ABSTRACT
Single-molecule-based synergistic phototherapy holds great potential for antimicrobial treatment. Herein, we report an orthogonal molecular cationization strategy to improve the reactive oxygen species (ROS) and hyperthermia generation of heptamethine cyanine (Cy7) for photodynamic and photothermal treatments of bacterial infections. Cationic pyridine (Py) is introduced at the mesoposition of the asymmetric Cy7 with intramolecular charge transfer (ICT) to construct an atypical electron-transfer triad, which reduces ΔES1-S0, circumvents rapid charge recombination, and simultaneously enhances intersystem crossing (ISC) based on spin-orbit charge-transfer ISC (SOCT-ISC) mechanism. This unique molecular construction produces anti-Stokes luminescence (ASL) because the rotatable CN bond enriched in high vibrational-rotational energy levels improves hot-band absorption (HBA) efficiency. The obtained triad exhibits higher singlet oxygen quantum yield and photothermal conversion efficiency compared to indocyanine green (ICG) under irradiation above 800 nm. Cationization with Py enables the triad to target bacteria via intense electrostatic attractions, as well as biocidal property against a broad spectrum of bacteria in the dark. Moreover, the triad under irradiation can enhance biofilm eradication performance in vitro and statistically improve healing efficacy of MRSA-infected wound in mice. Thus, this work provides a simple but effective strategy to design small-molecule photosensitizers for synergistic phototherapy of bacterial infections. STATEMENT OF SIGNIFICANCE: We developed an orthogonal molecular cationization strategy to enhance the reactive oxygen species and thermal effects of heptamethine cyanine (Cy7) for photodynamic and photothermal treatments of bacterial infections. Specifically, cationic pyridine (Py) was introduced at the mesoposition of the asymmetric Cy7 to construct an atypical electron-transfer triad, which reduced ΔES1-S0, circumvented rapid charge recombination, and simultaneously enhanced intersystem crossing (ISC). This triad, with a rotatable CN bond, produced anti-Stokes luminescence due to hot-band absorption. The triad enhanced antimicrobial performance and statistically improved the healing efficacy of MRSA-infected wounds in mice. This site-specific cationization strategy may provide insights into the design of small molecule-based photosensitizers for synergistic phototherapy of bacterial infections.
Subject(s)
Bacterial Infections , Photochemotherapy , Animals , Mice , Photosensitizing Agents/chemistry , Reactive Oxygen Species , Phototherapy , Coloring Agents , Bacterial Infections/drug therapy , Pyridines/pharmacologyABSTRACT
Synergistic photothermal immunotherapy has attracted widespread attention due to the mutually reinforcing therapeutic effects on primary and metastatic tumors. However, the lack of clinical approval nanomedicines for spatial, temporal, and dosage control of drug co-administration underscores the challenges facing this field. Here, a photothermal agent (Cy7-TCF) and an immune checkpoint blocker (NLG919) are conjugated via disulfide bond to construct a tumor-specific small molecule prodrug (Cy7-TCF-SS-NLG), which self-assembles into prodrug-like nano-assemblies (PNAs) that are self-delivering and self-formulating. In tumor cells, over-produced GSH cleaves disulfide bonds to release Cy7-TCF-OH, which re-assembles into nanoparticles to enhance photothermal conversion while generate reactive oxygen species (ROSs) upon laser irradiation, and then binds to endogenous albumin to activate near-infrared fluorescence, enabling multimodal imaging-guided phototherapy for primary tumor ablation and subsequent release of tumor-associated antigens (TAAs). These TAAs, in combination with the co-released NLG919, effectively activated effector T cells and suppressed Tregs, thereby boosting antitumor immunity to prevent tumor metastasis. This work provides a simple yet effective strategy that integrates the supramolecular dynamics and reversibility with stimuli-responsive covalent bonding to design a simple small molecule with synergistic multimodal imaging-guided phototherapy and immunotherapy cascades for cancer treatment with high clinical value.
