Publications by authors named "Xianli Meng"

55 Publications

Scutellarin ameliorates colitis-associated colorectal cancer by suppressing Wnt/β-catenin signaling cascade.

Eur J Pharmacol 2021 Jun 9;906:174253. Epub 2021 Jun 9.

State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. Electronic address:

Dysregulated Wnt/β-catenin signaling pathway plays a critical role in the pathogenesis of colorectal cancer (CRC). Scutellarin, a flavonoid compound in Scutellaria barbata, has been reported to suppress CRC, with the action mechanism elusive. In this study, Scutellarin was found to inhibit the carcinogenesis of colitis-associated cancer (CAC) in mice caused by azoxymethane/dextran sulfate sodium, with alleviation of pathologic symptoms. Besides, Scutellarin attenuated mouse serum concentrations of TNF-α and IL-6, heightened Bax expression and diminished B-cell lymphoma-2 (Bcl-2) level in CAC tissues of mice, through down-regulating Wnt/β-catenin signaling cascade. In CRC HT-29 cells, Scutellarin retarded the proliferation and migration, induced apoptosis, with boosted Bax expression and decreased Bcl-2 level, which may be attributed to its repression of Wnt/β-catenin signals in HT-29 cells. Our findings demonstrate that Scutellarin may ameliorate colitis-associated colorectal cancer by weakening Wnt/β-catenin signaling cascade.
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http://dx.doi.org/10.1016/j.ejphar.2021.174253DOI Listing
June 2021

Tibetan Medicine Duoxuekang Capsule Ameliorates High-Altitude Polycythemia Accompanied by Brain Injury.

Front Pharmacol 2021 11;12:680636. Epub 2021 May 11.

State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.

Duoxuekang (DXK) capsule is an empirical prescription for Tibetan medicine in the treatment of hypobaric hypoxia (HH)-induced brain injury in the plateau. This study aimed to investigate the protective effects and underlying molecular mechanisms of DXK on HH-induced brain injury. UPLC-Q-TOF/MS was performed for chemical composition analysis of DXK. The anti-hypoxia and anti-fatigue effects of DXK were evaluated by the normobaric hypoxia test, sodium nitrite toxicosis test, and weight-loaded swimming test in mice. Simultaneously, SD rats were used for the chronic hypobaric hypoxia (CHH) test. RBC, HGB, HCT, and the whole blood viscosity were evaluated. The activities of SOD and MDA in the brain, and EPO and LDH levels in the kidney were detected using ELISA. H&E staining was employed to observe the pathological morphology in the hippocampus and cortex of rats. Furthermore, immunofluorescence and Western blot were carried out to detect the protein expressions of Mapk10, RASGRF1, RASA3, Ras, and IGF-IR in the brain of rats. Besides, BALB/c mice were used for acute hypobaric hypoxia (AHH) test, and Western blot was employed to detect the protein expression of p-ERK/ERK, p-JNK/JNK, and p-p38/p38 in the cerebral cortex of mice. 23 different chemical compositions of DXK were identified by UPLC-Q-TOF/MS. The anti-hypoxia test verified that DXK can prolong the survival time of mice. The anti-fatigue test confirmed that DXK can prolong the swimming time of mice, decrease the level of LDH, and increase the hepatic glycogen level. Synchronously, DXK can decrease the levels of RBC, HGB, HCT, and the whole blood viscosity under the CHH condition. Besides, DXK can ameliorate CHH-induced brain injury, decrease the levels of EPO and LDH in the kidney, reduce MDA, and increase SOD in the hippocampus. Furthermore, DXK can converse HH-induced marked increase of Mapk10, RASGRF1, and RASA3, and decrease of Ras and IGF-IR. In addition, DXK can suppress the ratio of p-ERK/ERK, p-JNK/JNK, and p-p38/p38 under the HH condition. Together, the cerebral protection elicited by DXK was due to the decrease of hematological index, suppressing EPO, by affecting the MAPK signaling pathway in oxidative damage, and regulating the RAS signaling pathway.
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http://dx.doi.org/10.3389/fphar.2021.680636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144525PMC
May 2021

Anti-Apoptotic Role of Sanhuang Xiexin Decoction and Anisodamine in Endotoxemia.

Front Pharmacol 2021 21;12:531325. Epub 2021 Apr 21.

Innovative Institutes of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.

