Research progress of organic photothermal agents delivery and synergistic therapy systems.

Cancer is currently one of the leading causes of mortality worldwide. Due to the inevitable shortcomings of conventional treatments, photothermal therapy (PTT) has attracted great attention as an emerging and non-invasive cancer treatment method. Photothermal agents (PTAs) is a necessary component of PTT to play its role. It accumulates at the tumor site through appropriate methods and converts the absorbed light energy into heat energy effectively under near-infrared light irradiation, thus increasing the temperature of the tumor area and facilitating ablation of the tumor cells. Compared to inorganic photothermal agents, which have limitations such as non-degradability and potential long-term toxicity in vivo, organic photothermal agents exhibit excellent biocompatibility and biodegradability, thus showing promising prospects for the application of PTT in cancer treatment. And these organic photothermal agents can also be engineered into nanoparticles to improve their water solubility, extend their circulation time in vivo, and specifically target tumors. Moreover, further combination of PTT with other treatment methods can effectively enhance the efficacy of cancer treatment and alleviate the side effects associated with single treatments. This article briefly introduces several common types of organic photothermal agents and their nanoparticles, and reviews the applications of PTT based on organic photothermal agents in combination with chemotherapy, photodynamic therapy, chemodynamic therapy, immunotherapy, and multimodal combination therapy for tumor treatment, which expands the ideas and methods in the field of tumor treatment.

Integrated omic profiling of the medicinal mushroom Inonotus obliquus under submerged conditions.

BACKGROUND: The Inonotus obliquus mushroom, a wondrous fungus boasting edible and medicinal qualities, has been widely used as a folk medicine and shown to have many potential pharmacological secondary metabolites. The purpose of this study was to supply a global landscape of genome-based integrated omic analysis of the fungus under lab-growth conditions. RESULTS: This study presented a genome with high accuracy and completeness using the Pacbio Sequel II third-generation sequencing method. The de novo assembled fungal genome was 36.13 Mb, and contained 8352 predicted protein-coding genes, of which 365 carbohydrate-active enzyme (CAZyme)-coding genes and 19 biosynthetic gene clusters (BCGs) for secondary metabolites were identified. Comparative transcriptomic and proteomic analysis revealed a global view of differential metabolic change between seed and fermentation culture, and demonstrated positive correlations between transcription and expression levels of 157 differentially expressed genes involved in the metabolism of amino acids, fatty acids, secondary metabolites, antioxidant and immune responses. Facilitated by the widely targeted metabolomic approach, a total of 307 secondary substances were identified and quantified, with a significant increase in the production of antioxidant polyphenols. CONCLUSION: This study provided the comprehensive analysis of the fungus Inonotus obliquus, and supplied fundamental information for further screening of promising target metabolites and exploring the link between the genome and metabolites.

One pot preparation of muti-mode nanoplatform to combat ovarian cancer.

Ovarian cancer is one of the most common gynecological cancers with high mortality rate. The battle against ovarian cancer usually impaired by the evolved multidrug resistance (MDR) phenotype as well as metastasis in cancers, which urgently call for the development of multi-mode strategies to overcome the MDR and reduce metastasis. Considering the good benefits of ferroptosis and photothermal therapy (PTT) in cancer management, we herein proposed a facile way to construct nanoparticle platform (Fe-Dox/PVP) composed of ferric chloride, doxorubicin (Dox) and polyvinyl pyrrolidone (PVP) for the multi-mode therapy of ovarian cancer using chemotherapy, ferroptosis and mild hypothermia PTT. Our results demonstrated that Fe-Dox/PVP with mild hypothermia was shown to have improved endosomal escape/drug delivery, enhanced ferroptosis induction and good tumor targeting effects. Most importantly, the integration of all three effects into one platform provided increased anti-metastasis effect and promising in vitro/in vivo anticancer performance with high biocompatibility. In this study, we offer a facile and robust way to prepare a multi-mode nanoplatform to combat ovarian cancer, which can be further extended for the management of many other cancers.

Discovery of anti-infective adipostatins through bioactivity-guided isolation and heterologous expression of a type III polyketide synthase.

