failure (CRF) causes a reduction in glomerular filtration rate and damage to renal parenchyma. Fushengong decoction (FSGD) showed improvement in renal function in CRF rats. This study aims to analyze the differentially expressed proteins in CRF patients treated with Western medicine alone or in combination with FSGD. Sixty patients with CRF recruited from Yongchuan Traditional Chinese Medicine Hospital affiliated to Chongqing Medical University were randomly assigned into control (treated with Western medicine alone) and observation groups (received additional FSGD treatment thrice daily for 8 weeks). The clinical efficacy and changes in serum Bun, serum creatinine, Cystatin C, and transforming growth factor beta 1 (TGF-ß1) before and after treatment were observed. We employed isotope relative labeling absolute quantification labeling and liquid chromatography-mass spectrometry to identify differentially expressed proteins and carried out bioinformatics Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Patients in the observation group showed greater clinical improvement and lower levels of serum Bun, serum creatinine, Cyc-c, and TGF-ß1 than the control group. We identified 32 differentially up-regulated and 52 down-regulated proteins in the observation group. These proteins are involved in the blood coagulation system, protein serine/threonine kinase activity, and TGF-ß, which are closely related to the pathogenesis of CRF. Protein-protein-interaction network analysis indicated that candidate proteins fibronectin 1, fibrinogen alpha chain, vitronectin, and Serpin Family C Member 1 were in the key nodes. This study provided an experimental basis suggesting that FSGD combined with Western medicine could significantly improve renal function and renal fibrosis of CRF patients, which may be through the regulation of fibronectin 1, fibrinogen alpha chain, vitronectin, Serpin Family C Member 1, TGF-ß, and the complement coagulation pathway (see Graphical abstract S1, Supplemental Digital Content, http://links.lww.com/MD/L947).

Secondary metabolites from Penicillium sp. HS-11, a fungal endophyte of Huperzia serrata.

Three new sorbicillinoids sorbicatechols E-G (1-3), along with seven known compounds 4-10, were obtained from the ethanol extract of Penicillium sp. HS-11, a fungal endophyte of the medicinal plant Huperzia serrata. The structures of 1-3 were established by detailed interpretation of the spectroscopic data and their absolute configurations were established by comparative analyses of the ECD spectra. Sorbicatechol G (3) represented the first hybrid sorbicillinoid bearing a tetralone skeleton. In the in-vitro bioassay, trichodimerol (5) exhibited moderate inhibitory activity against the Escherichia coli ß-glucuronidase (EcGUS) with an IC50 value of 92.0 ± 9.4 µM.

Total iridoid glycoside extract of Lamiophlomis rotata (Benth) Kudo accelerates diabetic wound healing by the NRF2/COX2 axis.

BACKGROUND: Lamiophlomis rotata (Benth.) Kudo (L. rotata), the oral Traditional Tibetan herbal medicine, is adopted for treating knife and gun wounds for a long time. As previously demonstrated, total iridoid glycoside extract of L. rotata (IGLR) induced polarization of M2 macrophage to speed up wound healing. In diabetic wounds, high levels inflammatory and chemotactic factors are usually related to high reactive oxygen species (ROS) levels. As a ROS target gene, nuclear factor erythroid 2-related factor 2 (NRF2), influences the differentiation of monocytes to M1/M2 macrophages. Fortunately, iridoid glycosides are naturally occurring active compounds that can be used as the oxygen radical scavenger. Nevertheless, the influence of IGLR in diabetic wound healing and its associated mechanism is largely unclear. MATERIALS AND METHODS: With macrophages and dermal fibroblasts in vitro, as well as a thickness excision model of db/db mouse in vivo, the role of IGLR in diabetic wound healing and the probable mechanism of the action were investigated. RESULTS: Our results showed that IGLR suppressed oxidative distress and inflammation partly through the NRF2/cyclooxygenase2 (COX2) signaling pathway in vitro. The intercellular communication between macrophages and dermal fibroblasts was investigated by the conditioned medium (CM) of IGLR treatment cells. The CM increased the transcription and translation of collagen I (COL1A1) and alpha smooth muscle actin (α-SMA) within fibroblasts. With diabetic wound mice, the data demonstrated IGLR activated the NRF2/KEAP1 signaling and the downstream targets of the pathway, inhibited COX2/PEG2 signaling and decreased the interaction inflammatory targets of the axis, like interleukin-1beta (IL-1ß), interleukin 6 (IL-6), apoptosis-associated speck-like protein (ASC), cysteinyl aspartate specific proteinase1 (caspase1) and NOD-like receptor-containing protein 3 (NLRP3).In addition, the deposition of COL1A1, and the level of α-SMA, and Transforming growth factor-ß1 (TGF-ß1) obviously elevated, whereas that of pro-inflammatory factors reduced in the diabetic wound tissue with IGLR treatment. CONCLUSION: IGLR suppressed oxidative distress and inflammation mainly through NRF2/COX2 axis, thus promoting paracrine and accelerating wound healing in diabetes mice.