Endotoxemia is characterized by initial uncontrollable inflammation, terminal immune paralysis, significant cell apoptosis and tissue injury, which can aggravate or induce multiple diseases and become one of the complications of many diseases. Therefore, anti-inflammatory and anti-apoptotic therapy is a valuable strategy for the treatment of endotoxemia-induced tissue injury. Traditional Chinese medicine exhibits great advantages in the treatment of endotoxemia. In this review, we have analyzed and summarized the active ingredients and their metabolites of Sanhuang Xiexin Decoction, a famous formula in endotoxemia therapy. We then have summarized the mechanisms of Sanhuang Xiexin Decoction against endotoxemia and its mediated tissue injury. Furthermore, silico strategy was used to evaluate the anti-apoptotic mechanism of anisodamine, a well-known natural product that widely used to improve survival in patients with septic shock. Finally, we also have summarized other anti-apoptotic natural products as well as their therapeutic effects on endotoxemia and its mediated tissue injury.
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http://dx.doi.org/10.3389/fphar.2021.531325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099151PMC
April 2021

Amelioration of diabetic retinopathy in db/db mice by treatment with different proportional three active ingredients from Tibetan medicine Berberis dictyophylla F.

J Ethnopharmacol 2021 Aug 6;276:114190. Epub 2021 May 6.

Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. Electronic address:

Ethnopharmacological Relevance: Berberis dictyophylla F., a famous Tibetan medicine, has been used to prevent and treat diabetic retinopathy (DR) for thousands of years in clinic. However, its underlying mechanisms remain unclear.

Aim Of The Study: The present study was designed to probe the synergistic protection and involved mechanisms of berberine, magnoflorine and berbamine from Berberis dictyophylla F. on the spontaneous retinal damage of db/db mice.

Materials And Methods: The 14-week spontaneous model of DR in db/db mice were randomly divided into eight groups: model group, calcium dobesilate (CaDob, 0.23 g/kg) group and groups 1-6 (different proportional three active ingredients from Berberis dictyophylla F.). All mice were intragastrically administrated for a continuous 12 weeks. Body weight and fasting blood glucose (FBG) were recorded and measured. Hematoxylin-eosin and periodic acid-Schiff (PAS) stainings were employed to evaluate the pathological changes and abnormal angiogenesis of the retina. ELISA was performed to assess the levels of IL-6, HIF-1α and VEGF in the serum. Immunofluorescent staining was applied to detect the protein levels of CD31, VEGF, p-p38, p-JNK, p-ERK and NF-κB in retina. In addition, mRNA expression levels of VEGF, Bax and Bcl-2 in the retina were monitored by qRT-PCR analysis.

Results: Treatment with different proportional three active ingredients exerted no significant effect on the weight, but decreased the FBG, increased the number of retinal ganglionic cells and restored internal limiting membrane. The results of PAS staining demonstrated that the drug treatment decreased the ratio of endothelial cells to pericytes while thinned the basal membrane of retinal vessels. Moreover, these different proportional active ingredients can markedly downregulate the protein levels of retinal CD31 and VEGF, and serum HIF-1α and VEGF. The gene expression of retinal VEGF was also suppressed. The levels of retinal p-p38, p-JNK and p-ERK proteins were decreased by drug treatment. Finally, drug treatment reversed the proinflammatory factors of retinal NF-κB and serum IL-6, and proapoptotic Bax gene expression, while increased antiapoptotic Bcl-2 gene expression.

Conclusions: These results indicated that DR in db/db mice can be ameliorated by treatment with different proportional three active ingredients from Berberis dictyophylla F. The potential vascular protection mechanisms may be involved in inhibiting the phosphorylation of the MAPK signaling pathway, thus decreasing inflammatory and apoptotic events.
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http://dx.doi.org/10.1016/j.jep.2021.114190DOI Listing
August 2021

The Role of non-coding RNAs in colorectal cancer, with a focus on its autophagy.

Pharmacol Ther 2021 Apr 23;226:107868. Epub 2021 Apr 23.

State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China. Electronic address:

