Peptide targeting improves the delivery and therapeutic index of glucocorticoids to treat rheumatoid arthritis.

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by excessive inflammation in the joints. Glucocorticoid drugs are used clinically to manage RA symptoms, while their dosage and duration need to be tightly controlled due to severe adverse effects. Using dexamethasone (DEX) as a model drug, we explored here whether peptide-guided delivery could increase the safety and therapeutic index of glucocorticoids for RA treatment. Using multiple murine RA models such as collagen-induced arthritis (CIA), we found that CRV, a macrophage-targeting peptide, can selectively home to the inflammatory synovium of RA joints upon intravenous injection. The expression of the CRV receptor, retinoid X receptor beta (RXRB), was also elevated in the inflammatory synovium, likely being the basis of CRV targeting. CRV-conjugated DEX increased the accumulation of DEX in the inflamed synovium but not in healthy organs of CIA mice. Therefore, CRV-DEX demonstrated a stronger efficacy to suppress synovial inflammation and alleviate cartilage/bone destruction. Meanwhile, CRV conjugation reduced immune-related adverse effects of DEX even after a long-term use. Last, we found that RXRB expression was significantly elevated in human patient samples, demonstrating the potential of clinical translation. Taken together, we provide a novel, peptide-targeted strategy to improve the therapeutic efficacy and safety of glucocorticoids for RA treatment.

Design and synthesis of forsythin derivatives as anti-inflammatory agents for acute lung injury.

Acute lung injury (ALI) is a clinically high mortality disease, which has not yet been effectively treated. The development of anti-ALI drugs is imminent. ALI can be effectively treated by inhibiting the inflammatory cascade and reducing the inflammatory response in the lung. Forsythia suspense is a common Chinese herbal medicine with significant anti-inflammatory activity. Using forsythin as the parent, 27 Forsythin derivatives were designed and synthesized, and the anti-AIL activity of these compounds was evaluated. Among them, compound B5 has the best activity to inhibit the release of IL-6, and the inhibition rate reaches 91.79% at 25 µM, which was 7.5 times that of the parent forsythin. In addition, most of the compounds have no significant cytotoxicity in vitro. Further studies showed that compound B5 had a concentration-dependent inhibitory effect on NO, IL-6 and TNF-α. And the IC50 values of compound B5 for NO and IL-6 are 10.88 µM and 4.93 µM, respectively. We also found that B5 could significantly inhibit the expression of some immune-related cytotoxic factors, including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). In addition, B5 inhibits NF-κB/MAPK signaling pathway. In vivo experiments showed that B5 could alleviate lung inflammation in LPS-induced ALI mice and inhibit IL-6, TNF-α, COX-2 and iNOS. In summary, B5 has anti-inflammatory effects and alleviates ALI by regulating inflammatory mediators and inhibiting MAPK and NF-κB signaling pathways.

[Network Meta-analysis of Chinese patent medicines in treatment of coronary heart disease complicated with heart failure].

The efficacy and safety of different Chinese patent medicines in the treatment of coronary heart disease complicated with heart failure were evaluated by network Meta-analysis. The randomized controlled trial(RCT) of Chinese patent medicines for coronary heart disease complicated with heart failure was retrieved from CNKI, Wanfang, VIP, SinoMed, PubMed, Web of Science, EMbase, and Cochrane Library with the time interval from inception to July 5, 2023. The quality of the included RCT was evaluated by the Cochrane's risk of bias assessment tool, and a network Meta-analysis was performed in Stata 16.0. Finally, a total of 82 RCTs were included, involving 9 298 patients and 11 Chinese patent medicines. Network Meta-analysis yielded the following results based on the surface under the cumulative ranking curve(SUCRA).(1)In terms of improving the clinical response rate, the top three interventions were Qishen Yiqi Dripping Pills + conventional western medicine, Zhenyuan Capsules + conventional western medicine, and Tongxinluo Capsules + conventional western medicine.(2) In terms of increasing left ventricular ejection fraction(LVEF), the top three interventions were Shexiang Baoxin Pills + conventional western medicine, Compound Danshen Dripping Pills + conventional western medicine, and Tongxinluo Capsules + conventional western medicine.(3) In terms of reducing left ventricular end-diastolic diameter(LVEDD), the top three interventions were Shexiang Tongxin Dripping Pills + conventional western medicine, Tongxinluo Capsules + conventional western medicine, and Shexiang Baoxin Pills + conventional western medicine.(4) In terms of reducing N-terminal pro-brain natriuretic peptide(NT-proBNP), the top three interventions were Shexiang Baoxin Pills + conventional western medicine, Qi-shen Yiqi Dripping Pills + conventional western medicine, and Compound Danshen Dripping Pills + conventional western medicine.(5) In terms of reducing hyper-sensitive C-reactive protein(hs-CRP), the top three interventions were Naoxintong Capsules + conventional western medicine, Shexiang Baoxin Pills + conventional western medicine, and Compound Danshen Dripping Pills + conventional western medicine.(6) In terms of increasing the distance of the six-minute walking trail(6MWT), the top three interventions were Zhen-yuan Capsules + conventional western medicine, Qili Qiangxin Capsules + conventional western medicine, and Qishen Yiqi Dripping Pills + conventional western medicine. The results showed that Chinese patent medicines combined with conventional western medicine can effectively improve the clinical response rate, LVEF, and 6MWT and reduce LVEDD, NT-proBNP, and hs-CRP. However, due to the overall low quality of the articles included and the few articles of some Chinese patent medicines, direct comparison between diffe-rent Chinese patent medicines remains to be carried out and the results need to be further verified.

