Self-Assembled Nanoparticles from Xie-Bai-San Decoction: Isolation, Characterization and Enhancing Oral Bioavailability.

Background: Natural nanoparticles have been found to exist in traditional Chinese medicine (TCM) decoctions. However, whether natural nanoparticles can influence the oral bioavailability of active compounds has not been elucidated. Using Xie-Bai-San decoction (XBSD) as an example, the purpose of this study was to isolate, characterize and elucidate the mechanism of the nanoparticles (N-XBSD) in XBSD, and further to explore whether the bioavailability of the main active compounds could be enhanced by N-XBSD. Methods: N-XBSD were isolated from XBSD, and investigated its characterization and study of its formation mechanism, and evaluation of its ability to enhance bioavailability of active compounds. Results: The N-XBSD was successfully isolated with the average particle size of 104.53 nm, PDI of 0.27 and zeta potential of -5.14 mV. Meanwhile, all the eight active compounds were most presented in N-XBSD. Kukoamine B could self-assemble with mulberroside A or liquiritin to form nanoparticles, respectively. And the FT-IR and HRMS results indicated the possible binding of the ammonium group of kukoamine B with the phenolic hydroxyl group of mulberroside A or liquiritin, respectively. The established UPLC-MS/MS method was accurate and reliable and met the quantitative requirements. The pharmacokinetic behaviors of the N-XBSD and decoction were similar in rats. Most notably, compared to that of free drugs, the Cmax, AUC0-∞, AUC0-t, T1/2 and MRT0-∞ values of index compounds were the higher in N-XBSD, with a slower plasma clearance rate in rats. Conclusion: The major active compounds of XBSD were mainly distributed in N-XBSD, and N-XBSD was formed through self-assembly among active compounds. N-XBSD could obviously promote the bioavailability of active compounds, indicating natural nanoparticles of decoctions play an important role in therapeutic effects.

Validation of the IMPEDE VTE score for prediction of venous thromboembolism in Chinese patients with multiple myeloma: A single-center retrospective cohort study.

Multiple myeloma (MM) significantly increases the risk of venous thromboembolism (VTE) within 6 months of treatment initiation. The IMPEDE VTE score is a VTE risk prediction model which is recently incorporated into the National Comprehensive Cancer Network (NCCN) guidelines, but it lacks validation among Asians, including Chinese MM patients. We performed a retrospective chart review of 405 Chinese with newly diagnosed MM who started therapy at Beijing Jishuitan Hospital between April 2013 to October 2022. The 6-month cumulative incidence of VTE was 3.8 % (95 % CI:1.6-7.6), 8.6 % (95 % CI: 5.3-21.9) and 40.5 % (95 % CI: 24.9-55.7) in the low-, intermediate- and high-risk groups (P < 0.001), respectively. The C-statistic of the IMPEDE VTE scores for predicting VTE within 6 months of treatment initiation was 0.74 (95 % CI: 0.65-0.83). Of note, in this single-center cohort study, we propose that the anticoagulant LMWH may be more effective than the antiplatelet aspirin in potentially preventing VTE in newly diagnosed MM patients. Our findings suggest that the IMPEDE VTE score is a valid evidence-based risk stratification tool in Chinese patients with newly diagnosed MM.

Mitochondria-Targeting Multimodal Phototheranostics Based on Triphenylphosphonium Cation Modified Amphiphilic Pillararenes and A-D-A Fused-Ring Photosensitizers.

Tumor-targeting phototheranostics has gradually developed as a powerful tool for the precise diagnosis and treatment of cancer. However, the designs of tumor-targeting phototheranostics agents with excellent multimodal phototherapy and fluorescence imaging (FLI) capability, as well as very few components, are still scarce and challenging for cancer treatment. Herein, a mitochondria-targeting multimodal phototheranostics system has been constructed by combining a designed amphiphilic pillararene WP5-2PEG-2TPP and the A-D-A fused-ring photosensitizer F8CA5. WP5-2PEG-2TPP is constructed by attaching the triphenylphosphonium cations to our previously reported dual PEG-functionalized amphiphilic pillararene, which can self-assemble into regular spherical nanocarriers with outstanding mitochondria targeting and water solubility. The A-D-A photosensitizer F8CA5 containing two methyl cyanoacetate group modified end groups displays superior photothermal conversion ability and dual type I/II photodynamic activity as well as strong NIR fluorescence emission. Through their strong union, multifunctional mitochondria-targeting phototheranostics agent F8CA5 NPs were obtained to be applied into FLI-guided synergistic photothermal and type I/II photodynamic therapy. As a result, F8CA5 NPs show good mitochondria-targeting and phototherapy effects in various tumor cells. Not only that, they can combat tumor hypoxia, which hinders the efficacy of photodynamic therapy. Therefore, this work provides a creative ideal for the construction of multifunctional tumor-targeting phototheranostic agents with excellent performance.