Subject(s)
Nanoparticles , Neoplasms , Prodrugs , Humans , Prodrugs/therapeutic use , Theranostic Nanomedicine , Neoplasms/therapy , Phototherapy , Nanoparticles/chemistry , Antigens, Neoplasm , Immunotherapy , Disulfides , Cell Line, TumorABSTRACT
BACKGROUND: Huachansu (HCS), a known Chinese patent drug extracted from the Chinese toad skin, is frequently used for the treatment of various advanced cancers, especially gastric cancer, due to the good therapeutic effect. However, it is rather difficult to clarify the active substances and molecular mechanisms involved owing to the lack of appropriate research strategies. We recently proposed the concept and research ideas of compound-composed Chinese medicine formula. PURPOSE: To discover compound-composed Chinese medicine from Huachansu and to explore its mechanism of action in inducing apoptosis of gastric cancer cells. METHOD: Network pharmacology combined with serum pharmacochemistry was utilized to screen the predominant active constituents from HCS against gastric cancer. Then, the compound-composed Chinese medicine of HCS (CCMH) was prepared according to their relative contents in serum. The pharmacological effects and potential mechanisms for CCMH were investigated by assays for cell viability, cell cycle, apoptosis, mitochondrial membrane potential (MMP), proteomics, reactive oxygen species (ROS), N-Acetylcysteine (NAC) antagonism, proteasome activity, and western blot. RESULTS: CCMH was comprised of arenobufagin (11.14%), bufalin (18.67%), bufotalin (7.33%), cinobufagin (16.67%), cinobufotalin (16.74%), gamabufotalin (8.45%), resibufogenin (12.03%), and telocinobufagin (8.97%). CCMH evidently induced proliferation inhibition, cell cycle arrest, apoptosis, and MMP collapse in gastric cancer cells, possessing the better activities than HCS. Proteomic analysis showed that CCMH influenced ROS pathway, ubiquitin proteasome system, and PI3K/Akt and MAPK signaling pathways. CCMH markedly enhanced intracellular ROS levels in gastric cancer cells, which was reversed by NAC. Accordingly, NAC antagonized the apoptosis-inducing effect of CCMH. Significantly decreased proteasome 20S activity by CCMH was observed in gastric cancer cells. CCMH also regulated the expression of key proteins in PI3K/Akt and MAPK signaling pathways. CONCLUSION: CCMH possesses more significant apoptotic induction effects on gastric cancer cells than HCS, which is achieved primarily through suppression of proteasome activities and increase of ROS levels, followed by regulating PI3K/Akt and MAPK signaling pathways. Network pharmacology combined with serum pharmacochemistry is an effective strategy for discovering compound-composed Chinese medicine from traditional Chinese medicine, which can help clarify the pharmacological substances and mechanisms of action for traditional Chinese medicine.
Subject(s)
Amphibian Venoms , Stomach Neoplasms , Humans , Reactive Oxygen Species/metabolism , Stomach Neoplasms/drug therapy , Stomach Neoplasms/metabolism , Proteasome Endopeptidase Complex , Proto-Oncogene Proteins c-akt/metabolism , Medicine, Chinese Traditional , Phosphatidylinositol 3-Kinases/metabolism , Proteomics , Cell Line, Tumor , ApoptosisABSTRACT
Objective: To observe the levels of serum 3-nitrotyrosine (3-NT), neuronal PAS domain protein 4 (NPASDP-4), and S100ß protein in patients diagnosed with cerebral infarction and analyze their correlation with cognitive dysfunction in these patients. Methods: The study included a cohort of 158 patients suffering from cerebral infarction who were admitted to the Liwan District Hospital of Traditional Chinese Medicine between January 2021 and December 2022. After stabilizing vital signs, all patients underwent the Montreal Cognitive Assessment (MoCA) to assess their cognitive function. Based on the assessment results, they were divided into two groups: the cognitive dysfunction group (121 cases) and the normal cognitive function group (37 cases). The baseline characteristics and serum levels of 3-NT, neuronal PAS domain protein 4 (NPASDP-4), and S100ß protein were compared in the patient cohorts. Furthermore, the correlation between these three indicators and cognitive function in patients suffering from cerebral infarction was analyzed. A logistic regression model was constructed to analyze how serum levels of 3-NT, NPASDP-4, and S100ß protein levels affected cognitive function in patients suffering from cerebral infarction. ROC curve analysis was conducted to assess the predictive value of serum 3-NT, NPASDP-4, and S100ß protein levels for cognitive function in patients suffering from cerebral infarction. Results: Among the 158 patients with cerebral infarction, 121 (76.58%) had cognitive dysfunction, while 37 (23.42%) had normal cognitive function. The levels of 3-NT, NPASDP-4, and S100ß protein were found to be significantly higher in the cognitive dysfunction group compared to the normal cognitive function group (t = 5.788, 7.774, 6.460; P = .000, .000, .000). The point-biserial correlation analysis results showed a positive correlation between serum levels of 3-NT, NPASDP-4, and S100ß protein and the occurrence of cognitive dysfunction in patients suffering from cerebral infarction (r=0.420, 0.529, 0.424; P = .000, .000, .000). The logistic regression model demonstrated that serum levels of 3-NT(95%CI: 1.299-2.603), NPASDP-4(95%CI: 1.487-3.386), and S100ß protein(95%CI: 1.153-8.746) were risk factors for cognitive dysfunction in patients suffering from cerebral infarction (OR=1.839, 2.244, 1.429; P = .001, .000, .240). ROC curve analysis demonstrated that serum 3-NT, NPASDP-4, and S100ß protein levels exhibited a certain predictive value for cognitive function in patients with cerebral infarction (AUC = 0.789, 0.881, 0.820). Conclusion: Serum levels of 3-NT, NPASDP-4, and S100ß protein are closely related to the cognitive function of patients with cerebral infarction, and abnormal changes in these levels may exacerbate cognitive dysfunction in these patients.