Fufang Luohanguo Qingfei granules reduces influenza virus susceptibility via MAVS-dependent type I interferon antiviral signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Luohanguo Qingfei granules (LQG) is a Chinese patent medicine, clinically used to treat flu-like symptoms including cough with yellow phlegm, impeded phlegm, dry throat and tongue. However, the protective activity of LQG against influenza infection is indeterminate. AIM OF THE STUDY: This study is to investigate the therapeutic effect of LQG on influenza infection and elucidate its underlying mechanism. MATERIALS AND METHODS: In vivo: A viral susceptible mouse model induced by restraint stress was established to investigate LQG's beneficial effects on influenza susceptibility. MAVS knockout (Mavs-/-) mice were used to verify the potential mechanism of LQG. In vitro: Corticosteroid (CORT)-treated A549 cells were employed to identify the active ingredients in LQG. Mice morbidity and mortality were monitored daily for 21 days. Histopathologic changes and inflammatory cytokines in lung tissues were examined by H&E staining and ELISA. RNA-seq was used to explore the signaling pathway influenced by LQG and further confirmed by qPCR. Immunoblotting and immunohistochemistry (IHC) were used to determine the protein levels. CO-IP and DARTS were applied to detect protein-protein interaction and compound-protein interaction, respectively. RESULTS: LQG effectively attenuated the susceptibility of restrained mice to H1N1 infection. LQG significantly boosted the production of IFN-ß transduced by mitochondrial antiviral-signaling protein (MAVS), while MAVS deficiency abrogated its protective effects on restrained mice infected with H1N1. Moreover, in vitro studies further revealed that mogroside Ⅱ B, amygdalin, and luteolin are potentially active components of LQG. CONCLUSION: These results suggested that LQG inhibited the mitofusin 2 (Mfn2)-mediated ubiquitination of MAVS by impeding the E3 ligase synoviolin 1 (SYVN1) recruitment, thereby enhancing IFN-ß antiviral response. Overall, our work elaborates a potential regimen for influenza treatment through reduction of stress-induced susceptibility.

Tanshinone IIA normalized hepatocellular carcinoma vessels and enhanced PD-1 inhibitor efficacy by inhibiting ELTD1.

BACKGROUND: Hepatocellular carcinoma responds poorly to immune checkpoint inhibitors, such as PD-1 inhibitors, primarily due to the low infiltration capacity of TILs in the TME. Abnormal vasculature is an important factor which limiting the infiltration of TILs. According to recent research, targeting ELTD1 expression may improve TILs delivery to reverse immunosuppression and boost tumor responses to immunotherapy. Research has demonstrated that Tanshinone IIA (TSA) improves blood vessel normalization, but the precise mechanism is yet unknown. PURPOSE: The purpose of this study is to investigate the molecular processes for TSA's pro-vascular normalization of HCC in vitro and in vivo. METHODS: We established a mouse H22-luc in situ liver tumor model to evaluate the role of TSA vascular normalization and the immunosuppressive microenvironment. The role of ELTD1 in vascular and immune crosstalk was evaluated by bioinformatic analysis of the TCGA database. By creating a transwell co-culture cell model, the effects of TSA on enhancing tumor endothelial cell activities and ELTD1 intervention were evaluated. RESULTS: We investigated the effect of Tanshinone IIA (TSA), a major component of Salvia miltiorrhiza Bge., on the normalization of vasculature in situ HCC models. Our results demonstrated that TSA elicited vascular normalization in a hepatocellular carcinoma model in situ. In addition, the combination of TSA with anti-PD-1 significantly inhibited tumor development due to increased infiltration of immune cells in the tumor. Mechanistically, we demonstrated that TSA improved the immunosuppressive microenvironment by inhibiting tumor growth by suppressing ELTD1 expression, inhibiting downstream JAK1 and JAK2, promoting the expression of ZO-1, occlaudin, Claudin 5, and Col IV, and promoting vascular integrity and perfusion in situ. CONCLUSIONS: This study reveals a new mechanism between TSA and ELTD1 for vascular normalization, suggesting that therapeutic or pharmacological intervention with ELTD1 may enhance the efficacy of PD-1 inhibitors in HCC.