Transcriptomic and proteomic investigation of the ameliorative effect of total polyphenolic glycoside extract on hepatic fibrosis in Lamiophlomis rotata Kudo via the AGE/RAGE pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: During the regression of liver fibrosis, a decrease in hepatic stellate cells (HSCs) can occur through apoptosis or inactivation of activated HSCs (aHSCs). A new approach for antifibrotic therapy involves transforming hepatic myofibroblasts into a quiescent-like state. Lamiophlomis rotata (Benth.) Kudo (L. rotata), an orally available Tibetan herb, has traditionally been used to treat skin disease, jaundice, and rheumatism. In our previous study, we found that the total polyphenolic glycoside extract of L. rotata (TPLR) promotes apoptosis in aHSCs for the treatment of hepatic fibrosis. However, whether TPLR induces aHSCs to become inactivated HSCs (iHSCs) is unclear, and the underlying mechanism remains largely unknown. PURPOSE: This study aimed to examine the impact of TPLR on the phenotypes of hepatic stellate cells (HSCs) during the regression of liver fibrosis and explore the potential mechanism of action. METHODS: The effect of TPLR on the phenotypes of hepatic stellate cells (HSCs) was assessed using immunofluorescence (IF) staining, reverse transcription-polymerase chain reaction (RT-PCR), and Western blotting. Transcriptomic and proteomic methods were employed to identify the main signaling pathways involved. Based on the omics results, the likely mechanism of TPLR on the phenotypes of aHSCs was confirmed through overexpression and knockdown experiments in TGF-ß1-activated LX-2 cells. Using a CCl4-induced liver fibrosis mouse model, we evaluated the anti-hepatic fibrosis effect of TPLR and explored its potential mechanism based on omics findings. RESULTS: TPLR was found to induce the differentiation of aHSCs into iHSCs by significantly decreasing the protein expression of α-SMA and Desmin. Transcriptomic and proteomic analyses revealed that the AGE/RAGE signaling pathway plays a crucial role in the morphological transformation of HSCs following TPLR treatment. In vitro experiments using RAGE overexpression and knockdown demonstrated that the mechanism by which TPLR affects the phenotype of HSCs is closely associated with the RAGE/RAS/MAPK/NF-κB axis. In a model of liver fibrosis, TPLR obviously inhibited the generation of AGEs and alleviated liver tissue damage and fibrosis by downregulating RAGE and its downstream targets. CONCLUSION: The AGE/RAGE axis plays a pivotal role in the transformation of activated hepatic stellate cells (aHSCs) into inactivated hepatic stellate cells (iHSCs) following TPLR treatment, indicating the potential of TPLR as a therapeutic agent for the management of liver fibrosis.

Rhubarb charcoal-crosslinked chitosan/silk fibroin sponge scaffold with efficient hemostasis, inflammation, and angiogenesis for promoting diabetic wound healing.

Diabetic patients often experience long-term risks due to chronic inflammation and delayed re-epithelialization during impaired wound healing. Although the severity of this condition is well known, the treatment options for diabetic wounds are limited. Rhubarb charcoal, a well-known traditional Chinese medicine, has been used to treat skin wounds for thousands of years. We produced a chitosan/silk fibroin sponge scaffold loaded with natural carbonized rhubarb and crosslinked it by freeze-drying to create a highly efficient RCS/SF scaffold. Rhubarb carbon and carboxymethyl chitosan exhibit antibacterial activity and promote wound healing. Owing to its 3D porous structure, this scaffold is antibacterial and pro-angiogenic. It also possesses remarkable properties, such as excellent swelling and biocompatibility. The supportive effect of carbonized rhubarb on mouse fibroblast migration is mediated at the cellular/tissue level by increased skin neovascularization and re-epithelization. Compared to the control group, RCS/SF scaffolds promoted faster healing, increased neovascularization, enhanced collagen deposition, and re-epithelialization within two weeks. The scaffold's pro-healing properties and efficient release of carbonized rhubarb, with rapid hemostatic and good sterilization effects, make it an outstanding candidate for treating diabetic wounds and novel therapeutic interventions for diabetic ulcers.

The effect of Tuina based on the concept of hip-knee-ankle conjugation in patients with chronic ankle instability: study protocol for a randomized controlled trial.