ABSTRACT
Animal-derived drugs are an indispensable part of folk medicine worldwide. However, their chemical constituents are poorly approached, which leads to the low level of the quality standard system of animal-derived drugs and further causes a chaotic market. Natural peptides are ubiquitous throughout the organism, especially in animal-derived drugs. Thus, in this study, we used multi-source leeches, including Hirudo nipponica (HN), Whitmania pigra (WP), Whitmania acranulata (WA), and Poecilobdella manillensis (PM), as a model. A strategy integrating proteogenomics and novel pseudotargeted peptidomics was developed to characterize the natural peptide phenotype and screen for signature peptides of four leech species. First, natural peptides were sequenced against an in-house annotated protein database of closely related species constructed from RNA-seq data from the Sequence Read Archive (SRA) website, which is an open-sourced public archive resource. Second, a novel pseudotargeted peptidomics integrating peptide ion pair extraction and retention time transfer was established to achieve high coverage and quantitative accuracy of the natural peptides and to screen for signature peptides for species authentication. In all, 2323 natural peptides were identified from four leech species whose databases were poorly annotated. The strategy was shown to significantly improve peptide identification. In addition, 36 of 167 differential peptides screened by pseudotargeted proteomics were identified, and about one-third of them came from the leucine-rich repeat domain (LRR) proteins, which are widely distributed in organisms. Furthermore, six signature peptides were screened with good specificity and stability, and four of them were validated by synthetic standards. Finally, a dynamic multiple reaction monitoring (dMRM) method based on these signature peptides was established and revealed that one-half of the commercial samples and all of the Tongxinluo capsules were derived from WP. All in all, the strategy developed in this study was effective for natural peptide characterization and signature peptide screening, which could also be applied to other animal-derived drugs, especially for modelless species that are less studied in protein database annotation.
Subject(s)
Leeches , Proteogenomics , Animals , Leeches/chemistry , Leeches/genetics , Peptides/chemistry , ProteomicsABSTRACT
BACKGROUND: Adequate iodine intake during pregnancy is critical for maintaining maternal and fetal thyroid function and development. There are only limited data from iodine-balance studies to inform iodine requirements during pregnancy. OBJECTIVES: This is an iodine-balance study conducted to explore the associations among iodine intake, excretion, and retention to provide information regarding iodine requirements during pregnancy. METHODS: A 7-d iodine-balance experiment enrolled 93 healthy pregnant Chinese women from Hebei, Tanjin, and Shandong. Duplicates of all foods and beverages consumed were systematically collected and measured for iodine content. Iodine excretion was measured by collecting 24-h urine and feces samples. Simple linear regression models were used to assess relationships between total iodine intake and iodine retention, whereas mixed effect models were used to assess the relationship between daily iodine intake and iodine retention. RESULTS: The mean ± SD age of participating pregnant women was 29 ± 2 y at a median 22 (IQR: 13-30) wk of gestation. The mean 7-d iodine retention was 43.0 ± 1060 µg/7 d. A negative iodine balance was present in 56% of women whereas 44% had a positive balance. Pregnant women with iodine intakes <150 µg/d were in negative balance whereas those with intakes >550 µg/d were in positive balance. The daily iodine intake at zero balance was 343 µg/d, which was higher in women from Shandong (492 µg/d) than in those from Hebei and Tianjin (202 µg/d). CONCLUSIONS: Iodine intake at zero balance determined in pregnant women with adequate iodine nutrition is 202 µg/d, and the calculated recommended nutrient intake (RNI) is 280 µg/d. Iodine intakes of <150 µg/d and >550 µg/d are not recommended during pregnancy. This trial was registered at clinicaltrials.gov as NCT03710148.