Pharmacodynamic advantages and characteristics of traditional Chinese medicine in prevention and treatment of ischemic stroke.

Ischemic stroke (IS) is a severe cerebrovascular disease with a high incidence, mortality, and disability rate. The first-line treatment for IS is the use of recombinant tissue plasminogen activator (r-tPA). Regrettably, numerous patients encounter delays in treatment due to the narrow therapeutic window and the associated risk of hemorrhage. Traditional Chinese medicine (TCM) has exhibited distinct advantages in preventing and treating IS. TCM enhances cerebral microcirculation, alleviates neurological disorders, regulates energy metabolism, mitigates inflammation, reduces oxidative stress injuries, and inhibits apoptosis, thereby mitigating brain damage and preventing IS recurrence. This article summarizes the etiology, pathogenesis, therapeutic strategies, and relationship with modern biology of IS from the perspective of TCM, describes the advantages of TCM in the treatment of IS, and further reviews the pharmacodynamic characteristics and advantages of TCM in the acute and recovery phases of IS as well as in post-stroke complications. Additionally, it offers valuable insights and references for the clinical application of TCM in IS prevention and treatment, as well as for the development of novel drugs.

Clinical value-oriented research paradigm about inheritance and innovation development of TCM dominant diseases.

Modern medicine has made remarkable achievements in safeguarding people's life and health, however, it is increasingly found that in the face of complex diseases, selective targeting of single target is often difficult to produce a comprehensive rehabilitation effect, and is prone to induce drug resistance, toxic side effects. Traditional Chinese medicine (TCM) has a long history of clinical application, and its clinical value in the treatment of complex diseases such as cardiovascular and cerebrovascular diseases, digestive diseases, skin diseases, rheumatism and immunity diseases, and adjuvant treatment of tumors has been proven to have obvious advantages. However, its modern research is relatively lagging behind, and in the face of the aging society and the characteristics of the modern disease spectrum, the traditional knowledge-driven research paradigm seems to be stuck in a bottleneck and difficult to make greater breakthroughs. Focusing on the key issues of TCM development in the new era, the clinical value-oriented strategy becomes to be a new research paradigm of TCM inheritance and innovation development, and dominant diseases would be the focus of the TCM inheritance and innovation development, which has been highly valued in recent years by the TCM academia and the relevant national management departments. Based on the clinical value, a series of policies are formulated for the selection and evaluation of the TCM dominant diseases (TCMDD), and exploratory researches about the clinical efficacy characteristics, the modern scientific connotation interpretation were carried out. The clinical value-oriented research paradigm of TCMDD inheritance and innovation development has been initially formed, which is characterized by strong policy support as the guarantee, systematic and standardized selection and evaluation methods as the driving force, scientific and effective research on internal mechanisms as the expansion, and effective clinical guidelines and principles as the transformation, which is of great value in promoting the high-quality development of the industries and undertaking of TCM. In this paper, the main policy support, selection and evaluation methods, therapeutic effect characterization, and modern scientific connotation research strategies of TCMDD in recent years have been comprehensively sorted out, with a view to providing the healthy and benign development of the research on TCMDD.