Ginseng saponin metabolite 20(S)-protopanaxadiol relieves pulmonary fibrosis by multiple-targets signaling pathways.

Background: Panax ginseng Meyer is a representative Chinese herbal medicine with antioxidant and anti-inflammatory activity. 20(S)-Protopanaxadiol (PPD) has been isolated from ginseng and shown to have promising pharmacological activities. However, effects of PDD on pulmonary fibrosis (PF) have not been reported. We hypothesize that PDD may reverse inflammation-induced PF and be a novel therapeutic strategy. Methods: Adult male C57BL/6 mice were used to establish a model of PF induced by bleomycin (BLM). The pulmonary index was measured, and histological and immunohistochemical examinations were made. Cell cultures of mouse alveolar epithelial cells were analyzed with Western blotting, co-immunoprecipitation, immunofluorescence, immunohistochemistry, siRNA transfection, cellular thermal shift assay and qRT-PCR. Results: The survival rate of PPD-treated mice was higher than that of untreated BLM-challenged mice. Expression of fibrotic hallmarks, including α-SMA, TGF-ß1 and collagen I, was reduced by PPD treatment, indicating attenuation of PF. Mice exposed to BLM had higher STING levels in lung tissue, and this was reduced by phosphorylated AMPK after activation by PPD. The role of phosphorylated AMPK in suppressing STING was confirmed in TGF-ß1-incubated cells. Both in vivo and in vitro analyses indicated that PPD treatment attenuated BLM-induced PF by modulating the AMPK/STING signaling pathway. Conclusion: PPD ameliorated BLM-induced PF by multi-target regulation. The current study may help develop new therapeutic strategies for preventing PF.

Two-step model of paleohexaploidy, ancestral genome reshuffling and plasticity of heat shock response in Asteraceae.

An ancient hexaploidization event in the most but not all Asteraceae plants, may have been responsible for shaping the genomes of many horticultural, ornamental, and medicinal plants that promoting the prosperity of the largest angiosperm family on the earth. However, the duplication process of this hexaploidy, as well as the genomic and phenotypic diversity of extant Asteraceae plants caused by paleogenome reorganization, are still poorly understood. We analyzed 11 genomes from 10 genera in Asteraceae, and redated the Asteraceae common hexaploidization (ACH) event ~70.7-78.6 million years ago (Mya) and the Asteroideae specific tetraploidization (AST) event ~41.6-46.2 Mya. Moreover, we identified the genomic homologies generated from the ACH, AST and speciation events, and constructed a multiple genome alignment framework for Asteraceae. Subsequently, we revealed biased fractionations between the paleopolyploidization produced subgenomes, suggesting the ACH and AST both are allopolyplodization events. Interestingly, the paleochromosome reshuffling traces provided clear evidence for the two-step duplications of ACH event in Asteraceae. Furthermore, we reconstructed ancestral Asteraceae karyotype (AAK) that has 9 paleochromosomes, and revealed a highly flexible reshuffling of Asteraceae paleogenome. Of specific significance, we explored the genetic diversity of Heat Shock Transcription Factors (Hsfs) associated with recursive whole-genome polyploidizations, gene duplications, and paleogenome reshuffling, and revealed that the expansion of Hsfs gene families enable heat shock plasticity during the genome evolution of Asteraceae. Our study provides insights on polyploidy and paleogenome remodeling for the successful establishment of Asteraceae, and is helpful for further communication and exploration of the diversification of plant families and phenotypes.

End Group Nonplanarization Enhances Phototherapy Efficacy of A-D-A Fused-Ring Photosensitizer for Tumor Phototherapy.