Subject(s)
Iodine , Humans , Female , Pregnancy , Nutritional Status , Dietary Supplements , Nutritional Requirements , FecesABSTRACT
Background: Wellbeing may have a protective role in health maintenance. However, no specific study clarified the particular protective effect of the subjective wellbeing of rural elderly people on survival probability. Few studies have examined the effect of the lifestyle of rural elderly people on their subjective wellbeing from different perspectives. We investigated whether improving subjective wellbeing increased the probability of longevity of rural elderly people and the effects of lifestyle behaviors on the subjective wellbeing of rural elderly people in different birth generations. Materials and methods: Data were derived from the China Health and Nutrition Survey (CHNS), which is an ongoing open cohort study that adopts a multistage, random clustered sampling process. We used the data of elderly people who were aged 65 or over during 2006-2015 for analysis. The Kaplan-Meier method and log-rank test found that the survival probability of rural elderly people was significantly lower than urban elderly people. Based on a sample of rural elderly people, Cox regression and generalized estimating equations were performed as further analyses. Results: A total of 892 rural elderly people aged 65 or over were included in the sample in 2006. High subjective wellbeing was a protective factor against death. The subjective wellbeing of rural elderly people born in the 1940s/1930s/1908-1920s birth generations first decreased then increased. For rural elderly people born in the 1940s, there were significant positive effects of a preference for eating vegetables and walking/Tai Chi on subjective wellbeing. For rural elderly people born in the 1930s, preferences for eating vegetables, reading, and watching TV all had significant positive effects on subjective wellbeing. Rural elderly people born in the 1908-1920s who preferred watching TV had more subjective wellbeing. Conclusion: Improving subjective wellbeing extended the life span and reduced mortality risk in rural elderly people and may be achieved by the shaping of a healthy lifestyle, such as preferences for eating vegetables, walking/Tai Chi, and reading.
Subject(s)
Life Style , Longevity , Aged , Humans , Cohort Studies , Nutritional Status , Healthy Lifestyle , VegetablesABSTRACT
Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the striatum, leading to dopamine (DA) deficiency in the striatum and typical motor symptoms. A small molecule as a dietary supplement for PD would be ideal for practical reasons. Hordenine (HOR) is a phenolic phytochemical marketed as a dietary supplement found in cereals and germinated barley, as well as in beer, a widely consumed beverage. This study was aimed to identify HOR as a dopamine D2 receptor (DRD2) agonist in living cells, and investigate the alleviative effect and mechanism of HOR on PD-like motor deficits in mice and nematodes. Our results firstly showed that HOR is an agonist of DRD2, but not DRD1, in living cells. Moreover, HOR could improve the locomotor dysfunction, gait, and postural imbalance in MPTP- or 6-OHDA-induced mice or Caenorhabditis elegans, and prevent α-synuclein accumulation via the DRD2 pathway in C. elegans. Our results suggested that HOR could activate DRD2 to attenuate the PD-like motor deficits, and provide scientific evidence for the safety and reliability of HOR as a dietary supplement.
Subject(s)
Neurodegenerative Diseases , Parkinson Disease , Mice , Animals , Dopamine/metabolism , Caenorhabditis elegans/metabolism , Reproducibility of Results , Parkinson Disease/drug therapy , Receptors, Dopamine D2/agonists , Receptors, Dopamine D2/metabolism , Dopaminergic Neurons , Mice, Inbred C57BL , Disease Models, AnimalABSTRACT
OBJECTIVE: A multicriteria decision analysis (MCDA) model was used to evaluate the benefits and risks of traditional Chinese medicine preparations of sinomenine alone or in combination with conventional drugs in the treatment of rheumatoid arthritis (RA) and to provide a basis for the rational clinical application of sinomenine. METHODS: A study search was performed using six major databases, and Review Manager 5.3 was used for data analysis. Then, an MCDA model evaluation system was established for the treatment of RA with sinomenine preparations, and the benefit values, risk values, and total benefit-risk values of sinomenine preparations alone or in combination with conventional drugs were calculated using Hiview 3.2 software. Finally, Monte Carlo simulations were performed using Crystal Ball embedded in Excel software to calculate the 95% confidence intervals (95% CI), and the probability of the differences between the 2 drug regimens was determined to optimize the evaluation results. RESULTS: Forty-four randomized controlled trials (RCTs) were included. Quantitative assessment of the MCDA model showed that the sinomenine preparation alone offered less benefits than when combined with conventional drugs with a benefit difference of 20 (95% CI 3.06, 35.71). However, the risk of the combination was significantly lower with a risk difference of 13(95% CI -10.26, 27.52). The total value of the benefit-risk of sinomenine alone and in combination with conventional drugs was 46 and 53 at 60% and 40% of the benefit-risk ratio of the two dosing regimens, respectively, with a difference of 7 (95% CI -4.26, 22.12). The probability that the comprehensive score of the combined regimen is greater than that of sinomenine alone is 90.1%, and the evaluation was steady. CONCLUSION: The benefit-risk of the combined application regimen of sinomenine is greater than that of sinomenine alone.