Antibiotic resistance and emerging viral pandemics have posed an urgent need for new anti-infective drugs. By screening our microbial extract library against the main protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the notorious ESKAPE pathogens, an active fraction was identified and purified, leading to an initial isolation of adipostatins A (1) and B (2). In order to diversify the chemical structures of adipostatins toward enhanced biological activities, a type III polyketide synthase was identified from the native producer, Streptomyces davawensis DSM101723, and was subsequently expressed in an E. coli host, resulting in the isolation of nine additional adipostatins 3-11, including two new analogs (9 and 11). The structures of 1-11 were established by HRMS, NMR, and chemical derivatization, including using a microgram-scale meta-chloroperoxybenzoic acid epoxidation-MS/MS analysis to unambiguously determine the double bond position in the alkyl chain. The present study discovered SARS-CoV-2 main protease inhibitory activity for the class of adipostatins for the first time. Several of the adipostatins isolated also exhibited antimicrobial activity against selected ESKAPE pathogens.

Development and Evaluation of Oleanolic Acid Dosage Forms and Its Derivatives.

Oleanolic acid is a pentacyclic triterpenoid compound that exists widely in medicinal herbs and other plants. Because of the extensive pharmacological activity, oleanolic acid has attracted more and more attention. However, the structural characteristics of oleanolic acid prevent it from being directly made into new drugs, which limits the application of oleanolic acid. Through the application of modern preparation techniques and methods, different oleanolic acid dosage forms and derivatives have been designed and synthesized. These techniques can improve the water solubility and bioavailability of oleanolic acid and lay a foundation for the new drug development. In this review, the recent progress in understanding the oleanolic acid dosage forms and its derivatives are discussed. Furthermore, these products were evaluated comprehensively from the perspective of characterization and pharmacokinetics, and this work may provide ideas and references for the development of oleanolic acid preparations.

hiPSC-Derived Cardiac Tissue for Disease Modeling and Drug Discovery.

Relevant, predictive normal, or disease model systems are of vital importance for drug development. The difference between nonhuman models and humans could contribute to clinical trial failures despite ideal nonhuman results. As a potential substitute for animal models, human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) provide a powerful tool for drug toxicity screening, modeling cardiovascular diseases, and drug discovery. Here, we review recent hiPSC-CM disease models and discuss the features of hiPSC-CMs, including subtype and maturation and the tissue engineering technologies for drug assessment. Updates from the international multisite collaborators/administrations for development of novel drug discovery paradigms are also summarized.

Integrated Label-Free and 10-Plex DiLeu Isobaric Tag Quantitative Methods for Profiling Changes in the Mouse Hypothalamic Neuropeptidome and Proteome: Assessment of the Impact of the Gut Microbiome.

Gut microbiota can regulate host physiological and pathological status through gut-brain communications or pathways. However, the impact of the gut microbiome on neuropeptides and proteins involved in regulating brain functions and behaviors is still not clearly understood. To address the problem, integrated label-free and 10-plex DiLeu isobaric tag-based quantitative methods were implemented to compare the profiling of neuropeptides and proteins in the hypothalamus of germ-free (GF)- vs conventionally raised (ConvR)-mice. A total of 2943 endogenous peptides from 63 neuropeptide precursors and 3971 proteins in the mouse hypothalamus were identified. Among these 368 significantly changed peptides (fold changes over 1.5 and a p-value of <0.05), 73.6% of the peptides showed higher levels in GF-mice than in ConvR-mice, and 26.4% of the peptides had higher levels in ConvR-mice than in GF-mice. These peptides were mainly from secretogranin-2, phosphatidylethanolamine-binding protein-1, ProSAAS, and proenkephalin-A. A quantitative proteomic analysis employing DiLeu isobaric tags revealed that 282 proteins were significantly up- or down-regulated (fold changes over 1.2 and a p-value of <0.05) among the 3277 quantified proteins. These neuropeptides and proteins were mainly involved in regulating behaviors, transmitter release, signaling pathways, and synapses. Interestingly, pathways including long-term potentiation, long-term depression, and circadian entrainment were involved. In the present study, a combined label-free and 10-plex DiLeu-based quantitative method enabled a comprehensive profiling of gut microbiome-induced dynamic changes of neuropeptides and proteins in the hypothalamus, suggesting that the gut microbiome might mediate a range of behavioral changes, brain development, and learning and memory through these neuropeptides and proteins.