Background: Chronic ankle instability (CAI) is a common sports injury disease and characterized by limited mobility, perceived instability and muscle weakness, combined treatment of hip-knee-ankle is a common rehabilitation method. Tuina, as a traditional Chinese manual therapy, is usually used for CAI, but many of them only focus on the local ankle joint rather than the combination of hip and knee joint. Therefore, we have designed a randomized controlled trial (RCT) to investigate the effects of Tuina base on the concept of hip-knee-ankle conjugation on the stability and balance of lower limbs and ankle function in patients with CAI. Methods: We have designed a randomized controlled trial. A total of 72 participants with CAI will be randomly divided into functional training groups and hip-knee-ankle Tuina combined with functional training group in a 1:1 ratio. Participants in control group will receive 8 sessions of functional training (30 min per session, twice a week for 4 weeks). Participants in intervention group will receive 8 sessions of Tuina combined with functional training (twice a week for 4 weeks). The primary outcomes include the Y-Balance Test (YBT) and Cumberland Ankle Instability Tool (CAIT). The Secondary outcomes include the Foot and Ankle Ability Measure (FAAM) and ankle range of motion (ROM). The outcome assessments will be conducted before the first intervention and after the last intervention. Discussion: The aim of this study is to explore a safe and effective manipulation program and serve as reference for clinical treatment of CAI and expect to provide the necessary theoretical and practical support to our future research. Clinical Trial Registration: Chinese Clinical Trail Registry ChiCTR2300068274.

Conservation planning for the endemic and endangered medicinal plants under the climate change and human disturbance: a case study of Gentiana manshurica in China.

Human activities and climate change have significantly impacted the quantity and sustainable utilization of medicinal plants. Gentiana manshurica Kitagawa, a high-quality original species of Gentianae Radix et Rhizoma, has significant medicinal value. However, wild resources have experienced a sharp decline due to human excavation, habitat destruction, and other factors. Consequently, it has been classified as an Endangered (EN) species on the IUCN Red List and is considered a third-level national key-protected medicinal material in China. The effects of climate change on G. manshurica are not yet known in the context of the severe negative impacts of climate change on most species. In this study, an optimized MaxEnt model was used to predict the current and future potential distribution of G. manshurica. In addition, land use data in 1980, 2000, and 2020 were used to calculate habitat quality by InVEST model and landscape fragmentation by the Fragstats model. Finally, using the above-calculated results, the priority protection areas and wild tending areas of G. manshurica were planned in ZONATION software. The results show that the suitable area is mainly distributed in the central part of the Songnen Plain. Bio15, bio03, bio01, and clay content are the environmental variables affecting the distribution. In general, the future potential distribution is expected to show an increasing trend. However, the species is expected to become threatened as carbon emission scenarios and years increase gradually. At worst, the high suitability area is expected to disappear completely under SSP585-2090s. Combined with the t-test, this could be due to pressure from bio01. The migration trends of climate niche centroid are inconsistent and do not all move to higher latitudes under different carbon emission scenarios. Over the past 40 years, habitat quality in the current potential distribution has declined yearly, and natural habitat has gradually fragmented. Existing reserves protect only 9.52% of G. manshurica's priority conservation area. To avoid extinction risk and increase the practicality of the results, we clarified the hotspot counties of priority protection area gaps and wild tending areas. These results can provide an essential reference and decision basis for effectively protecting G. manshurica under climate change.

Multichip multidimensional quantum networks with entanglement retrievability.

Quantum networks provide the framework for quantum communication, clock synchronization, distributed quantum computing, and sensing. Implementing large-scale and practical quantum networks relies on the development of scalable architecture and integrated hardware that can coherently interconnect many remote quantum nodes by sharing multidimensional entanglement through complex-medium quantum channels. We demonstrate a multichip multidimensional quantum entanglement network based on mass-manufacturable integrated-nanophotonic quantum node chips fabricated on a silicon wafer by means of complementary metal-oxide-semiconductor processes. Using hybrid multiplexing, we show that multiple multidimensional entangled states can be distributed across multiple chips connected by few-mode fibers. We developed a technique that can efficiently retrieve multidimensional entanglement in complex-medium quantum channels, which is important for practical uses. Our work demonstrates the enabling capabilities of realizing large-scale practical chip-based quantum entanglement networks.

Review of Molybdenum Disulfide Research in Slurry Bed Heavy Oil Hydrogenation.