Enhancing the phototherapy efficacy of organic photosensitizers through molecular design is a fascinating but challenging task. Herein, we propose a simple design strategy to first realize the generation of superoxide anion radical (O2•-) by A-D-A fused-ring photosensitizers. Through replacing one cyano group of traditional end group with an ester group, we designed a novel nonplanar end group (A unit) to synthesize a novel A-D-A photosensitizer F8CA. In a comparison with its counterpart F8CN with the traditional end group, F8CA displays more loose packing and larger spin-orbit coupling constants. The F8CA nanoparticles showed higher photodynamic activities with the generation capability of singlet oxygen (1O2), hydroxyl radical (•OH), and O2•-, while F8CN nanoparticles could only generate 1O2 and •OH. In addition, F8CA nanoparticles still remain high photothermal conversion efficiency (61%). As a result, F8CA nanoparticles perform well in hypoxia-tolerant tumor phototherapy. This study brings an effective design thought for A-D-A photosensitizers.

Research on safety early warning of uranium tailings dam based on abnormal radioactive indexes of water leachate.

The radioactive index value of the leachate of the uranium tailings dam is affected by the internal damage of the dam. Therefore, a way of using the deviation of the radioactive index concentration in the leachate to warn the instability of the dam is innovatively proposed in this paper. Firstly, the SSA-BP algorithm is used to predict and analyze the five groups of parameters U, Ra, ∑ α, ∑ ß and Rn. Then, the deviation between the actual value and the predicted value is computed. Finally, an early warning is given based on the entropy weight extension decision-making model. The model is verified by the leachate environment monitoring data of a uranium tailings dam in southern China from 2016 to 2020, which shows that the model can effectively caution of the instability of the uranium tailings dam and provides a reference for the subsequent decommissioning management.

A nanoplatform for mild-temperature photothermal and type I & II photodynamic therapy in the NIR-II biowindow.

In the current work, we synthesized an A-D-A smallmolecule photosensitizer, denoted as DPTTIC, and a dual PEG-functionalized pillararene, denoted as WP5-8C-2PEG, and used them to construct novel DPTTIC nanoparticles (NPs) displaying NIR II absorption. Under 980 nm-wavelength laser irradiation, DPTTIC NPs performed well in mild-temperature photothermal and type I & II photodynamic anti-tumor therapy.

Nitric oxide-containing supramolecular polypeptide nanomedicine based on [2]biphenyl-extended-pillar[6]arenes for drug resistance reversal.

A kind of supramolecular polypeptide nanomedicine (BPC/DOX-ICG) was constructed with an anionic water-soluble [2]biphenyl-extended-pillar[6]arene (AWBpP6), and pyridinium-terminal- and S-nitrosothiol (SNO)-modified polypeptide (PPNC) via host-guest interactions to co-deliver doxorubicin (DOX) and indocyanine green (ICG) for drug resistance reversal. Upon near-infrared (NIR) irradiation, the NO generation could down-regulate the P-glycoprotein (P-gp) expression level to reverse multidrug resistance (MDR). Subsequently, the resulting reverse MDR could sensitize the free DOX and assist photothermal therapy (PTT) to enhance the tumoricidal potential. This supramolecular polypeptide nanomedicine provides an effective strategy for the multimodal synergistic therapies of photothermal therapy, NO generation therapy, and chemotherapy (i.e., PTT-NO-CT) to overcome MDR.

Bryodulcosigenin attenuates bleomycin-induced pulmonary fibrosis via inhibiting AMPK-mediated mesenchymal epithelial transition and oxidative stress.