Subject(s)
Arthritis, Rheumatoid , Medicine, Chinese Traditional , Humans , Arthritis, Rheumatoid/drug therapy , Decision Support Techniques , Risk AssessmentABSTRACT
BACKGROUND: Pinelliae Rhizoma (PR), a toxic medication, with long history, is commonly used for eliminating phlegm. Due to the shortage of wild resources and the relative lacking of cultivation technology, it is often confused with its counterfeit species in the market, such as Typhonii Rhizoma (TR), Arisaematis Rhizoma (AR) and tubers of Typhonium flagelliforme (TF) and Pinellia pedatisecta (PP). PURPOSE: It was aimed to screen signature enzymatic peptides from toxic proteins to identify PR and its four counterfeit species. STUDY DESIGN: A comparative proteogenomics strategy based on open-source transcriptome data was applied for screening signature peptides from toxic proteins, which were applied for species authentication of PR and its counterfeit species. METHODS: Firstly, the open-source transcriptome data was used for constructing the annotated protein database, which was used for peptides identification. Secondly, the toxicity of different fractions of PR were evaluated by the rat peritoneal inflammation model. Furthermore, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) were used to profile the main proteins bands of five species, whose sequences were identified based on the in-gel digestion experiment by using ultra-high-performance liquid chromatography/quadrupole-Orbitrap mass spectrometry. Finally, the label-free proteomic analysis was performed to character the proteins and screen the signature peptides of five species, which were validated in commercially available products by dynamic multi reaction monitor (DMRM). RESULTS: The results in this study confirmed that protein was the main toxic components of PR. Both Pinellia ternata agglutinin (PTA) and trypsin inhibitor (TI) like proteins are the main proteins, which were characterized by proteomic analysis based on four annotated protein database. Meanwhile, seven signature peptides from toxic proteins were screened and validated with good repeatability and specificity in commercial products. CONCLUSION: Seven signature enzymatic peptides from toxic protein screened by the comparative proteogenomics strategy based on open-source transcriptome data achieved good identification ability of PR and its four counterfeit species.
Subject(s)
Drugs, Chinese Herbal , Pinellia , Agglutinins , Animals , Drugs, Chinese Herbal/pharmacology , Peptides , Pinellia/chemistry , Proteomics , Rats , Sodium Dodecyl Sulfate , Trypsin InhibitorsABSTRACT
BACKGROUND: The use of industrial by-products rich in bioactive compounds as animal feeds can reduce greenhouse gas production. Paulownia leaves silage (PLS) was supplemented to dairy cows' diet and evaluated in vitro (Exp. 1; Rusitec) and in vivo (Exp. 2, cannulated lactating dairy cows and Exp. 3, non-cannulated lactating dairy cows). The study investigated the PLS effect on ruminal fermentation, microbial populations, methane production and concentration, dry matter intake (DMI), and fatty acid (FA) proportions in ruminal fluid and milk. RESULTS: Several variables of the ruminal fluid were changed in response to the inclusion of PLS. In Exp. 1, the pH increased linearly and quadratically, whereas ammonia and total volatile fatty acid (VFA) concentrations increased linearly and cubically. A linear, quadratic, and cubical decrease in methane concentration was observed with increasing dose of the PLS. Exp. 2 revealed an increase in ruminal pH and ammonia concentrations, but no changes in total VFA concentration. Inclusion of PLS increased ruminal propionate (at 3 h and 6 h after feeding), isovalerate, and valerate concentrations. Addition of PLS also affected several populations of the analyzed microorganisms. The abundances of protozoa and bacteria were increased, whereas the abundance of archaea were decreased by PLS. Methane production decreased by 11% and 14% in PLS-fed cows compared to the control in Exp. 2 and 3, respectively. Exp. 3 revealed a reduction in the milk protein and lactose yield in the PLS-fed cows, but no effect on DMI and energy corrected milk yield. Also, the PLS diet affected the ruminal biohydrogenation process with an increased proportions of C18:3 cis-9 cis-12 cis-15, conjugated linoleic acid, C18:1 trans-11 FA, polyunsaturated fatty acids (PUFA), and reduced n6/n3 ratio and saturated fatty acids (SFA) proportion in milk. The relative transcript abundances of the 5 of 6 analyzed genes regulating FA metabolism increased. CONCLUSIONS: The dietary PLS replacing the alfalfa silage at 60 g/kg diet can reduce the methane emission and improve milk quality with greater proportions of PUFA, including conjugated linoleic acid, and C18:1 trans-11 along with reduction of SFA. Graphical abstract of the experimental roadmap.