Colorectal cancer (CRC) is one of malignant afflictions burdening people worldwide, mainly caused by shortages of effective medical intervention and poorly mechanistic understanding of the pathogenesis of CRC. Non-coding RNAs (ncRNAs) are a type of heterogeneous transcripts without the capability of coding protein, but have the potency of regulating protein-coding gene expression. Autophagy is an evolutionarily conserved catabolic process in which cytoplasmic contents are delivered to cellular lysosomes for degradation, resulting in the turnover of cellular components and producing energy for cell functions. A growing body of evidence reveals that ncRNAs, autophagy, and the crosstalks of ncRNAs and autophagy play intricate roles in the initiation, progression, metastasis, recurrence and therapeutic resistance of CRC, which confer ncRNAs and autophagy to serve as clinical biomarkers and therapeutic targets for CRC. In this review, we sought to delineate the complicated roles of ncRNAs, mainly including miRNAs, lncRNAs and circRNAs, in the pathogenesis of CRC, particularly focus on the regulatory role of ncRNAs in CRC-related autophagy, attempting to shed light on the complex pathological mechanisms, involving ncRNAs and autophagy, responsible for CRC tumorigenesis and development, so as to underpin the ncRNAs- and autophagy-based therapeutic strategies for CRC in clinical setting.
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http://dx.doi.org/10.1016/j.pharmthera.2021.107868DOI Listing
April 2021

Colorectal Cancer, Gut Microbiota and Traditional Chinese Medicine: A Systematic Review.

Am J Chin Med 2021 6;49(4):805-828. Epub 2021 Apr 6.

State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.

Based on the study and research on the pathogenesis of colorectal cancer, the types and functions of gut microbiota, and its role in guiding and regulating the occurrence and development of diseases, we have explored the mechanism of traditional Chinese medicine in the treatment of colorectal cancer by regulating the gut microbiota. Genetic variation, abnormal responses of innate and adaptive immunity, mucosal barrier dysfunction, imbalance of intestinal microbial colonization, personal and environmental risk factors are the main pathogenesis of colorectal cancer. The gut microbiota mainly includes (including , , and ) and (including and ), which have biological antagonism, nutrition for the organism, metabolic abilities, immune stimulation, and ability to shape cancer genes functions to body. The gut microbiota can be related to the health of the host. Current studies have shown that Chinese herbal compound, single medicinal materials, and monomer components can treat colorectal cancer by regulating the gut microbiota, such as Xiaoyaosan can increase the abundance of , , and and decrease the abundance of and . Therefore, studying the regulation and mechanism of gut microbiota on colorectal cancer is of great benefit to disease treatment.
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http://dx.doi.org/10.1142/S0192415X21500385DOI Listing
April 2021

Assessment of the anti-inflammatory effects of three rhubarb anthraquinones in LPS-Stimulated RAW264.7 macrophages using a pharmacodynamic model and evaluation of the structure-activity relationships.

J Ethnopharmacol 2021 Jun 17;273:114027. Epub 2021 Mar 17.

Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, China. Electronic address:

Ethnopharmacological Relevance: Rhubarb (Rhei Radix et Rhizoma) is a traditional Chinese medicine, has been used as a strong astringent in China to treat inflammation-related diseases, such as acute pancreatitis, acute cholecystitis, appendicitis and so on. Rhein, emodin and aloe-emodin are the important active anthraquinone in rhubarb, and are considered to be the main ingredients contributing to anti-inflammatory.

Aim Of The Study: Rhein, emodin and aloe-emodin, anthraquinones with the same parent structure that are found in rhubarb, have beneficial anti-inflammatory effects in vitro and in vivo. Anthraquinone derivatives also have important clinical roles. However, their pharmacodynamic differences and the structure-activity relationships associated with their anti-inflammatory properties have not been systematically explored. The present study was designed to quantify the effects of three rhubarb anthraquinones on inflammation and to explore the structure-activity relationships of these compounds.

Materials And Methods: In this study, we detected NF-κB phosphorylation, iNOS protein expression, and IL-6 and NO production in LPS-stimulated RAW264.7 cells and then calculated median effect equations and built a dynamic pharmacodynamic model to quantitatively evaluate the efficacy of these three anthraquinones. Additionally, to determine the structure-activity relationships, we investigated the physicochemical properties and molecular electrostatic potentials of the drug molecules.

Results: We found that rhein, emodin, and aloe-emodin exerted at least dual-target (NF-κB, iNOS) inhibition of LPS-induced inflammatory responses. Compared with rhein and emodin, aloe-emodin had a stronger anti-inflammatory effect, and its inhibition of iNOS protein expression was approximately twice that of NF-κB phosphorylation. In addition, aloe-emodin had the strongest hydrophobic effect among the three anthraquinones.

Conclusions: Overall, we concluded that the receptor binding the rhubarb anthraquinones had a hydrophobic pocket. Anthraquinone molecules with stronger hydrophobic effects had higher affinity for the receptor, resulting in greater anti-inflammatory activity. These results suggest that the addition of a hydrophobic group is a potential method for structural modification to design anti-inflammatory anthraquinone derivatives with enhanced potency.
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http://dx.doi.org/10.1016/j.jep.2021.114027DOI Listing
June 2021

Tibetan medicine Ershiwuwei Lvxue Pill attenuates collagen-induced arthritis via inhibition of JAK2/STAT3 signaling pathway.