Liquid Chromatography Tandem Mass Spectrometry Based Label-Free Quantification Method for Assessment of Allergen-Induced Anaphylactoid Reactions.

Mast cells are essential in mediating inflammatory processes. When activated, mast cells can rapidly release characteristic granules and various mediators into the interstitium. Tryptase (TPS) and ß-hexosaminidase (HEXB) are typical protease mediators stored in granules and released upon activation. They have been recognized as important biomarkers of anaphylaxis, and the released level is associated with the severity of allergic reactions. In this study, a sensitive, accurate, and selective liquid chromatography tandem mass spectrometry (LC-MS/MS) method for simultaneously quantifying the two biomarkers was developed and validated in LAD2 cell culture supernatant, and P14R was used as internal standard. Good linearity was observed in the range of 50-2500 ng/mL for TPS and 10-2000 ng/mL for HEXB both with R2 > 0.99. The matrix effect and recovery were both within acceptable limits. We quantified TPS and HEXB released from Laboratory of Allergic Disease 2 (LAD2) mast cells treated with several potential allergens, and the results demonstrate that the method can be used to investigate TPS and HEXB levels in LAD2 mast cell model during allergy research. We anticipate our approach to be a robust and sensitive assessment method for more biomarkers with similar kinetics characteristics and to be a major tool of allergic drug assessment or antiallergic drug development in research.

A strategy for identifying species-specific peptide biomarkers in deer-hide gelatin using untargeted and targeted mass spectrometry approaches.

Deer-hide gelatin (DHG) is an important animal-derived traditional Chinese medicine (TCM), which has been applied in TCM for over 400 years. However, it is extremely difficult to distinguish DHG with adulteration or made with other animal skins due to the highly processing procedure. Therefore, a simple strategy for identifying species-specific peptide biomarkers in deer-hide gelatin (DHG) is needed. In the present study, untargeted and targeted mass spectrometry approaches were implemented to analyze comprehensive peptidomic profiles of trypsin-digested animal gelatins. Mathematics set theory was then used to interrogate the relationship between different samples and peptides in the target species set, while the peptides were not considered as species-specific biomarkers in other sets. Two peptides were identified as DHG-specific peptides. Targeted mass spectrometry approach was then used to verify these two peptides. It showed that these two peptides could be used for distinguishing DHG from other animal hide gelatins. The present strategy provides a simple method for peptide biomarker discovery, which can be applied in the identification of specific peptides in some highly processed animal derived traditional Chinese medicines (TCMs). Thus, the present work provides an effective strategy for rapid, simple discovery and application of species-specific peptide biomarkers to ensure animal derived TCMs quality and make them authenticable and traceable.

A Multifaceted Mass Spectrometric Method to Probe Feeding Related Neuropeptide Changes in Callinectes sapidus and Carcinus maenas.

Food intake is regulated by various neuromodulators, including numerous neuropeptides. However, it remains elusive at the molecular and cellular level as to how these important chemicals regulate internal processes and which regions of the neuronal organs are responsible for regulating the behavior. Here we report a comparative neuropeptidomic analysis of the brain and pericardial organ (PO) in response to feeding in two well-studied crustacean physiology model organisms, Callinectes sapidus and Carcinus maenas, using mass spectrometry (MS) techniques. A multifaceted MS-based approach has been developed to obtain complementary information on the expression changes of a large array of neuropeptides in the brain and PO. The method employs stable isotope labeling of brain and PO extracts for relative MS quantitation, capillary electrophoresis (CE)-MS for fractionation and high-specificity analysis, and mass spectrometric imaging (MSI) for in-situ molecular mapping of peptides. A number of neuropeptides, including RFamides, B-type allatostatins (AST-B), RYamides, and orcokinins exhibit significant changes in abundance after feeding in this investigation. Peptides from the AST-B family found in PO tissue were shown to have both altered expression and localization changes after feeding, indicating that they may be a class of vital neuropeptide regulators involved in feeding behavior. Graphical Abstract ᅟ.

Relative Quantitation of Neuropeptides at Multiple Developmental Stages of the American Lobster Using N, N-Dimethyl Leucine Isobaric Tandem Mass Tags.