ABSTRACT
SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome is a rare disease clinically characterized by a wide range of cutaneous and osteoarticular manifestations. Here, we report a case of SAPHO syndrome with cutis verticis gyrata (CVG) and investigated the genetic causes in the four members of this pedigree. After failure of conventional treatments, a recombinant human TNF-α receptor II:IgG Fc fusion protein (rhTNFR:Fc, YISAIPU®) achieved good control of the disease at the 2-year follow-up. We did not identify any pathogenic mutation in this pedigree. We also summarized the clinical and therapeutic characteristics of 83 patients with SAPHO syndrome through the China National Knowledge Infrastructure (CKNI) database from 2016 to 2021. Patients with acne were young and predominantly male. About 45.8% patients were treated with biological therapies or traditional Chinese medicine (TCM), 84.2% of which showed positive effects against cutaneous and osteoarticular manifestations. We report a case of SAPHO syndrome with CVG that was successfully treated with rhTNFR:Fc. Our results reveal the genetic heterogeneity involved. Biologics and TCM are likely alternative options for the treatment of SAPHO syndrome.
ABSTRACT
Panax notoginseng (PN) is a Chinese medicinal herb that is traditionally used to treat inflammation and immune-related diseases. Its major active constituents are saponins, the types and levels of which can be changed in the process of steaming. These differences in saponins are causally relevant to the differences in the therapeutic efficacies of raw and steamed PN. In this study, we have prepared the extracts of steamed PN (SPNE) with 70% ethanol and investigated their immunomodulatory effect using a zebrafish tail-fin amputation model. A fingerprint-effect relationship analysis was performed to uncover active constituents of SPNE samples related to the inhibitory effect on neutrophil number. The results showed that SPNE significantly inhibited the neutrophil number at the amputation site of zebrafish larvae. And SPNE extracts steamed at higher temperatures and for longer time periods showed a stronger inhibitory effect. Ginsenosides Rh1, Rk3, Rh4, 20(S)-Rg3, and 20(R)-Rg3, of which the levels were increased along with the duration of steaming, were found to be the major active constituents contributing to the neutrophil-inhibiting effect of SPNE. By additionally investigating the number of neutrophils in the entire tail of zebrafish larvae and performing TUNEL assays, we found that the decreased number of neutrophils at the amputation site was due to both the inhibition of their migration and apoptosis-inducing effects of the ginsenosides in SPNE on neutrophils. Among them, Rh1 and 20(R)-Rg3 did not affect the number of neutrophils at the entire tail, suggesting that they only inhibit the migration of neutrophils. In contrast, ginsenosides Rk3, Rh4, 20(S)-Rg3, and SPNE did not only inhibit the migration of neutrophils but also promoted neutrophilic cell death. In conclusion, this study sheds light on how SPNE, in particular the ginsenosides it contains, plays a role in immune modulation.
ABSTRACT
Achyranthes bidentata Blume is widely used as a traditional Chinese medicine with the effects of nourishing the liver and kidneys and strengthening muscles and bones. In this work, a rapid and simple strategy was developed for characterizing phytoecdysteroids by ultra-high-performance liquid chromatography coupled with liner ion trap-Orbitrap mass spectrometry using electrospray ionization in the negative mode. As a result, 47 phytoecdysteroids were unambiguously or tentatively characterized. Among them, seven known compounds were identified according to the reference standards along with molecular formula, retention time and fragmentation patterns, while others were mostly potential new compounds. Through targeted isolation, the structures of three new compounds were determined by NMR spectra, which were consistent with LC-MS characterization. The present study provides an efficient method to deeply characterize phytoecdysteroids.