J Ethnopharmacol 2021 Apr 16;270:113820. Epub 2021 Jan 16.

Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. Electronic address:

Ethnopharmacological Relevance: Ershiwuwei Lvxue Pill (ELP, མགྲིན་མཚལ་ཉེར་ལྔ།), a traditional Tibetan medicine preparation, has been used hundreds of years for the clinical treatment of rheumatoid arthritis (RA) in the highland region of Tibet, China. However, the underlying mechanism of its therapeutic effect remains unclear.

Aim Of The Study: The present study aimed to investigate the potential pharmacological mechanisms of anti-arthritic effect of ELP.

Materials And Methods: The main chemical constituents of ELP were analyzed by ultra-performance liquid chromatography quadrupole-time-flight mass spectrometry (UPLC-Q-TOF-MS). Forty-eight male Wistar rats (220 ± 20 g) were randomly divided into six groups: normal group, collagen-induced arthritis (CIA) group, methotrexate group (1.05 mg/kg), ELP groups (115, 230 and 460 mg/kg). CIA rat models were assigned to evaluate the anti-RA activity of ELP by determining the paws swelling, arthritis score, organ coefficients of spleen and thymus, and histopathological analysis of knee joints of synovial tissues. The levels of TNF-α, IL-10, IL-6 and IL-17 in serum were measured by ELISA. In addition, mRNA and protein expression levels associated with JAK2/STAT3 signaling pathway in synovial tissues of CIA rats were detected by qRT-PCR, immunohistochemistry and Western blot analyses.

Results: Fourteen main chemical constituents of ELP were quantitatively determined by UPLC-Q-TOF-MS analysis. Treatment with ELP reduced the paw swelling, arthritis score and organ coefficients of spleen and thymus. Histopathological examination revealed the protective effects of ELP on CIA rats with knee joint injury. The levels of serum pro-inflammatory cytokines (TNF-α, IL-6 and IL-17) were markedly reduced while the anti-inflammatory cytokine IL-10 was significantly increased with the treatment of ELP. Further investigations showed ELP down-regulated the mRNA and protein expression levels of Bcl-2, whereas up-regulated Bax, SOCS1 and SOCS3. Meanwhile, the ratios of p-JAK2/JAK2 and p-STAT3/STAT3 proteins from synovial tissues were dramatically decreased with the treatment of ELP, whereas no changes of the mRNA and protein expression levels of JAK2 and STAT3 were observed.

Conclusion: These results indicated that ELP reduced the severity of arthritis and joint swelling, suggesting an antirheumatic effect on CIA rats. The possible mechanism is related to inhibiting inflammatory response and inducing apoptosis in synovial tissues by regulating JAK2/STAT3 signaling pathway. However, further in vivo and in vitro investigations are still needed to clarify the underlying mechanism of ELP in treating RA.
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http://dx.doi.org/10.1016/j.jep.2021.113820DOI Listing
April 2021

Pyroptosis by caspase-11 inflammasome-Gasdermin D pathway in autoimmune diseases.

Pharmacol Res 2021 Mar 4;165:105408. Epub 2021 Jan 4.

Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611130, PR China. Electronic address:

Inflammasomes are a group of supramolecular complexes primarily comprise a sensor, adaptor protein and an effector. Among them, canonical inflammasomes are assembled by one specific pattern recognition receptor, the adaptor protein apoptosis-associated speck-like protein containing a CARD and procaspase-1. Murine caspase-11 and its human ortholog caspase-4/5 are identified as cytosolic sensors which directly responds to LPS. Once gaining access to cytosol, LPS further trigger inflammasome activation in noncanonical way. Downstream pore-forming Gasdermin D is a pyroptosis executioner. Emerging evidence announced in recent years demonstrate the vital role played by caspase-11 non-canonical inflammasome in a range of autoimmune diseases. Pharmacological ablation of caspase-11 and its related effector results in potent therapeutic effects. Though recent advances have highlighted the potential of caspase-11 as a drug target, the understanding of caspase-11 molecular activation and regulation mechanism remains to be limited and thus hampered the discovery and progression of novel inhibitors. Here in this timeline review, we explored how caspase-11 get involved in the pathogenesis of autoimmune diseases, we also collected the reported small-molecular caspase-11 inhibitors. Moreover, the clinical implications and therapeutic potential of caspase-11 inhibitors are discussed. Targeting non-canonical inflammasomes is a promising strategy for autoimmune diseases treatment, while information about the toxicity and physiological disposition of the promising caspase-11 inhibitors need to be supplemented before they can be translated from bench to bedside.
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http://dx.doi.org/10.1016/j.phrs.2020.105408DOI Listing
March 2021

Upconversion NIR-II fluorophores for mitochondria-targeted cancer imaging and photothermal therapy.