Efficacy of acupuncture combined with active exercise training in improving pain and function of knee osteoarthritis individuals: a systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis to investigate the clinical efficacy of acupuncture combined with active exercise training in improving pain and function of knee osteoarthritis (KOA) individuals. DATA SOURCES: PubMed, EMBASE, The Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wan Fang Data, Technology Periodical Database and China Biology Medicine were searched from their inceptions to April 5, 2023. REVIEW METHODS: We analyzed trials of acupuncture combined with active exercise training for KOA. The included studies were of high quality (Jadad ≥ 4) and RCTs. Study selection, data extraction, risk of bias and quality assessment were independently performed by two reviewers. We performed systematic analyses based on different outcome measures, including total efficiency rate, visual analogue scale (VAS), the Western Ontario and Mcmaster Universities Osteoarthritis Index (WOMAC), the Lysholm Knee Scale (LKS) and range of motion (ROM). We used Review Manager 5.3 and Stata/MP 14.0 to analyze the data. And it was verified by trial sequence analysis (TSA). If I2 > 50% and p < 0.05, we performed sensitivity analysis and subgroup analysis to find the source of heterogeneity. Publication bias was studied by funnel plot and Egger's test was used to verify it. RESULTS: Full 11 high-quality studies (Jadad ≥ 4) including 774 KOA individuals were included in this review for meta-analysis. The results showed that acupuncture combined with active exercise training (combined group) was superior to the acupuncture group in improving the total effective rate [RR = 1.13, 95%CI (1.05, 1.22), I2 = 0%, P = 0.70], reducing the pain level (VAS) [MD = - 0.74, 95%CI (- 1.04, - 0.43), I2 = 68%, P < 0.05], improving knee joint function (WOMAC) [MD = - 6.97, 95%CI (- 10.74, - 3.19), I2 = 76%, P < 0.05] and improving joint range of motion (ROM) [MD = 6.25, 95%CI (2.37, 10.04), I2 = 0%, P = 0.71]. Similarly, the combined group showed significant improvements in the total effective rate [RR = 1.31, 95% CI (1.18, 1.47), I2 = 48%, P = 0.10], pain (VAS) [MD = 1.42, 95% CI (- 1.85, - 1.00), I2 = 65%, P = 0.02] and knee function (WOMAC) [MD = 7.05, 95% CI (- 11.43, - 2.66), I2 = 86%, P < 0.05] compared with the non-acupuncture group. CONCLUSION: The combined effect of all studies showed significant benefits of acupuncture combined with active exercise training in improving the total effective rate, reducing pain, promoting recovery of knee function and expanding range of motion. However, some evaluation indicators are highly subjective and need to be further confirmed by more objective and evidence-based high-quality RCTs in future. SYSTEMATIC REVIEW REGISTRATION: [PROSPERO], identifier [No. CRD42023425823].

Pharmacological overview of hederagenin and its derivatives.

Hederagenin is a pentacyclic triterpenoid isolated from plants and widely distributed in a variety of medicinal plants. By integrating and analyzing external related literature reports, the latest research progress on the pharmacological effects and structural modification of hederagenin was reviewed. Hederagenin has a wide range of pharmacological activities, including antitumor, anti-inflammatory, antidepressant, anti-neurodegenerative, antihyperlipidemic, antidiabetic, anti-leishmaniasis, and antiviral activities. Among them, it shows high potential in the field of anti-tumor treatment. This paper also reviews the structural modifications of hederagenin, including carboxyl group modifications and two hydroxyl group modifications. Future research on hederagenin will focus on prolonging its half-life, improving its bioavailability and structural modification to enhance its pharmacological activity, accelerating the preclinical research stage of hederagenin for it to enter the clinical research stage as soon as possible.

Clinical implications of micro lymph node metastasis for patients with gastric cancer.

BACKGROUND: Lymph node size is considered as a criterion for possible lymph node metastasis in imageology. Micro lymph nodes are easily overlooked by surgeons and pathologists. This study investigated the influencing factors and prognosis of micro lymph node metastasis in gastric cancer. METHODS: 191 eligible gastric cancer patients who underwent D2 lymphadenectomy from June 2016 to June 2017 in the Third Surgery Department at the Fourth Hospital of Hebei Medical University were retrospectively analyzed. Specimens were resected en bloc and the postoperative retrieval of micro lymph nodes was carried out by the operating surgeon for each lymph node station. Micro lymph nodes were submitted for pathological examination separately. According to the results of pathological results, patients were divided into the "micro-LNM (micro lymph node metastasis)" group (N = 85) and the "non micro-LNM" group (N = 106). RESULTS: The total number of lymph nodes retrieved was 10,954, of which 2998 (27.37%) were micro lymph nodes. A total of 85 (44.50%) gastric cancer patients had been proven to have micro lymph node metastasis. The mean number of micro lymph nodes retrieved was 15.7. The rate of micro lymph node metastasis was 8.1% (242/2998). Undifferentiated carcinoma (90.6% vs. 56.6%, P = 0.034) and more advanced Pathological N category (P < 0.001) were significantly related to micro lymph node metastasis. The patients with micro lymph node metastasis had a poor prognosis (HR for OS of 2.199, 95% CI = 1.335-3.622, P = 0.002). For the stage III patients, micro lymph node metastasis was associated with shorter 5-year OS (15.6% vs. 43.6%, P = 0.0004). CONCLUSIONS: Micro lymph node metastasis is an independent risk factor for poor prognosis in gastric cancer patients. Micro lymph node metastasis appears to be a supplement to N category in order to obtain more accurate pathological staging.