Subject(s)
Achyranthes , Achyranthes/chemistry , Chromatography, High Pressure Liquid/methods , Gas Chromatography-Mass Spectrometry , Mass Spectrometry , Medicine, Chinese Traditional , Spectrometry, Mass, Electrospray Ionization/methodsABSTRACT
Traditional herbal medicine (THM) is used worldwide for its safety and effectiveness against various diseases. Huoxiang Zhengqi (HXZQ) is an extensively used Chinese THM formula targeting gastrointestinal disordered gastroenteritis via regulating the intestinal microbiome/immuno-microenvironment. However, the specific mechanisms remain largely unexplored, besides as a lifestyle drug, its safety on the gut microbiome homeostasis has never been investigated. In this study, the effects of HXZQ on the gut microbiome of healthy adults were investigated for the first time, and the antibiotic-induced gut microbiota dysbiosis mice model was applied for verification. Based on healthy adults, our results revealed that HXZQ exhibited mild and positive impacts on the bacterial diversity and the composition of the gut microbiome in a healthy state. As for an unhealthy state of the gut microbiome (with low bacterial diversity and deficient compositions), HXZQ significantly restored the bacterial diversity and recovered the abundance of Bacteroidetes. In the antibiotic-induced mice model, HXZQ distinctly revived the deficient gut microbial compositions impaired by antibiotics. At the genus level, the abundances that responded most strongly and positively to HXZQ were Bifidobacterium in healthy adults and Muribaculaceae, Lactobacillus, and Akkermansia in mice. In contrast, the abundance of Blautia in healthy adults, Enterococcus, and Klebsiella in mice showed inversely associated with HXZQ administration. At last, HXZQ might exhibit an anti-inflammatory effect by regulating the concentration of interleukin-6 in plasma while causing no significant changes in the colon tissue structure in mice. In conclusion, our results elucidate that the safety of HXZQ in daily use further reveals the modulatory effects of HXZQ on gut microbial community structure. These results will provide new insights into the interaction of THM and gut microbiome homeostasis and clues about the safe use of THM as a lifestyle drug for its further development.
ABSTRACT
BACKGROUND: The compound Sophora flavescenes (Kushen) decoction was found to reduce the inflammatory symptom of Ulcerative Colitis (UC). However, there exists a very limited understanding of the molecular pharmacological mechanisms. OBJECTIVE: This study aimed to explore the mechanism of compound Sophora flavescens (Kushen) decoction in treating ulcerative colitis from the perspective of network pharmacology. METHODS: Active components and potential targets of compound Sophora flavescens (Kushen) decoction were obtained through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. GeneCards and other databases were used to predict and screen ulcerative colitis-related genes. Cytoscape software was applied to construct the "drugactive component-disease-target" network. GO function and KEGG pathway enrichment analyses revealed the potential pathway of the compound Sophora flavescenes (Kushen) decoction for UC. RESULTS: After the screening, a total of 124 active ingredients and 163 potential therapeutic targets for UC were obtained from the compound Sophora flavescens (Kushen) decoction. Protein interaction network analysis showed that 15 key targets could be identified for the possible treatment of UC. GO and KEGG analyses showed that the active ingredients in the compound Sophora flavescens (Kushen) decoction were mainly enriched in 2556 biological processes and 172 signaling pathways. CONCLUSION: The study showed that the compound Sophora flavescens (Kushen) decoction has therapeutic effects on UC through multi-component, multi-target, and multi-pathway.
Subject(s)
Colitis, Ulcerative , Sophora , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/genetics , Drugs, Chinese Herbal , Molecular Docking Simulation , Network Pharmacology , TechnologyABSTRACT
Many studies have demonstrated that natural plant extracts have inhibitory effects on microorganisms. The purpose of this study was to investigate the inhibitory effect of phenolic acids from rice straw (PAs) on Escherichia coli and their synergistic effect in combination with antibiotics. PAs can inhibit the growth of E. coli effectively by inducing the formation of H2O2; PA-treated cells had a tenfold greater intracellular H2O2 concentration than the control group. The synergistic effect caused by the interaction of PAs and antibiotics on inhibiting the growth of E. coli was significant. This effect may be caused by a PA-induced change in the permeability of E. coli cell membrane. The treatment with PAs made the extracellular K+ concentration reached 15 mg/L within 30 min, while the K+ concentration in the control group was very low and did not change significantly over time. Similarly to the extracellular K+, the extracellular protein concentration exceeded 150 mg/L in the PA treatment group, while it remained very low in the control group. Due to the increased cell permeability, more antibiotics can enter the cell. Hence, this study may provide a novel method of improving the safe use of antibiotics.