Fibrosis is a pathological result of a dysfunctional repair response to tissue injury and occurs in several organs, including the lungs. Bryodulcosigenin (BDG) is a cucurbitane-type triterpene isolated from Siratia grosvenori and has clear-cut anti-inflammatory effects, yet its benefit of pulmonary fibrosis (PF) remains unclear. In this study, we investigated the protective effects of BDG (10 mg/kg/day, for 14 days) against TGF-ß1-stimulated mouse alveolar epithelial MLE-12 cells and bleomycin (BLM)-induced PF mice. In vitro experiments showed that BDG could inhibit epithelial-mesenchymal transition (EMT) and oxidative stress. In vivo experiments indicated that BDG could ameliorate BLM-induced PF in mice as evidenced by characteristic structural changes in histopathology, increased collagen deposition and reduced survival and weight of mice. The abnormal increased expressions of TGF-ß1, p-Smad2/3, α-SMA, COL-I, and NOX4 and decreased expressions for Sirt1 and p-AMPK were improved in BDG treatment. But these beneficial effects could be eliminated by co-treatment with Compound C (CC, a selective AMPK inhibitor). Molecular docking technology also revealed the potential of BDG to activate AMPK. In summary, AMPK activation modulated by BDG not only ameliorated TGF-ß1/Smad2/3 signaling pathways but also partially mediated the suppression effects on EMT and oxidative stress, thus mediating the anti-fibrotic effects.

Polydopamine-drug conjugate nanocomposites based on ZIF-8 for targeted cancer photothermal-chemotherapy.

Stimuli-responsive prodrug-based nanoplatform with synergistic antitumor activity is of central importance to the development of promising nanomedicines for cancer therapy. Here, we describe a polydopamine-drug conjugate nanocomposite (ZP-PDA-DOX) with targeted cancer photothermal-chemotherapy (PTT-CT), which constructed by a gradual copolymerization of dopamine (DA) and pH-sensitive dopamine-derived prodrug (DA-DOX) into the porous channels of zeolite imidazolate frameworks-8 (ZIF-8), followed by PEGylation with amino-terminated folic acid-polyethylene glycol (NH2 -PEG-FA) to acquire the high biocompatibility, specificity, and excellent tumor-targeting property. The incorporation of polydopamine strengthened the stability and dispersion of ZIF-8, and also conferred photothermal conversion effect. In the tumor acidic microenvironment, the acid-labile hydrazone linker of DA-DOX and ZIF-8 promptly degraded to release activated DOX. Moreover, the generated hyperthermia due to the high photothermal conversion efficiency of PDA component could accelerate drug release, and simultaneously thermally ablate tumor tissue to maximize the DOX-induced CT, which could also assist PTT to eradicate tumor cells. This study provides a promising strategy for targeted cancer PTT-CT with synergistic anti-tumor effect.

Traditional Chinese Medicine Strategy for Patients with Tourette Syndrome Based on Clinical Efficacy and Safety: A Meta-Analysis of 47 Randomized Controlled Trials.

OBJECTIVE: Although increasing evidence reveals the efficacy of traditional Chinese medicine (TCM) and its safety on Tourette Syndrome (TS) patients, whether TCM is indeed improving TS remains unclear. The purpose of the current study is to perform a meta-analysis to evaluate the efficacy and safety of TCM on treating TS patients. METHOD: An elaborate search strategy was conducted based on several databases including Medline, Embase, Cochrane, Web of Science, CINAHL, CBM, VIP, CNKI, and Wanfang Data in order to identify the relevant randomized controlled trials (RCTs) from their inception to as late as May 1st, 2020. General information and data needing analysis were extracted simultaneously for the necessity of various analyses such as descriptive analysis and metaquantitative analysis. RESULTS: Forty-seven trials with 5437 TS patients in total were eventually included according to our criteria. All trials were conducted in China, and the publication years ranged from 2004 to 2017. In terms of clinical efficacy, clinical symptoms of patients with TCM were more likely to be improved compared with the control group (odds ratio, OR = -1.29, 95% confidence interval, CI: -2.54 to -0.06, I 2 = 0.00%). As to the outcome of recurrence rate, the pooled results revealed that the TCM group was more inclined to stabilize the recurrence (OR = 0.44, 95% CI: 0.24 to 0.78, I 2 = 0.00%). Similar results were observed in adverse reaction (OR = 0.32, 95% CI: 0.24 to 0.43, I 2 = 32.90%). CONCLUSION: The results of our study recommend applying TCM to treat TS patients for better efficacy and safety. Results need to be interpreted cautiously due to certain limitations in our study.

NIR-II light triggered nitric oxide release nanoplatform combined chemo-photothermal therapy for overcoming multidrug resistant cancer.