Quality assessment of traditional Chinese medicine using quality biomarkers: Compound DanShen dripping pills as an example.

BACKGROUND: The quality control of traditional Chinese medicine (TCM) is one of the main topics in TCM modernisation research. To date, the overwhelming majority of research has focused on chemical ingredients in the quality control of TCM. However, detecting a single or multiple chemical components cannot fully demonstrate the specificity and correlation between quality and efficacy. PURPOSE: To solve the problem that the association between quality control and efficacy is lacking. The present study was designed to establish a methodology for quality control based on quality biomarkers (Q-biomarkers) and the vasodilatation efficacy of compound DanShen dripping pills (CDDP) as a case. METHODS: Guided by the basic principles of Q-biomarkers, the compounds in TCM were determined by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry. Predicted targets were screened through network pharmacology. The potential Q-biomarkers were further screened through proteomics and partial least squares regression analysis. The protein-protein interaction network that combines both predicted targets and potential Q-biomarkers was constructed to screen Q-biomarkers. RESULTS: There were 32 components and 79 predictive targets for CDDP. Proteomic results indicated that the expression of 23 differential proteins changed as pharmacodynamic and componential changes. CPSF6, RILP11, TMEM209, COQ7, VPS18, PPPP1CA, NF2, and ARFRP1 highly correlated with vasodilation. Protein interaction network analysis showed that NF2 and PPPP1CA were closely related to predicted proteins. Thus, NF2 and PPPP1CA could be considered as Q-biomarkers of CDDP. CONCLUSION: Our preliminary study suggested the feasibility of the Q-biomarkers theory in the quality of TCM. The concept of Q-biomarkers provided a powerful method to strengthen the link between clinical efficacy and the quality of TCM. In conclusion, a novel, more scientific, and standard quality control method was established in this study.

Efficacy and safety of three species of Rhodiola L. in patients with chronic obstructive pulmonary disease: A systematic review and meta-analysis.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by chronic hypoxia, inflammation, oxidative stress, and irreversible airflow limitations. Rhodiola L. is a genus of botanical drugs used in traditional medicine that may influence COPD. Objective: A systematic review of the safety and efficacy of Rhodiola L. in patients with COPD. Material and methods: We searched the PubMed, Embase, Cochrane Library, Web of Science, Scopus, China National Knowledge Infrastructure (CNKI), Chongqing VIP, Wanfang, and SinoMed databases. The search strategy used terms including "COPD" and "Rhodiola." Two independent reviewers conducted the literature screening, data extraction, and risk of bias assessment, with a third reviewer involved to resolve disagreements. Statistical analysis was conducted in Review Manager (version 5.4.1), following the Cochrane Handbook. Results: This review included nine studies, of which two focused on Rhodiola crenulata (Hook.f. and Thomson) H. Ohba (R. crenulata) and two on Rhodiola kirilowii (Regel) Maxim (R. kirilowii); the remaining five focused on Rhodiola wallichiana (Hook.) S.H.Fu (R. wallichiana). Compared with the placebo, patients who received Rhodiola L. presented no more adverse events (p = 0.65) but showed significant improvement in the percentage of forced expiratory volume in 1 s at prediction (FEV1%pred), forced expiratory volume in 1 s (FEV1), the ratio of forced expiratory volume in 1 s on forced vital capacity (FEV1/FVC), saturation of oxygen in arterial blood, partial pressure of oxygen in arterial blood (PaO2), partial pressure of carbon dioxide in arterial blood (PaCO2), systolic pulmonary arterial pressure, diastolic pulmonary arterial pressure, COPD assessment test, efficient rate, C-reactive protein, and N-terminal pro-B-type natriuretic peptide (all p < 0.01). Compared with ambroxol, R. kirilowii provided additional benefits to patients with COPD in FEV1%pred, FEV1, FEV1/FVC, PaO2, PaCO2, 8-iso-prostaglandin F2α, superoxide dismutase, glutathione, malondialdehyde, and total antioxidant capacity (all p < 0.01). Conclusion: Among the Rhodiola L. genus, this review included R. wallichiana, R. crenulata, and R. kirilowii, which might be safe and effective in COPD. Although this study has several limitations, further RCTs are needed. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/ display_record.php?RecordID=302881], identifier [CRD42022361890].