With the growing demand for gasoline and diesel fuel and the shortage of conventional oil reserves, there has been extensive interest in upgrading technologies for unconventional feedstocks such as heavy oil. Slurry bed reactors with high tolerance to heavy oil have been extensively investigated. Among them, dispersive MoS2 is favored for its excellent hydrogenation ability for heavy oil even under harsh reaction conditions such as high pressure and high temperature, its ability to effectively prevent damage to equipment from deposited coke, and its ability to meet the requirement of high catalyst dispersion for slurry bed reactors. This paper reviews the relationship between the structure and hydrogenation effectiveness of dispersive molybdenum disulfide, the hydrogenation mechanism, and the improvement of its hydrogenation performance by adding defects and compares the application of molybdenum disulfide in heavy oil hydrogenation, desulfurization, deoxygenation, and denitrification. It is found that the current research on dispersive molybdenum disulfide catalysts focuses mostly on the reduction of stacking layers and catalytic performance, and there is a lack of research on the lateral dimensions, microdomain regions, and defect sites of MoS2 catalysts. The relationship between catalyst structure and hydrogenation effect also lags far behind the application of MoS2 in the precipitation of hydrogen, etc. Oil-soluble and water-soluble MoS2 catalysts eventually need to be converted to a solid sulfide state to have hydrogenation activity. The conversion history of soluble catalysts to solid-type catalysts and the key to their improved catalytic effectiveness remain unclear.

Du Huo Ji Sheng Tang inhibits Notch1 signaling and subsequent NLRP3 activation to alleviate cartilage degradation in KOA mice.

BACKGROUND: Knee osteoarthritis (KOA) has a complex pathological mechanism and is difficult to cure. The traditional medicine Du Huo Ji Sheng Tang (DHJST) has been used for the treatment of KOA for more than one thousand years, but its mechanism for treating KOA has not been revealed. In our previous study, we confirmed that DHJST inhibited the activation of NLRP3 signaling in rats and humans. In the current study, we aimed to determine how DHJST inhibits NLRP3 to alleviate knee cartilage damage. METHODS: Mice were injected with NLRP3 shRNA or Notch1-overexpressing adenovirus into the tail vein to construct systemic NLRP3 low-expressing or Notch1 high-expressing mice. Mice were injected with papain into the knee joint to replicate the KOA model. DHJST was used to treat KOA model mice with different backgrounds. The thickness of the right paw was measured to evaluate toe swelling. The pathohistological changes and the levels of IL-1ß, MMP2, NLRP3, Notch1, collagen 2, collagen 4, HES1, HEY1, and Caspase3 were detected by HE staining, ELISA, immunohistochemical staining, western blotting, or real-time qPCR. RESULTS: DHJST reduced tissue swelling and serum and knee cartilage IL-1ß levels, inhibited cartilage MMP2 expression, increased collagen 2 and collagen 4 levels, decreased Notch1 and NLRP3 positive expression rates in cartilage, and decreased HES1 and HEY1 mRNA levels in KOA model mice. In addition, NLRP3 interference decreased cartilage MMP2 expression and increased collagen 2 and collagen 4 levels without affecting the expression levels of notch1, HES1 and HEY1 mRNA levels in the synovium of KOA mice. In KOA mice with NLRP interference, DHJST further reduced tissue swelling and knee cartilage damage in mice. Finally, Notch1-overexpressing mice not only showed more severe tissue swelling and knee cartilage degradation but also abolished the therapeutic effect of DHJST on KOA mice. Importantly, the inhibitory effects of DHJST on the mRNA expression of NLRP3, Caspase3 and IL-1ß in the knee joint of KOA mice were completely limited after Notch1 overexpression. CONCLUSION: DHJST significantly reduced inflammation and cartilage degradation in KOA mice by inhibiting Ntoch1 signaling and its subsequent NLRP3 activation in the knee joint.

Network Pharmacology-Based Approach for Investigating the Role of Xanthii Fructus in Treatment of Allergic Rhinitis.

Xanthii Fructus (XF) has been used for treatment of allergic rhinitis (AR), but its pharmacological mechanism of action remains unclear. We aimed to explore the potential mechanism of XF in treatment of AR by using a network pharmacology approach combined with in vivo verification experiments in this study. We identified 945 AR-related pathogenic genes, 11 active components in XF and 178 targets of those active components by corresponding databases. Finally, 54 targets of active components from XF in treatment of AR were identified by the Protein-protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, among which Tumor Necrosis Factor (TNF), Mitogen-activated Protein Kinase 3 (MAPK3), Prostaglandin G/H Synthase 2 (PTGS2), Epidermal Growth Factor Receptor (EGFR) showed strongest interactions. The molecular docking analysis showed that moupinamide could bind to EGFR at LEU704 and LEU703, and PTGS2 at TRP387; 24-Ethylcholest-4-en-3-one was identified to bind to MAPK3 at THR347. The validation of quantitative real-time reverse transcription PCR (RT-PCR) showed that XF decreased the levels of MAPK3, PTGS2, and EGFR expression in the nasal mucosa from AR mice gavaged with an XF water decoction. Meanwhile, the levels of interleukin (IL)-4, IL-5 and IL-13were also decreased after the treatment of XF by Enzyme-linked immunosorbent assay (ELISA). Our results provide the pharmacological mechanism and possible intervention targets of XF in treatment of AR.