Neuromodulators and neurotransmitters play important roles in neural network development. The quantitative changes of these signaling molecules often reflect their regulatory roles in physiological processes. Currently, several commercial tags (e.g., iTRAQ and TMT) have been widely used in proteomics. With reduced cost and higher labeling efficiency, we employed a set of custom-developed N, N-dimethyl leucine (DiLeu) 4-plex isobaric tandem mass tags as an attractive alternative for the relative quantitation of neuropeptides in brain tissue of American lobster Homarus americanus at multiple developmental stages. A general workflow for isobaric labeling of neuropeptides followed by LC-MS/MS analysis has been developed, including optimized sample handling procedures. Overall, we were able to quantify 18 trace-amount neuropeptides from 6 different families using a single adult brain as a control. The quantitation results indicated that the expressions of different neuropeptide families had significant changes over distinct developmental stages. Additionally, our data revealed intriguing elevated expression of neuropeptides in the early juvenile development stage. The methodology presented here advanced the workflow of DiLeu as an alternative labeling approach and the application of DiLeu-based quantitative peptidomics, which can be extended to areas beyond neuroscience.

Simultaneous identification of the anaphylactoid components from traditional Chinese medicine injections using rat basophilic leukemia 2H3 and laboratory of allergic disease 2 dual-mixed/cell membrane chromatography model.

Traditional Chinese medicine (TCM) has been used for prevention and treatment of various diseases for many decades. TCM injection is a new dosage form, with incidence of anaphylactoid reactions increasing every year. In this study, the rat basophilic leukemia 2H3 (RBL-2H3) and laboratory of allergic disease 2 (LAD2) dual-mixed/CMC was established and was coupled with an HPLC-ESI-IT-TOF-MS system to identify the potential allergenic components in Haqing injection. Cinobufagin, piperine, osthole, praeruptorin A, and schizandrin A were screened from Haqing injection via this coupled system. Competitive binding assay showed piperine, praeruptorin A, and schizandrin A acting on MrgprX2 and cinobufagin and osthole act on the IgE receptor. The release of mediators of anaphylaxis results showed cinobufagin and osthole can cause anaphylactoid reactions by triggering the release of ß-hexosaminidase and histamine via IgE-R. Praeruptorin A and schizandrin A could promote the release of ß-hexosaminidase and histamine via MrgprX2 receptor. In summary, the dual-mixed/CMC model can significantly improve the efficiency of target component identification from a complex sample. When combined with competitive binding assay and validation of biological activities, this model enables accurate determination of the dual-target components, offering improved methods for quality control of TCM injections.

Quantitative Mass Spectrometry Reveals Food Intake-Induced Neuropeptide Level Changes in Rat Brain: Functional Assessment of Selected Neuropeptides as Feeding Regulators.

Endogenous neuropeptides are important signaling molecules that function as regulators of food intake and body weight. Previous work has shown that neuropeptide gene expression levels in a forebrain reward site, the nucleus accumbens (NAc), were changed by feeding. To directly monitor feeding-induced changes in neuropeptide expression levels within the NAc, we employed a combination of cryostat dissection, heat stabilization, neuropeptide extraction and label-free quantitative neuropeptidomics via a liquid chromatography-high resolution mass spectrometry platform. Using this methodology, we described the first neuropeptidome in NAc and discovered that feeding caused the expression level changes of multiple neuropeptides derived from different precursors, especially proSAAS-derived peptides such as Big LEN, PEN and little SAAS. We further investigated the regulatory functions of these neuropeptides derived from the ProSAAS family by performing an intra-NAc microinjection experiment using the identified ProSAAS neuropeptides, 'Big-LEN' and 'PEN'. Big LEN significantly increased rats' food and water intake, whereas both big LEN and PEN affected other behaviors including locomotion, drinking and grooming. In addition, we quantified the feeding-induced changes of peptides from hippocampus, hypothalamus and striatum to reveal the neuropeptide interplay among different anatomical regions. In summary, our study demonstrated neuropeptidomic changes in response to food intake in the rat NAc and other key brain regions. Importantly, the microinfusion of ProSAAS peptides into NAc revealed that they are behaviorally active in this brain site, suggesting the potential use of these peptides as therapeutics for eating disorders.

Prevalence and Determinants of Suboptimal Vitamin D Levels in a Multiethnic Asian Population.