The overexpression of P-glycoprotein (P-gp) in multidrug resistance (MDR) cancer cells increases the efflux of anticancer drugs thereby causing the failure of clinical chemotherapy. To address this obstacle, in this study, we rationally designed a near-infrared (NIR) light-responsive nitric oxide (NO) delivery nanoplatform for targeting the MDR tumors based on core-shell structured nanocomposites. The mesoporous silica shell provided abundant sites for modification of the NO donor, N-diazeniumdiolate, and tumor-targeting molecule, folic acid (FA), and enabled high encapsulation capacity for doxorubicin (DOX) loading. Under NIR light irradiation, the generation of NO gas can efficiently augment chemotherapeutic effects via the inhibition of P-gp expression. Simultaneously, the photothermal conversion agents of the Cu2-xSe core produce a large amount of heat for photothermal therapy (PTT). Finally, this combinational gas/chemo/PTT not only displays a superior and synergistic effect for overcoming MDR cancer, but also provides an efficient strategy to construct a multifunctional nano-drug delivery system with diversified therapeutic modalities.

Carnosol suppresses RANKL-induced osteoclastogenesis and attenuates titanium particles-induced osteolysis.

Osteolysis is a common medical condition characterized by excessive activity of osteoclasts and bone resorption, leading to severe poor quality of life. It is essential to identify the medications that can effectively suppress the excessive differentiation and function of osteoclasts to prevent and reduce the osteolytic conditions. It has been reported that Carnosol (Car), isolated from rosemary and salvia, has anti-inflammatory, antioxidative, and anticancer effects, but its activity on osteolysis has not been determined. In this study, we found that Car has a strong inhibitory effect on the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation dose-dependently without any observable cytotoxicity. Moreover, Car can inhibit the RANKL-induced osteoclastogenesis and resorptive function via suppressing NFATc1, which is a result of affecting MAPK, NF-κB and Ca2+ signaling pathways. Moreover, the particle-induced osteolysis mouse model confirmed that Car could be effective for the treatment of bone loss in vivo. Taken together, by suppressing the formation and function of RANKL-induced osteoclast, Car, may be a therapeutic supplementary in the prevention or the treatment of osteolysis.

Speech frequency-following response in human auditory cortex is more than a simple tracking.

The human auditory cortex is recently found to contribute to the frequency following response (FFR) and the cortical component has been shown to be more relevant to speech perception. However, it is not clear how cortical FFR may contribute to the processing of speech fundamental frequency (F0) and the dynamic pitch. Using intracranial EEG recordings, we observed a significant FFR at the fundamental frequency (F0) for both speech and speech-like harmonic complex stimuli in the human auditory cortex, even in the missing fundamental condition. Both the spectral amplitude and phase coherence of the cortical FFR showed a significant harmonic preference, and attenuated from the primary auditory cortex to the surrounding associative auditory cortex. The phase coherence of the speech FFR was found significantly higher than that of the harmonic complex stimuli, especially in the left hemisphere, showing a high timing fidelity of the cortical FFR in tracking dynamic F0 in speech. Spectrally, the frequency band of the cortical FFR was largely overlapped with the range of the human vocal pitch. Taken together, our study parsed the intrinsic properties of the cortical FFR and reveals a preference for speech-like sounds, supporting its potential role in processing speech intonation and lexical tones.

Mitochondria-targeting NO gas nanogenerator for augmenting mild photothermal therapy in the NIR-II biowindow.

An intelligent nitric oxide gas-releasing nanoplatform based on CuS-nanoplates has been designed to overcome the heat endurance of tumor cells by the inhibition of HSP90 expression with the released NO gas in mitochondria and thereby realize enhanced PTT under mild temperature conditions.

Functional Food XingJiuTang Attenuates Alcohol-Induced Liver Injury by Regulating SIRT1/Nrf-2 Signaling Pathway.

Lipid accumulation, inflammatory responses and oxidative stress have been implicated in the pathology of alcohol-induced liver injury (ALI). In this work, we evaluated the effects of the functional food XingJiuTang (XJT) on ALI and explored the underlying mechanism. We used alcohol-stimulated human normal hepatocytes L02 for in vitro experiments, while for in vivo experiments, 55 % alcohol was intragastrically administrated to C57BL/6 mice at 16 mL/kg with pre-administration of bifendate and XJT. Liver histology and function, along with the inflammatory cytokines, oxidative mediators and SIRT1/Nrf-2 pathway were evaluated. The results showed that XJT treatment significantly alleviated ALI, ameliorated lipid peroxidation, improved the liver function impaired by alcohol and inhibited the hepatocytes apoptosis in vitro and in vivo. In addition, XJT treatment modulated the activation of the SIRT1/Nrf-2 signaling pathway and suppressed the overexpression of NOX4. Overall, the functional food XJT effectively protects against experimental ALI via activating the SIRT1/Nrf-2 pathway.