Aptamer and Peptide-Engineered Polydopamine Nanospheres for Target Delivery and Tumor Perfusion in Synergistic Chemo-Phototherapy of Pancreatic Cancer.

Pancreatic cancer (PC) is the fourth leading cause of cancer death, and the 5 year survival rate is only 4%. Chemotherapy is the treatment option for the majority of PC patients diagnosed at an advanced stage, whereas the desmoplastic stroma of PC could block the perfusion of chemotherapeutic agents to tumor tissues and contribute generally to chemoresistance. Therefore, the clinical status of PC calls for an urgent exploration in the effective treatment strategy. Chemo-phototherapy is an emerging modality against malignant tumors, but owing to the low targeting ability of theranostic agents or unspecific accumulation in the tumor region, majority of chemo-phototherapy techniques have disappointing therapeutic efficiencies. Herein, we have explored CD71-specific targeting aptamers and paclitaxel (PTX)-modified polydopamine (PDA) nanospheres with the conjugation of peptidomimetic AV3 (termed Apt-PDA@PTX/AV3 bioconjugates) to specifically target and combat PC in vivo by synergistic chemo-phototherapy. After the delivery of nanotheranostic agents to the tumor microenvironment (TME) or subsequent endocytic uptake by PC cells, a simultaneous release of AV3 and PTX from Apt-PDA@PTX/AV3 bioconjugates via near-infrared (NIR) irradiation can decrease desmoplastic stroma to enhance tumor perfusion and tumor-killing effects. Meanwhile, PDA cores utilize NIR laser to create unendurable hyperthermia within TME to "cook" tumors. Taken together, the current study finally suggests that our Apt-PDA@PTX/AV3 bioconjugates could act as a novel therapeutic approach by synergistic chemo-phototherapy for the programmable inhibition of PC.

The total iridoid glycoside extract of Lamiophlomis rotata Kudo induces M2 macrophage polarization to accelerate wound healing by RAS/ p38 MAPK/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Lamiophlomis rotata (Benth.) Kudo (L. rotata), a Tibetan medicinal plant, is used to treat "yellow-water diseases", such as skin disease, jaundice and rheumatism. Our previous study showed that the iridoid glycoside extract of L. rotata (IGLR) is the major constituent of skin wound healing. However, the role of IGLR in the biological process of trauma repair and the probable mechanism of the action remain largely unknown. AIM OF THE STUDY: To investigate the role of IGLR in the biological process of trauma repair and the probable mechanism of the action. MATERIALS AND METHODS: The role of IGLR in wound healing was investigated by overall skin wound in mice with Hematoxylin and Eosin (H&E) and Masson trichrome staining. The anti-inflammatory, angiogenesis-promoting and fibril formation effects of IGLR were visualized in wound skin tissue by immunofluorescence staining, and the proinflammatory factors and growth factors were assayed by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Macrophages, dermal fibroblasts, and endothelial cells were cultured to measure the direct/indirect interaction effects of IGLR on the proliferation and migration of cells, and flow cytometry was employed to assess the role of IGLR on macrophage phenotype. Network pharmacology combined with Western blot experiments were conducted to explore possible mechanisms of the actions. RESULTS: IGLR increased the expression of CD206 (M2 markers) through the RAS/p38 MAPK/NF-κB signaling pathway during wound injury in vivo and in vitro. IGLR suppressed the inflammatory cytokines iNOS, IL-1ß and TNF-α in the early stage of wound healing. During the proliferation step of wound repair, IGLR promoted angiogenesis and fibril formation by increasing the expression of VEGF, CD31, TGF-ß and α-SMA in wound tissue, and similar results were verified by RT-PCR and ELISA. In a paracrine mechanism, the extract promoted the proliferation of dermal fibroblasts, and endothelial cells were founded by the conditioned medium (CM). CONCLUSION: IGLR induced M2 macrophage polarization in the early stage of wound healing; in turn, IGLR played a key role in the transition from inflammation to cell proliferation during the biological process of wound healing.

New strategies for identifying and masking the bitter taste in traditional herbal medicines: The example of Huanglian Jiedu Decoction.