[Preparation of two tanshinone â ¡_A-astragaloside â £ co-loaded nano-delivery systems and in vitro antitumor activity comparison].

This study screened excellent carriers for co-loading tanshinone Ⅱ_A(TSA) and astragaloside Ⅳ(As) to construct antitumor nano-drug delivery systems for TSA and As. TSA-As microemulsions(TSA-As-MEs) were prepared by water titration. TSA-As metal-organic framework(MOF) nano-delivery system was prepared by loading TSA and As in MOF by the hydrothermal method. Dynamic light scattering(DLS), transmission electron microscopy(TEM), and scanning electron microscopy(SEM) were used to characterize the physicochemical properties of the two preparations. Drug loading was determined by HPLC and the effects of the two preparations on the proliferation of vascular endothelial cells, T lymphocytes, and hepatocellular carcinoma cells were detected by the CCK-8 method. The results showed that the particle size, Zeta potential, and drug loading of TSA-As-MEs were(47.69±0.71) nm,(-14.70±0.49) mV, and(0.22±0.01)%, while those of TSA-As-MOF were(258.3±25.2) nm,(-42.30 ± 1.27) mV, and 15.35%±0.01%. TSA-As-MOF was superior to TSA-As-MEs in drug loading, which could inhibit the proliferation of bEnd.3 cells at a lower concentration and improve the proliferation ability of CTLL-2 cells significantly. Therefore, MOF was preferred as an excellent carrier for TSA and As co-loading.

Integrating metabolomics and lipidomics revealed a decrease in plasma fatty acids but an increase in triglycerides in children with drug-refractory epilepsy.

OBJECTIVE: The drug-refractory epilepsy (DRE) in children is commonly observed but the underlying mechanisms remain elusive. We examined whether fatty acids (FAs) and lipids are potentially associated with the pharmacoresistance to valproic acid (VPA) therapy. METHODS: This single-center, retrospective cohort study was conducted using data from pediatric patients collected between May 2019 and December 2019 at the Children's Hospital of Nanjing Medical University. Ninety plasma samples from 53 responders with VPA monotherapy (RE group) and 37 non-responders with VPA polytherapy (NR group) were collected. Non-targeted metabolomics and lipidomics analysis for those plasma samples were performed to compare the potential differences of small metabolites and lipids between the two groups. Plasma metabolites and lipids passing the threshold of variable importance in projection value >1, fold change >1.2 or <0.8, and p-value <0.05 were regarded as statistically different substances. RESULTS: A total of 204 small metabolites and 433 lipids comprising 16 different lipid subclasses were identified. The well-established partial least squares-discriminant analysis (PLS-DA) revealed a good separation of the RE from the NR group. The FAs and glycerophospholipids status were significantly decreased in the NR group, but their triglycerides (TG) levels were significantly increased. The trend of TG levels in routine laboratory tests was in line with the lipidomics analysis. Meanwhile, cases from the NR group were characterized by a decreased level of citric acid and L-thyroxine, but with an increased level of glucose and 2-oxoglutarate. The top two enriched metabolic pathways involved in the DRE condition were biosynthesis of unsaturated FAs and linoleic acid metabolism. SIGNIFICANCE: The results of this study suggested an association between metabolism of FAs and the medically intractable epilepsy. Such novel findings might propose a potential mechanism linked to the energy metabolism. Ketogenic acid and FAs supplementation might therefore be high-priority strategies for DRE management.

Garlic-derived exosomes regulate PFKFB3 expression to relieve liver dysfunction in high-fat diet-fed mice via macrophage-hepatocyte crosstalk.