[Research progress of liver injury induced by Polygoni Mulitiflori Radix].

Polygoni Mulitiflori Radix, or dried root tuber of Polygonum multiflorum(PM), is a traditional Chinese tonic medicine, with the effect in nourishing liver and kidney, and benefiting blood essence and hair. It is widely used in clinical and healthcare products. In recent years, more and more reports about adverse reactions of root tuber of P.multiflorum and its preparations have been reported. Fortunately, there is also substantial progress in the experimental study on liver injury induced by PM. According to the literature review, the possible causes of liver injury were found to be the mixture of raw and processed PM and long-term high-dose administration. In addition, the liver injury induced by PM is idiosyncratic liver injury, and individual factors are also the important cause. At the same time, according to the literature reports, the effects of chemical components in different pathological animal models were summarized, finding that 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside was the main component for liver injury; based on the clinical manifestations of liver injury induced by PM, the effects of some chemical components on bilirubin and bile acid metabolism were analyzed. This paper reviews the study progress of liver injury induced by PM.

A novel mitochondria-targetted near-infrared fluorescent probe for selective and colorimetric detection of sulfite and its application in vitro and vivo.

Overdoses of SO2 and its derivatives (SO32-/HSO3-) in food or organisms are harmful to health. To detect SO32-/HSO3-, a novel NIR fluorescent probe 1, based upon the intramolecular charge transfer (ICT) mechanism, was developed. This probe was easily synthesized, and gave noticeable colorimetric and linear fluorescence changes at 690 nm after reaction with sulfite from 3.13 to 200 µM. Moreover, probe 1 displayed high sensitivity (LOD = 0.46 µM), excellent selectivity (among 13 kinds of anions and 3 kinds of biothiols) and quick response (within 30 min) towards SO32-/HSO3-. The SO32-/HSO3- sensing mechanism was confirmed as the Michael addition reaction. Furthermore, the probe showed wide applications for measuring SO32-/HSO3- in real samples, including sugar, tap water, wine and traditional Chinese medicine. The probe could also be used to detect SO32-/HSO3- in mitochondria of HepG2 cells and zebrafish, which suggested potential application for monitoring SO2 derivatives in clinical diagnostics.

Anti-Inflammatory Activity of Sanjie Zhentong Capsule Assessed By Network Pharmacology Analysis of Adenomyosis Treatment.

BACKGROUND: Sanjie Zhentong capsule (SZC) offers excellent effect in treating adenomyosis (AM), which is a common and difficult gynecological disease in the clinic. However, the systematic analysis of its mechanism has not been carried out yet and further studies are needed to reveal the role of SZC. METHODS: A systematic network pharmacology analysis was conducted by integrating construction of SZC compound database and AM target database, prediction of potential active compounds and targets by molecular docking combined with compound-target prediction graph (CTPG), protein-protein interaction (PPI) analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Then, the anti-inflammation experiments in vitro were performed by investigating SZC and the representative compounds regulating nitric oxide (NO), interleukin-6 (IL-6), and interleukin-10 (IL-10). RESULTS: Our findings show that SZC mainly treated AM by stimulating 28 core targets through 30 key potential active compounds, and affecting 4 crucial pathways. The treatment was associated with inflammation reaction, hormone regulation, cell adhesion, proliferation, and angiogenesis. Additionally, SZC achieved the anti-inflammatory activity by the cooperation of the compounds through inhibiting NO and IL-6, both promoting and inhibiting IL-10. CONCLUSION: This study investigated the anti-inflammatory activity of SZC based on a systematic analysis of SZC remedying AM, which was revealed to be one of the essential mechanisms. These findings will provide valuable guidance for further research of the SZC treatment of AM, and help improve the comprehension of SZC pharmacological basis as well as AM pathogenesis.