Suppressing the bitter taste of traditional Chinese medicine (TCM) largely has been a major clinical challenge due to complex and diverse metabolites and high dispersion of bitter metabolites in liquid preparations. In this work, we developed a novel strategy for recognizing bitter substances, hiding their bitter taste, and elucidated the mechanism of flavor masking in TCM. Huanglian Jie-Du Decoction (HLJDD) with an intense bitter taste was studied as a typical case. UHPLC-MS/MS was used to analyze the chemical components in HLJDD, whereas the bitter substances were identified by pharmacophores. Additionally, the screening results of the pharmacophores were further validated by using experimental assays. The mask formula of HLJDD was effectively screened under the condition of clear bitter substances. Subsequently, computational chemistry, molecular docking, and infrared characterization (IR) techniques were then used to explicate the mechanism of flavor masking. Consequently, neotame, γ-CD, and mPEG2000-PLLA2000 significantly reduced the bitterness of HLJDD. Specifically, mPEG2000-PLLA2000 increased the colloid proportion in the decoction system and minimized the distribution of bitter components in the real solution. Sweetener neotame suppressed the perception of bitter taste and inhibited bitter taste receptor activation to eventually reduce the bitter taste. The γ-CD included in the decoction bound the hydrophobic groups of the bitter metabolites in real solution and "packed" all or part of the bitter metabolites into the "cavity". We established a novel approach for screening bitter substances in TCM by integrating virtual screening and experimental assays. Based on this strategy, the bitter taste masking of TCM was performed from three different aspects, namely, changing the drug phase state, component distribution, and interfering with bitter taste signal transduction. Collectively, the methods achieved a significant effect on bitter taste suppression and taste masking. Our findings will provide a novel strategy for masking the taste of TCM liquid preparation/decoction, which will in return help in improving the clinical efficacy of TCM.

Baicalein Prevents Fructose-Induced Hepatic Steatosis in Rats: In the Regulation of Fatty Acid De Novo Synthesis, Fatty Acid Elongation and Fatty Acid Oxidation.

Non-alcoholic fatty liver disease (NAFLD), ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), hepatic fibrosis and even hepatocellular carcinoma, is a liver disease worldwide without approved therapeutic drugs. Baicalein (BAL), a flavonoid compound extracted from the Traditional Chinese Medicine (TCM) Scutellariae Radix (Scutellaria baicalensis Georgi.), has been used in TCM clinical practice for thousands of years to treat liver diseases due to its "hepatoprotective effect". However, the underlying liver-protecting mechanisms remain largely unknown. Here, we found that oral administration of BAL significantly decreased excess serum levels of triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST) as well as hepatic TG in fructose-fed rats. Attenuation of the increased vacuolization and Oil Red O staining area was evident on hepatic histological examination in BAL-treated rats. Mechanistically, results of RNA-sequencing, western-blot, real-time quantitative PCR (RT-qPCR) and hepatic metabolomics analyses indicated that BAL decreased fructose-induced excessive nuclear expressions of mature sterol regulatory element-binding protein 1c (mSREBP1c) and carbohydrate response element-binding protein (ChREBP), which led to the decline of lipogenic molecules [including fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), elongation of very long chain fatty acids 6 (ELOVL6), acetyl-CoA carboxylase (ACC)], accompanying with the alternation of hepatic fatty acids composition. Meanwhile, BAL enhanced fatty acid oxidation by activating AMPK/PGC1α signaling axis and PPARα signal pathway, which elicited high expression of carnitine palmitoyl transferase 1α (CPT1α) and Acyl-CoA oxidase 1 (ACO1) in livers of fructose-fed rats, respectively. BAL ameliorated fructose-induced hepatic steatosis, which is associated with regulating fatty acid synthesis, elongation and oxidation.

Metabolomics combined with network pharmacology to explore the mechanisms of modified Guishen pill to ameliorate polycystic ovary syndrome.

BACKGROUND: The modified Guishen pill (MGP) has a prominent therapeutic effect on polycystic ovary syndrome (PCOS). However, its mechanism is still unclear. This study aimed to uncover the mechanism of MGP for PCOS treatment through a comprehensive strategy integrating metabolomics and network pharmacology. METHODS: A letrozole-induced PCOS model was used to evaluate ovarian function in rats. Plasma metabolomics was used to authenticate differential metabolites and enriched related pathways using the MetaboAnalyst platform. Network pharmacology was utilized to explore the endogenous targets of MGP treatment for PCOS. Finally, the potential targets and related biological functions were verified experimentally. RESULTS: MGP improved PCOS symptoms by regulating abnormal levels of sex hormones and alleviating ovarian pathological changes in rats; fifty-four potential differential metabolites involved in MGP treatment for PCOS, and the hub genes derived from network pharmacology were consistent with the metabolomic analysis results to varying degrees. The comprehensive analysis identified that a key novel target for endothelial nitric oxide synthase (eNOS/NOS3), five key metabolites (ornithine, citrulline, l-glutamic acid, acetylornithine, and hydroxyproline), and one pathway (arginine and proline metabolism) were related to the therapy of PCOS with MGP. Subsequently, we verified the localization and expression of eNOS in the ovaries, and it significantly improved insulin resistance, apoptosis, and oxidative stress in letrozole-induced PCOS rats. CONCLUSION: Our work reveals the complex mechanism of MGP therapy for PCOS. This study is a successful paradigm for elucidating the pharmacological mechanism of the traditional Chinese medicine compound.