This population-based cross-sectional study examined the prevalence and risk factors of suboptimal vitamin D levels (assessed using circulating 25-hydroxycholecalciferol (25(OH)D)) in a multi-ethnic sample of Asian adults. Plasma 25(OH)D concentration of 1139 Chinese, Malay and Indians (40-80 years) were stratified into normal (≥30 ng/mL), and suboptimal (including insufficiency and deficiency, <30 ng/mL) based on the 2011 Endocrine Society Clinical Practice Guidelines. Logistic regression models were used to assess the associations of demographic, lifestyle and clinical risk factors with the outcome. Of the 1139 participants, 25(OH)D concentration was suboptimal in 76.1%. In multivariable models, age ≤65 years (compared to age >65 years), Malay and Indian ethnicities (compared to Chinese ethnicity), and higher body mass index, HbA1c, education and income levels were associated with suboptimal 25(OH)D concentration (p < 0.05). In a population-based sample of Asian adults, approximately 75% had suboptimal 25(OH)D concentration. Targeted interventions and stricter reinforcements of existing guidelines for vitamin D supplementation are needed for groups at risk of vitamin D insufficiency/deficiency.

Herbal drugs against cardiovascular disease: traditional medicine and modern development.

Herbal products have been used as conventional medicines for thousands of years, particularly in Eastern countries. Thousands of clinical and experimental investigations have focused on the effects and mechanisms-of-action of herbal medicine in the treatment of cardiovascular diseases (CVDs). Considering the history of clinical practice and the great potentials of herb medicine and/or its ingredients, a review on this topic would be helpful. This article discusses possible effects of herbal remedies in the prevention and treatment of CVDs. Crucially, we also summarize some underlying pharmacological mechanisms for herb products in cardiovascular regulations, which might provide interesting information for further understanding the effects of herbal medicines, and boost the prospect of new herbal products against CVDs.

[Pharmacokinetics of gastrodin from Tiangou Jiangya capsule in rats].

The paper aims to study the pharmacokinetic parameters of gastrodin in rats effected by compound compatibilitiy and different doses of Tiangou Jiangya capsule. The extracts from Gastrodiae Rhizoma( equivalent to gastrodin 16.82 mg x kg(-1) and Tiangou jiangya capsule (equivalent to gastrodin 8.410, 16.82, 33.64 mg x kg(-1)) were oral administrated to rats respectively. The plasma were taken at various time points and treated with acetonitrile to measure the contents of gastrodin by HPLC method. The mean plasma concentration-time data were analyzed by 3P97 pharmacokinetic software and the pharmacokinetic parameters between groups were treated by SPSS 16.0. The results showed that gastrodin in rat was fitted to one-compartment model, Cmax and AUC of Tiangou Jiangya capsule were in direct proportion to oral administration, and t1/2Ka had nothing to do with doses, which indicated that gastrodin was fitted first-order rate transfter process in vivo. Morever, comparison with the Gastrodiae Rhizoma extract, isodose gastrodin in Tiangou Jiangya capsule showed a significant decrease for Cmax, Ke and increase for t1/2Ke, V/Fc, this indicated that compound compatibility can delay the absorbtion of gastrodin, prolong the resident time and promote the distribution in vivo, but its bioavailability is not significantly effected.

[Study on in situ intestinal absorption of baicalin contained in Tiangou Jiangya capsules].

OBJECTIVE: To study in situ intestinal absorption kinetics of baicalin contained in Tiangou Jiangya capsules, and the effect of different intestinal segments, pH value, drug concentration and P-gp inhibitor on the absorption. METHOD: The in situ intestinal perfusion test was adopted, and HPLC method was used to determine the content of baicalin in samples at different time points. Ultra-violet (UV) spectrophotometry was used to determine the content of phenol red in samples at different time points. RESULT: When pH value was at 5. 0, 6. 5, 7. 4, the absorption of baicalin was not impacted. P-gp inhibitor verapamil could enhance the absorption of baicalin. When the quality concentration of the test solution ranged between 5-20 g L -1 , the linearity of the absorption amount of baicalin increased. The absorption kinetic equation of baicalin was Y = -0. 073 7X +0. 118 7 (r = 0. 994 8) , K. 0. 073 7 h -1 , t1/2 9. 40 h. CONCLUSION: Baicalin is mainly absorbed in colon. The absorption of baicalin shows the first-order kinetics process, with the absorption mechanism of passive diffusion. Baicalin is a substrate for P-gp.