BACKGROUND: Although macrophage-mediated low-grade chronic inflammation and liver dysfunction have been found to be associated with the development of non-alcoholic fatty (NAFLD) and widely reported, but strategies and drugs targeting macrophages for the treatment of NAFLD are limited. HYPOTHESIS/PURPOSE: Garlic-derived exosomes (GDE) can be useful for NAFLD due to its anti-inflammatory activity. Clarify whether GDE improves liver dysfunction through macrophage-hepatocyte crosstalk. METHODS: GDE was isolated with PEG precipitation and ultracentrifuge. Inflammatory cytokines were detected by qRT-PCR and ELISA. Expression of 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) was determined using qRT-PCR and western blot. Crosstalk between macrophages and hepatocytes was identified through a co-culture experiment. Small RNA sequencing and bioinformatic analysis were used to identify the key element of GDE regulating the expression of PFKFB3 gene. RESULTS: GDE regulated the expression of PFKFB3 to reduce the inflammatory response in LPS-treated differentiated THP-1 macrophages. Data from small RNA sequencing and bioinformatics analysis reveal that miR-396e, one of the most abundant miRNAs of GDE, is the key component to regulate PFKFB3 expression. Mechanistically, miR-396e-mediating PFKFB3 expression plays a crucial role in GDE inhibiting inflammatory response and enhancing lipid metabolism in hepatocytes via the macrophage-hepatocyte crosstalk. Notably, GDE supplementation reduced the inflammatory response and improved liver dysfunction in high-fat diet-fed mice. CONCLUSION: GDE may be useful for improving the symptoms of NAFLD via macrophage-hepatocyte crosstalk and its role in PFKFB3 expression.

Metabonomics and 16S rRNA gene sequencing to study the therapeutic mechanism of Danggui Sini decoction on collagen-induced rheumatoid arthritis rats with Cold Bi syndrome.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent joint inflammation. The development of rheumatoid arthritis is directly correlated with the disturbance of gut microbiome and its metabolites. RA can be effectively treated with the Danggui Sini decoction (DSD), a Traditional Chinese medicine (TCM) prescription from the Treatise on Febrile Diseases. Further research is needed to clarify the precise mechanism of DSD in the treatment of RA. In this study, 1H NMR metabonomics and 16 S rRNA gene sequencing techniques were used to clarify the intervention of DSD on CIA-induced RA. The results of 1H NMR metabolomics of feces revealed that five metabolites (alanine, glucose, taurine, betaine, and xylose) were disturbed, which could be regarded as potential biomarkers of RA. The intestinal microbiome of RA rats had changed, according to the results of 16 S rRNA gene sequencing; eight microbes (g_norank_f_Eubacterium_coprostanoligenes_group, g_Ruminococcus_torques_group, g_Dubosiell, g_Lactobacillus, g_norank_f_Desulfovibrionaceae, g_Bacteroides, g_Oscillibacter, and g_Romboutsia) occurred significantly at the genus level, and DSD significantly impacted six of them (g_Dubosiell, g_Lactobacillus, g_norank_f_Eubacterium_coprostanoligenes_group, g_Ruminococcus_torques_grou, g_Bacteroides, and g_Romboutsia). Three of them (g_norank_f_Eubacterium_ coprostanoligenes_group, g_Romboutsia, and g_Lactobacillus) were regarded as key microbiomes for DSD to treat RA, and three common metabolic pathways (taurine and hypotaurine metabolism; alanine, aspartate, and glutamate metabolism; primary bile acid biosynthesis) were discovered based on the 1H NMR metabonomics and PICRUST2 prediction of 16 S rRNA gene sequencing. Six SCFAs in feces (acetic acid, butyric acid, propionic acid, caproic acid, isobutyric acid, and valeric acid) increased significantly in RA, according to the outcomes of targeting SCFAs, while five SCFAs (acetic acid, butyric acid, propionic acid, caproic acid, and valeric acid) had decreased significantly due to DSD treatment. In conclusion, our study indicated that DSD could regulate RA's metabolic disorder by affecting intestinal microbiome and its metabolites. It also establishes a framework for future research into exploiting gut microbes therapeutic to treat RA.

Garlic-derived exosomes carrying miR-396e shapes macrophage metabolic reprograming to mitigate the inflammatory response in obese adipose tissue.

Low-grade chronic inflammation originating from the adipose tissue and imbalance of lipid metabolism in the liver are the main drivers of the development of obesity and its related metabolic disorders. In this work, we found that garlic-derived exosomes (GDE) supplementation improved insulin resistance, altered the levels of inflammatory cytokines in serum and epididymal white adipose tissue (eWAT) by decreasing the accumulation of macrophages in HFD-fed mice. Meanwhile, we also observed that GDE regulated the expression of 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3), one of the critical glycolytic enzymes, to shape the metabolic reprograming of macrophage induced by lipopolysaccharide (LPS) and mitigate the inflammatory response in adipocytes via macrophage-adipocyte cross-talk. Data from small RNA sequencing, bioinformatical analysis and the gene over-expression revealed that miR-396e, one of the most abundant miRNAs of GDE, played a critical role in promoting the metabolic reprogramming of macrophage by directly targeting PFKFB3. The findings of this study not only provide an in-depth understanding of GDE protecting against inflammation in obesity but supply evidence to study the molecular mechanisms associated with the interspecies communication.