Nat Commun 2020 12 3;11(1):6183. Epub 2020 Dec 3.

State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE), Hubei Provincial Key Laboratory of Developmentally Originated Disease, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China.

NIR-II fluorophores have shown great promise for biomedical applications with superior in vivo optical properties. To date, few small-molecule NIR-II fluorophores have been discovered with donor-acceptor-donor (D-A-D) or symmetrical structures, and upconversion-mitochondria-targeted NIR-II dyes have not been reported. Herein, we report development of D-A type thiopyrylium-based NIR-II fluorophores with frequency upconversion luminescence (FUCL) at ~580 nm upon excitation at ~850 nm. H4-PEG-PT can not only quickly and effectively image mitochondria in live or fixed osteosarcoma cells with subcellular resolution at 1 nM, but also efficiently convert optical energy into heat, achieving mitochondria-targeted photothermal cancer therapy without ROS effects. H4-PEG-PT has been further evaluated in vivo and exhibited strong tumor uptake, specific NIR-II signals with high spatial and temporal resolution, and remarkable NIR-II image-guided photothermal therapy. This report presents the first D-A type thiopyrylium NIR-II theranostics for synchronous upconversion-mitochondria-targeted cell imaging, in vivo NIR-II osteosarcoma imaging and excellent photothermal efficiency.
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http://dx.doi.org/10.1038/s41467-020-19945-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713230PMC
December 2020

Tibetan medicine Duoxuekang ameliorates hypobaric hypoxia-induced brain injury in mice by restoration of cerebrovascular function.

J Ethnopharmacol 2021 Apr 25;270:113629. Epub 2020 Nov 25.

School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; NMPA Key Laboratory for Quality Evaluation of Traditional Chinese Medicine (Traditional Chinese Patent Medicine), Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. Electronic address:

Ethnopharmacological Relevance: Duoxuekang (DXK, ཁྲག་འཕེལ་བདེ་བྱེད།) is a clinical experience prescription of CuoRu-Cailang, a famous Tibetan medicine master, which has effective advantages in the treatment of hypobaric hypoxia (HH)-induced brain injury. However, its underlying mechanisms remain unclear.

Aim Of The Study: The present study was designed to investigate the effects of DXK on cerebrovascular function of HH-induced brain injury in mice.

Materials And Methods: DSC-MR imaging was used to evaluate the effect of DXK on the brain blood perfusion of patients with hypoxic brain injury. HPLC analysis was used to detect the content of salidroside, gallic acid, tyrosol, corilagin, ellagic acid, isorhamnetin, quercetin and gingerol in DXK. The model of HH-induced brain injury in mice was established by an animal hypobaric and hypoxic chamber. The BABL/c mice were randomly divided into six groups: control group, model group, Hongjingtian oral liquid group (HOL, 3.3 ml/kg) and DXK groups (0.9, 1.8 and 3.6 g/kg). All mice (except the control group) were intragastrically administrated for a continuous 7 days and put into the animal hypobaric and hypoxic chamber after the last intragastric administration. Hematoxylin-eosin staining was employed to evaluate the pathological changes of brain tissue. Masson and Weigert stainings were used to detect the content of collagen fibers and elastic fibers of brain, respectively. Routine blood test and biochemical kits were used to analyze hematological parameters and oxidative stress indices. Immunofluorescence staining was applied to detect the protein levels of VEGF, CD31/vWF and α-SMA.

Results: The results of DSC-MR imaging confirmed that DXK can increased CBV in the left temporal lobe while decreased MTT in the right frontal lobe, right temporal lobe and right occipital lobe of the brain. DXK contains salidroside, gallic acid, tyrosol, corilagin, ellagic acid, isorhamnetin, quercetin and gingerol. Compared with the model group, DXK can ameliorate the atrophy and deformation, and increase the number of pyramidal neurons in hippocampal CA3 area and cortical neurocytes. Masson and Weigert stainings results revealed that DXK can significantly increase the content of collagen fibers and elastic fibers in brain. Routine blood test results demonstrated that DXK can dramatically decrease the levels of WBC, MCH and MCHC, while increase RBC, HGB, HCT, MCV and PLT in the blood samples. Biochemical results revealed that DXK can markedly increase SOD, CAT and GSH activities, while decrease MDA activity. Immunofluorescence revealed that DXK can notably increase the protein levels of VEGF, CD31/vWF and α-SMA.