Mass spectrometric evaluation of neuropeptidomic profiles upon heat stabilization treatment of neuroendocrine tissues in crustaceans.

Tissue heat stabilization is a vital component in successful mammalian neuropeptidomic studies. Heat stabilization using focused microwave irradiation, conventional microwave irradiation, boiling, and treatment with the Denator Stabilizor T1 have all proven effective in arresting post-mortem protein degradation. Although research has reported the presence of protein fragments in crustacean hemolymph when protease inhibitors were not added to the sample, the degree to which post-mortem protease activity affects neuropeptidomic tissue studies in crustacean species has not been investigated in depth. This work examines the need for Stabilizor T1 or boiling tissue stabilization methods for neuropeptide studies of Callinectes sapidus (blue crab) pericardial organ tissue. Neuropeptides in stabilized and nonstabilized tissue were extracted using acidified methanol or N,N-dimethylformamide (DMF) and analyzed by MALDI-TOF and nanoLC-ESI-MS/MS platforms. Post-mortem fragments did not dramatically affect MALDI analysis in the range m/z 650-1600, but observations in ESI MS/MS experiments suggest that putative post-mortem fragments can mask neuropeptide signal and add spectral complexity to crustacean neuropeptidomic studies. The impact of the added spectral complexity did not dramatically affect the number of detected neuropeptides between stabilized and nonstabilized tissues. However, it is prudent that neuropeptidomic studies of crustacean species include a preliminary experiment using the heat stabilization method to assess the extent of neuropeptide masking by larger, highly charged molecular species.

Mass spectral charting of neuropeptidomic expression in the stomatogastric ganglion at multiple developmental stages of the lobster Homarus americanus.

The stomatogastric nervous system (STNS) of the American lobster Homarus americanus serves as a useful model for studies of neuromodulatory substances such as peptides and their roles in the generation of rhythmic behaviors. As a central component of the STNS, the stomatogastric ganglion (STG) is rich in neuropeptides and contains well-defined networks of neurons, serving as an excellent model system to study the effect of neuropeptides on the maturation of neural circuits. Here, we utilize multiple mass spectrometry (MS)-based techniques to study the neuropeptide content and abundance in the STG tissue as related to the developmental stage of the animal. Capillary electrophoresis (CE)-MS was employed to unambiguously identify low abundance neuropeptide complements, which were not fully addressed using previous methods. In total, 35 neuropeptides from 7 different families were detected in the tissue samples. Notably, 10 neuropeptides have been reported for the first time in this study. In addition, we utilized a relative quantitation method to compare neuropeptidomic expression at different developmental stages and observed sequential appearance of several neuropeptides. Multiple isoforms within the same peptide family tend to show similar trends of changes in relative abundance during development. We also determined that the relative abundances of tachykinin peptides increase as the lobster grows, suggesting that the maturation of circuit output may be influenced by the change of neuromodulatory input into the STG. Collectively, this study expands our knowledge about neuropeptides in the crustacean STNS and provides useful information about neuropeptide expression in the maturation process.

[Simultaneous determination of four active compounds in tiangou capsules by HPLC].

OBJECTIVE: To establish a method for quantitative analysis of gastrodin, baicalin, paeonolum and pinoresinol diglucoside in Tiangou capsules by HPLC. METHOD: The separation was performed on SinoChrom ODS-BP column (4.6 mm x 150 mm, 5 microm). The mobile phase consisted of acetonitrile and 0.2% phosphoric acid aqueous solution with gradient elution program. The flow rate was 1.0 ml x min(-1) and the column temperature was 30 degrees C. UV detection wavelength was set at 230 nm. RESULT: The linear ranges of gastrodin, baicalin, paeonolum and pinoresinol diglucoside were 0.1168-1.1680, 0.1142-1.1420, 0.0512-0.5120, 0.0556-0.5560 microg, respectively. The average recoveries of gastrodin, baicalin, paeonolum and pinoresinol diglucoside were 100.3% (RSD 0.53%), 99.96% (RSD 1.15%), 99.90% (RSD 1.17%), 99.97% (RSD 1.62%), respectively. CONCLUSION: The method is accurate, simple, feasible and reliable, and is available for the quality control of Tiangou capsules.