Deep learning and machine intelligence: New computational modeling techniques for discovery of the combination rules and pharmacodynamic characteristics of Traditional Chinese Medicine.

It has been increasingly accepted that Multi-Ingredient-Based interventions provide advantages over single-target therapy for complex diseases. With the growing development of Traditional Chinese Medicine (TCM) and continually being refined of a holistic view, "multi-target" and "multi-pathway" integration characteristics of which are being accepted. However, its effector substances, efficacy targets, especially the combination rules and mechanisms remain unclear, and more powerful strategies to interpret the synergy are urgently needed. Artificial intelligence (AI) and computer vision lead to a rapidly expanding in many fields, including diagnosis and treatment of TCM. AI technology significantly improves the reliability and accuracy of diagnostics, target screening, and new drug research. While all AI techniques are capable of matching models to biological big data, the specific methods are complex and varied. Retrieves literature by the keywords such as "artificial intelligence", "machine learning", "deep learning", "traditional Chinese medicine" and "Chinese medicine". Search the application of computer algorithms of TCM between 2000 and 2021 in PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), Elsevier and Springer. This review concentrates on the application of computational in herb quality evaluation, drug target discovery, optimized compatibility and medical diagnoses of TCM. We describe the characteristics of biological data for which different AI techniques are applicable, and discuss some of the best data mining methods and the problems faced by deep learning and machine learning methods applied to Chinese medicine.

Arctigenin: pharmacology, total synthesis, and progress in structure modification.

Arctium lappa L. is a prevalent medicinal herb and a health supplement that is commonly used in Asia. Over the last few decades, the bioactive component arctigenin has attracted the attention of researchers because of its anti-inflammatory, antioxidant, immunomodulatory, multiple sclerosis fighting, antitumor, and anti-leukemia properties. After summarising the research and literature on arctigenin, this study outlines the current status of research on pharmacological activity, total synthesis, and structural modification of arctigenin. The purpose of this study is to assist academics in obtaining a more comprehensive understanding of the research progress on arctigenin and to provide constructive suggestions for further investigation of this useful molecule.

Exploring the mechanism of action of Sanzi formula in intervening colorectal adenoma by targeting intestinal flora and intestinal metabolism.

Background: Sanzi formula (SZF) is a kind of Chinese herbal compound that has a certain effect on the prevention and treatment of colorectal adenoma (CRA), which can prevent and control the process of CRA-cancer transformation. In this study, we explored the mechanism of action of SZF in anti-CRA using 16S rRNA sequencing and metabolomics technology. Methods: Mice were randomly divided into three groups: Control group, Apcmin/+ model group, and SZF treatment group. Except for the Control group, which used C57BL/6 J mice, the remaining two groups used Apcmin/+ mice. The Control group and Apcmin/+ model group were treated with ultrapure water by gavage, while the SZF treatment group was treated with SZF for 12 weeks. During this period, the physical changes of mice in each group were observed. The gut microbiota was determined by high-throughput sequencing of the 16S rRNA gene, and LC-ESI-MS/MS was used for colorectal metabolomics analysis. Results: Sequencing of the 16S rRNA gut flora yielded 10,256 operational taxonomic units and metabolomic analysis obtained a total of 366 differential metabolites. The intestinal flora analysis showed that SZF could improve intestinal flora disorders in Apcmin/+ mice. For instance, beneficial bacteria such as Gastranaerophilales significantly increased and harmful bacteria such as Angelakisella, Dubosiella, Muribaculum, and Erysipelotrichaceae UCG-003 substantially decreased after the SZF intervention. In addition, metabolomic data analysis demonstrated that SZF also improved the colorectal metabolic profile of Apcmin/+ mice. In Apcmin/+ mice, metabolites such as Anserine and Ectoine were typically increased after SZF intervention; in contrast, metabolites such as Taurocholic acid, Taurochenodesoxycholic acid, Hyocholic acid, Cholic acid, and Tauro-alpha-muricholic acid showed noteworthy reductions. Metabolic flora association analysis indicated that 13 differential flora and 11 differential metabolites were associated. Conclusion: SZF affects the abundance of specific intestinal flora and regulates intestinal flora disorders, improves colorectal-specific metabolites, and ameliorates intestinal metabolic disorders to prevent and treat CRA. Furthermore, the application of intestinal flora and colorectal metabolomics association analysis offers new strategies to reveal the mechanism of action of herbal medicines for the treatment of intestinal diseases.