[Clinical anatomical study on the treatment of tarsal tunnel syndrome with four-point vertical acupotomy].

OBJECTIVE: To explore safety and accuracy of four-point acupotomy for the treatment of tarsal tunnel syndrome regarding release of ankle tunnel flexor retinaculum to provide an anatomical basis of clinical treatment. METHODS: Twenty-nine adult specimens (15 males and 14 females) fixed with 10% formalin, aged from 47 to 98 years old with an average age of (81.10±11.14) years old, 29 on the right side and 29 on the left side, which were selected for the study from September 2020 to October 2020. Simulate the operation of loosening flexor retinaculumt with a needle knife on the human specimen, and place the specimen on the frog position of lower limbs with medial malleolus upward to determine the center of medial malleolus. Choose 4 different positions near the flexor retinaculum to insert the needle so that the needle body was perpendicular to skin and cutting edge direction was perpendicular to the running direction of the flexor retinaculum. The needle knife penetrates the skin and explores slowly. When the flexor retinaculum was reached, the needle tip may touch the tough tissue. At this time, the cutting is loosened for 4 times. After acupotomy release operation was completed, make a lateral incision on the skin surface along acupotomy direction, open the area of the exposed flexor retinaculum, dissecting layer by layer, observe and record the needle knife and its surrounding anatomical structure. The length of acupotomy cutting marks of flexor retinaculum was measured by electronic vernier caliper. The safety and accuracy of acupotomy loosening of ankle canal flexor retinaculum were evaluated by observing the number and degree of ankle canal contents such as tendons and nerves injured by needle knife. The safety is to count the number of cases of acupotomy injury to the contents of the ankle canal, and to calculate the injury rate, that is, the number of injury cases/total cases × 100%. The effective release was defined as the release length L ≥ W/2(W is the width of the flexor retinaculum, defined as 20 mm). RESULTS: For safety, there were no acupotomy injuries to nerves or blood vessels in 58 cases, 26 cases injuried to posterior tibial tendon which 17 of these tendon injury cases, the tendon was penetrated and severely injured, and flexor digitorum longus tendon was injured in 12 cases. Among these cases, tendon was penetrated and severely injured in 4 cases, and total injury rate was 32.14%. No nerve and vessel injury on c3 and c4 point. For accuracy, 58 specimens were successfully released. The length Lc of releasing trace for acupotomy was (10.40±1.36) cm, and length range 6.38 to 12.88 cm. Among all cases, the length of releasing trace was ≥10 mm in 37 cases. The overall success rate of release was 100.00%. Layered structure of ankle tube flexor retinaculumt:fiber diaphragm from flexor retinaculum divides contents of ankle tube into different chambers inward, and fiber diaphragm meets here to synthesize a complete flexor retinaculum at the midpoint of the line between the medial malleolus tip and calcaneal tubercle(above the neurovascular course). CONCLUSION: Four-point needle-knife method of releasing flexor retinaculum for the treatment of tarsal tunnel syndrome is performed at the attachment of the two ends of flexor retinaculum;the tendon, but not the nerves and blood vessels, is easily damaged. It is safe to insert needle on the side of calcaneus. The extent of release is relatively complete, but due to the "layered" structure of the flexor retinaculum, classic surgical technique could only release one layer of flexor retinaculum when a needle is inserted at the edge of the bone and cannot achieve complete release of the full thickness of the flexor. Therefore, it remains to be determined whether the desired effect can be achieved clinically.

Ultrathin-FeOOH-Coated MnO2 Sonosensitizers with Boosted Reactive Oxygen Species Yield and Remodeled Tumor Microenvironment for Efficient Cancer Therapy.