Conclusions: In conclusion, this study proved that DXK can ameliorate HH-induced brain injury by improving brain blood perfusion, increasing the number of collagen and elastic fibers and inhibiting oxidative stress injury. The underlying mechanisms may be involved in maintaining the integrity of cerebrovascular endothelial cells and vascular function. However, further in vivo and in vitro investigations are still needed to elucidate the mechanisms of DXK on regulating cerebral blood vessels.
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http://dx.doi.org/10.1016/j.jep.2020.113629DOI Listing
April 2021

Ethyl acetate extract of Tibetan medicine Rhamnella gilgitica ameliorated type II collagen-induced arthritis in rats via regulating JAK-STAT signaling pathway.

J Ethnopharmacol 2021 Mar 24;267:113514. Epub 2020 Oct 24.

Ethnic Medicine Academic Heritage Innovation Research Center,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China. Electronic address:

Ethnopharmacological Relevance: Rhamnella gilgitica Mansf. et Melch. (སེང་ལྡེང་།, RG) is a traditional Tibetan medicinal plant that is currently grown throughout Tibet. According to the theory of Tibetan medicine, RG is efficient for removing rheumatism, reducing swelling, and relieving pain. Hence, it has been used for the treatment of rheumatoid arthritis (RA) in Tibet for many years. However, there are no previous reports on the anti-RA activities of ethyl acetate extract of RG (RGEA).

Aim Of The Study: This study aimed to explore the anti-RA effect and mechanism of RGEA on collagen-induced arthritis (CIA) in rats.

Materials And Methods: The CIA model was established in male Wister rats by intradermal injection of bovine type II collagen and Complete Freund's Adjuvant at the base of the tail and left sole, respectively. The rats were orally administered with RGEA (9.71, 19.43, or 38.85 mg/kg) for 23 days. The body weight, swelling volume, arthritis index score, thymus and spleen indices, and pathological changes were observed to evaluate the effect of RGEA on RA. Furthermore, the inflammatory cytokines in serum, such as interleukin1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), interleukin6 (IL-6), interleukin17 (IL-17), interferon-γ (INF-γ), interleukin4 (IL-4), and interleukin10 (IL-10) were measured by enzyme linked immunosorbent assay (ELISA) to explore the anti-inflammatory effects of RGEA. The terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining was used to examine apoptosis. Finally, the protein and gene expression of B-cell lymphoma-2-associated X (Bax), B-cell lymphoma 2 (Bcl-2), Caspase3, janus-activated kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signaling1 (SOCS1), and 3 (SOCS3) in synovial tissue were detected using immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR).

Results: After the treatment with RGEA, the body weight of rats was restored, both the arthritis index and paw swelling were suppressed, and spleen and thymus indices were decreased. RGEA reduced the inflammatory cells and synovial hyperplasia in the synovial tissue of the knee joint, and suppressed bone erosion. Meanwhile, RGEA decreased the levels of IL-1β, IL-6, IL-17, TNF-α, and INF-γ, while increased the levels of IL-4 and IL-10. TUNEL fluorescence apoptosis results confirmed that RGEA obviously promoted the apoptosis of synovial cells. Further studies showed that RGEA inhibited the proteins and mRNAs expression of JAK2 and STAT3 as well as increased the proteins and mRNAs expression of SOCS1 and SOCS3. In addition, RGEA upregulated the expression of Bax and Caspase3, and downregulated the expression of Bcl-2.

Conclusion: The anti-RA effectof RGEA might be related to the promotion of apoptosis and inhibition of inflammation, which regulated the JAK-STAT pathway.
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http://dx.doi.org/10.1016/j.jep.2020.113514DOI Listing
March 2021

Gallic acid: Pharmacological activities and molecular mechanisms involved in inflammation-related diseases.

Biomed Pharmacother 2021 Jan 16;133:110985. Epub 2020 Nov 16.

Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. Electronic address:

Gallic acid (GA), also known as 3,4,5-trihydroxybenzoic acid, is a natural secondary metabolite and widely isolated from various fruits, plants and nuts. In recent years, GA has received increasing attention for its powerful anti-inflammatory properties. The purpose of this review is to clearly illuminate the pharmacological activities and related molecular mechanisms of GA in inflammatory diseases. After consulting a large number of literatures, we made a comprehensive exposition on the chemical characteristics, plant origins, pharmacokinetics and toxicity of GA, especially its pharmacological activities and mechanisms of action. Although the plant source of GA is very rich, its lower extraction rate limits the application of GA in development. It is worth mentioning that GA can not only be separated from many plants, but also be produced in large quantities through biological and chemical synthesis. According to pharmacokinetic studies, the absorption and elimination of GA after oral administration are fast, while the structural optimization or dosage form adjustment of GA is beneficial to increase its bioavailability. Promisingly, toxicity studies have shown that GA scarcely has obvious toxicity or side effects in a variety of animal experiments and clinical trials. The results show that the anti-inflammatory mechanisms of GA mainly involved MAPK and NF-κB signaling pathways. It thus weakens the inflammatory response by reducing the release of inflammatory cytokines, chemokines, adhesion molecule and cell infiltration. Due to its excellent pharmacological activities, GA is expected to be a potential candidate for the treatment of various inflammation-related diseases. This paper will provide theoretical basis for the clinical application of GA and guide the future research and medicinal development of GA.
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http://dx.doi.org/10.1016/j.biopha.2020.110985DOI Listing
January 2021

A review of traditional Chinese medicine on treatment of diabetic retinopathy and involved mechanisms.

Biomed Pharmacother 2020 Dec 13;132:110852. Epub 2020 Oct 13.

Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. Electronic address:

As a common ocular complication and microangiopathy of type 2 diabetic mellitus, diabetic retinopathy (DR) can lead to vision loss or even blindness in diabetic patients. At present, the treatment methods of DR mainly include laser and anti-VEGF therapies. Nevertheless, the higher cost and obvious side effects seriously disturb the normal life of DR patients. Promisingly, traditional Chinese medicine (TCM) has been demonstrated to be effective in treating DR by tonifying Qi and nourishing Yin, as well clearing heat and breeding body fluids, thus activating blood and removing blood stasis. Therefore, we screened the literatures on TCM treatment of DR through the web of science, ScienceDirect, PubMed, Google scholar and CNKI online databases. The representative prescriptions, herbs and extracts, and identified compounds for treatment of DR were further summarized and analyzed. Moreover, the detailed mechanisms and involved network pathways of herbs-compounds-targets were visualized by Cytoscape software. Meanwhile, we discussed the existing limitations and deficiencies of TCM on treatment of DR and gave corresponding measures. In conclusion, TCM could significantly ameliorate DR via anti-inflammation, anti-oxidative stress, anti-angiogenesis and anti-apoptosis.
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http://dx.doi.org/10.1016/j.biopha.2020.110852DOI Listing
December 2020

Potential applications of microfluidics based blood brain barrier (BBB)-on-chips for in vitro drug development.

Biomed Pharmacother 2020 Dec 12;132:110822. Epub 2020 Oct 12.

Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China. Electronic address:

The human blood-brain barrier (BBB) is a complex multi-dimensional reticular barrier system composed of cerebral microvascular endothelial cells, pericytes, astrocytes and a variety of neurons. The conventional in vitro cell culture model fails to truly present the dynamic hemodynamics of BBB and the interaction between neurons. And it is even more impossible to explore brain-related multi-organ diseases, which brings huge obstacles to explore diseases of the central nervous system and the interaction between brain-related multi-organs, and evaluate drug efficacy. Miniaturized microfluidics based BBB chips are being commonly used to co-culture a variety of cells on a small-sized chip to construct a three-dimensional (3D) BBB or BBB-related organ disease models. By combining with other electrophysiological, biochemical sensors or equipment and imaging systems, it can in real time and quickly screen disease-related markers and evaluate drug efficacy. This review systematically summarized the research progress of in vitro BBB and BBB-related organ chips, and analyzed the obstacles of BBB models in depth. Parallelly combined with the current research trends and hot spots, we give the further improvement measures of microfluidic BBB chips.
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http://dx.doi.org/10.1016/j.biopha.2020.110822DOI Listing
December 2020

Traditional Chinese medicine may be further explored as candidate drugs for pancreatic cancer: A review.

Phytother Res 2021 Feb 23;35(2):603-628. Epub 2020 Sep 23.

Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.