Subject(s)
Escherichia coli Infections , Oryza , Anti-Bacterial Agents/pharmacology , Escherichia coli , Escherichia coli Infections/microbiology , Hydrogen Peroxide/pharmacology , Microbial Sensitivity TestsABSTRACT
This study systematically searched CNKI and Web of Science(WoS) for the research papers on the toxicity of Tripterygium wilfordii included from database inception to August 31, 2021, and visually displayed the authors, research institutions, keywords, and other contents using bibliometrics and CiteSpace 5.8.3. Furthermore, the current situation and research progress on T. wilfordii safety were also analyzed based on information extraction to find the research hotspot, evolution path, and development trend, and to provide references for future research. A total of 1 876 Chinese papers and 243 English papers were included in the study. The analysis of authors showed that WANG Qi and ZHANG Luyong had the most publications in Chinese and English papers, respectively. According to the analysis of research institutions, National Institutes for Food and Drug Control and China Pharmaceutical University possessed the largest number of Chinese and English papers, respectively, but there was less cooperation between them. The analysis of keywords in Chinese and English papers showed that the research contents of the safety of T. wilfordii mainly focused on clinical monitoring, mechanism, dosage form improvement, quality standard, component analysis, monomer research, efficiency and toxicity reduction, etc. Metabonomics, tripterine, and the underlying mechanism of toxicity were the research hotspots in the future. At present, the research on the toxicity of T. wilfordii is still under development. It is necessary to highlight the in-depth research and strengthen the inter-group and inter-region cooperation of authors or institutions to provide references for the research on the toxicity of T. wilfordii.
Subject(s)
Drugs, Chinese Herbal , Tripterygium , Bibliometrics , China , Drugs, Chinese Herbal/toxicity , HumansABSTRACT
The calcium/calmodulin-dependent protein phosphase calcineurin (CaN) regulates synaptic plasticity by controlling the phosphorylation of synaptic proteins including AMPA type glutamate receptors. The regulator of calcineurin 1 (RCAN1) is characterized as an endogenous inhibitor of CaN and its dysregulation is implicated in multiple neurological disorders. However, whether RCAN1 is engaged in nociceptive processing in the spinal dorsal horn remains unrevealed. In this study, we found that RCAN1 was predominately expressed in pain-related neurons in the superficial dorsal horn of the spinal cord. Intraplantar injection of complete Freund's adjuvant (CFA) specifically increased the total and synaptic expression of the RCAN1.4 isoform in spinal dorsal horn. The CFA-induced inflammation also caused an increased binding of RCAN1.4 to CaN. Overexpression of RCAN1.4 in spinal dorsal horn of intact mice produced both mechanical allodynia and thermal hyperalgesia, which were accompanied by increased synaptic expression and phosphorylation of GluA1 subunit. Furthermore, the siRNA-mediated knockdown of RCAN1.4 significantly attenuated the development of pain hypersensitivity, meanwhile, decreased the synaptic expression of GluA1 in mice with peripheral inflammation. These data suggested that the increased expression of RCAN1.4 contributed to the development of inflammatory pain hypersensitivity, at least in part by promoting the synaptic recruitment of GluA1-containing AMPA receptor.
Subject(s)
Calcineurin , Spinal Cord Dorsal Horn , Animals , Calcineurin/metabolism , Freund's Adjuvant/metabolism , Freund's Adjuvant/toxicity , Hyperalgesia/metabolism , Inflammation/metabolism , Mice , Pain/metabolism , Posterior Horn Cells/metabolism , Receptors, AMPA/metabolism , Spinal Cord/metabolism , Spinal Cord Dorsal Horn/metabolism , Up-RegulationABSTRACT
Metabolic reprogramming is one of the hallmarks of tumor. Growing evidence suggests metabolic changes that support oncogenic progression may cause selective vulnerabilities that can be exploited for cancer treatment. Increasing demands for certain nutrients under genetic determination or environmental challenge enhance dependency of tumor cells on specific nutrient, which could be therapeutically developed through targeting such nutrient dependency. Various nutrients including several amino acids and glucose have been found to induce dependency in genetic alteration- or context-dependent manners. In this review, we discuss the extensively studied nutrient dependency and the biological mechanisms behind such vulnerabilities. Besides, existing applications and strategies to target nutrient dependency in different cancer types, accompanied with remaining challenges to further exploit these metabolic vulnerabilities to improve cancer therapies, are reviewed.