Sonodynamic therapy (SDT) typically suffers from compromised anticancer efficacy owing to the low reactive oxygen species (ROS) yield and complicated tumor microenvironment (TME) which can consume ROS and support the occurrence and development of tumors. Herein, ultrathin-FeOOH-coated MnO2 nanospheres (denoted as MO@FHO) as sonosensitizers which can not only facilitate ultrasound (US)-triggered ROS but also tune the TME by hypoxia alleviation, H2 O2 consumption as well as glutathione (GSH) depletion are designed. The FeOOH coating will boost the production yield of singlet oxygen (1 O2 ) and hydroxyl radicals (• OH) by inhibiting the recombination of US-initiated electron-hole pairs and Fenton-like reaction, respectively. Additionally, the catalase-like and GSH peroxidase-like activities of MO@FHO nanospheres enable them to break the TME equilibrium via hypoxia alleviation and GSH depletion. The combination of high ROS yield and fundamental destruction of TME equilibrium results in satisfactory antitumor outcomes, as demonstrated by the high tumor suppression efficacy of MO@FHO on MDA-MB-231-tumor-bearing mice. No obvious toxicity is detected to normal tissues at therapeutic doses in vivo. The capability to modulate the ROS production and TME simultaneously can afford new probability for the development of advanced sonosensitizers for synergistic comprehensive cancer therapy.

Spectrum-Effect Relationships Between High-Performance Liquid Chromatography Fingerprints and Hepatoprotective Activities of Cuscutae Semen.

BACKGROUND: Cuscutae Semen (CS) is a commonly used hepatoprotective traditional Chinese medicine, but the chemical components responsible for its hepatoprotective activity are unclear. OBJECTIVE: The purpose of this study was to evaluate the spectrum-effect relationships between HPLC fingerprints and hepatoprotective effects of CS, and to identify its bioactive components. METHODS: Phytochemical isolation of CS extracts was first carried out and 14 potential bioactive compounds were obtained. Chemical fingerprinting was performed on 27 batches of CS from different sources by HPLC, and further analyzed by similarity analysis (SA) and hierarchical clustering analysis (HCA). Pharmacodynamic testing was performed in a CCl4-induced, acute liver injury cell model to assess the hepatoprotective activity of CS by measuring the cell viability and levels of alanine transaminase (ALT) and aspartate aminotransferase (AST). Bivariate correlations analysis (BCA) and orthogonal projections to latent structures (OPLS) were used to analyze the spectrum-effect relationships of CS. RESULTS: The results showed that the chemical fingerprints of CS were closely correlated with its hepatoprotective activity. Peaks 1, 10, 18, 19, 21, 22, and 24 might be potential hepatoprotective compounds in CS, and the validation experiments of isolated compounds indicated that chlorogenic acid (P10), hyperoside (P21), isoquercitrin (P22), and astragalin (P24) were the main hepatoprotective components. CONCLUSION: By combining chemical fingerprints with hepatoprotective evaluation, the present study provides important guidance for QC and clinical use of CS. HIGHLIGHTS: (1) Ten potential bioactive compounds were isolated from CS; (2) The spectrum-effect relationship of CS was molded by HPLC and analysed by OPLS and BCA. (3) Four compounds including chlorogenic acid were the main hepatoprotective components.

Baicalin ameliorates alcohol-induced hepatic steatosis by suppressing SREBP1c elicited PNPLA3 competitive binding to ATGL.

Baicalin is a flavonoid compound abundant in multiple edible and medicinal plants such as Scutellaria baicalensis Georgi. In this study, we provide evidence to support the fact that baicalin ameliorates alcohol-induced hepatic steatosis via regulating SREBP1c elicited PNPLA3 competitive binding to ATGL. Results showed that baicalin significantly attenuated the development of metabolic disorders and hepatic steatosis in alcohol-induced rats after four weeks of treatment. It was evident that baicalin treatment significantly normalized the serous contents of hepatic triglyceride (TG), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), and attenuated the increase of hepatic vacuolization and Oil Red O staining area caused by alcohol. Meanwhile, baicalin relieves alcohol-induced hepatic fibrosis by masson staining and RT-qPCR analysis. Mechanistically, alcohol aggravated the nuclear expression of SREBP1c, which contributed to the high expression of PNPLA3 and FASN, thereby enhancing the binding of PNPLA3 to ABHD5, and indirectly impairing the binding ability between ATGL and ABHD5, ultimately causing a decline in the hydrolysis capacity in liver lipid droplets. As expected, these alcohol-induced pathobolism were reversed by baicalin treatment both in vivo and in vitro. In conclusion, this study has demonstrated that baicalin can protect against alcohol-induced hepatic lipid accumulation by activating hepatic lipolysis via suppressing SREBP1c elicited PNPLA3 competitive binding to ATGL. Baicalin is a promising natural product for preventing alcohol-induced hepatic steatosis.