Pancreatic cancer is a disease with a high mortality rate. Although survival rates for different types of cancers have improved in recent years, the five-year survival rate of pancreatic cancer stands at 8%. Moreover, the current first-line therapy, gemcitabine, results in low remission rates and is associated with drug resistance problems. Alternative treatments for pancreatic cancer such as surgery, chemotherapy and radiation therapy provide marginal remission and survival rates. This calls for the search of more effective drugs or treatments. Traditional Chinese medicine contains numerous bioactive ingredients some of which show activity against pancreatic cancer. In this review, we summarize the mechanisms of five types of traditional Chinese medicine monomers. In so-doing, we provide new potential drug candidates for the treatment of pancreatic cancer.
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http://dx.doi.org/10.1002/ptr.6847DOI Listing
February 2021

ameliorates exhaustive exercise-induced fatigue in mice by suppressing mitophagy in skeletal muscle.

Exp Ther Med 2020 Oct 29;20(4):3161-3173. Epub 2020 Jul 29.

Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, P.R. China.

The aim of present study was to evaluate the potential effects of oral liquid (RCOL) on exhaustive exercise (EE)-induced fatigue in mice. Male Institute of Cancer Research mice from five treatment groups (n=10 per group) were orally administered with sterilized water for the Control and EE groups and/or RCOL at doses of 1.02, 3.03 and 6.06 ml/kg/day, once daily for 2 weeks. Anti-fatigue activity was subsequently evaluated by measuring the levels of creatine kinase (CK), lactic acid (LA), lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and total anti-oxidative capability (T-AOC). Histopathology was assessed using hematoxylin and eosin staining. Ultrastructures of mitochondria were observed by transmission electron microscopy. Energy supply capacity was assessed using citrate synthase (CS), succinate dehydrogenase (SDH), Na-K-ATPase, and liver and quadriceps glycogen content assays. Expression levels of mRNA and protein associated with mitophagy in the skeletal muscle were measured by reverse transcription-quantitative PCR and western blotting, respectively. RCOL was observed to markedly inhibit fatigue-induced oxidative stress by increasing the activities of SOD, CAT and T-AOC, whilst reducing the accumulation of LA, CK, LDH and MDA. Histological analysis of the quadriceps femoris tissue suggested increased numbers of muscle fibers in the RCOL groups compared with those in the EE group. RCOL administration was found to reverse EE-induced mitochondrial structural damage and alleviated defects inflicted onto the energy supply mechanism by increasing CS, SDH, Na-K-ATPase and glycogen levels. Additionally, RCOL reduced the protein expression of PTEN-induced kinase 1 (PINK1), Parkin, microtubule-associated proteins 1A/1B light chain 3, sequestosome 1 and ubiquitin, whilst lowering the gene expression of PINK1 and Parkin. Taken together, results from the present study clarified the anti-fatigue effect of RCOL, where the underlying mechanism may be associated with increased antioxidant activity, enhanced energy production and the inhibition of mitophagy by suppressing the PINK1/Parkin signaling pathway.
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http://dx.doi.org/10.3892/etm.2020.9072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444336PMC
October 2020

Andrographolide promotes skeletal muscle regeneration after acute injury through epigenetic modulation.

Eur J Pharmacol 2020 Dec 18;888:173470. Epub 2020 Aug 18.

Chengdu University of Traditional Chinese Medicine, College of Basic Medicine, Chengdu, China. Electronic address:

Myopathy is a muscle disease in which muscle fibers do not function properly, and eventually cause severe diseases, such as muscular dystrophy. The properly regeneration of skeletal muscle plays a pivotal role to maintain the muscle function after muscle injury. The aim of this study is to determine whether andrographolide plays an effect role on regulating skeletal muscle regeneration. Mouse satellite cells, C2C12 cells and Cardiotoxin (CTX) intramuscular injection induced acute skeletal muscle injury model were used to evaluate whether andrographolide is essential for skeletal muscle regeneration. The underling mechanism detected using immunohistochemistry stain, western blot, real time PCR. Andrographolide promotes mouse skeletal muscle regeneration. In cardiotoxin induced skeletal muscle injury model, andrographolide treatment enhanced myotube generation and promoted myotube fusion. Andrographolide treatment dramatically increased expression of myotube differentiation related genes, including Desmin, MyoD, MyoG, Myomaker, Tnni2, Dmd, Myoz1 and Myoz3. For the mechanism studies, we observed that andrographolide treatment significantly promoted histone modification, such as H3K4Me2, H3K4Me3 and H3K36Me2, both in vivo and in vitro. Treatment with DZNep, a Lysine methyltransferase EZH2 inhibitor, significantly attenuated andrographolide-induced expression of Myf5, Myomaker, Skeletal muscle α-actin, MyoD and MyoG. Taken together, our data in this study demonstrate andrographolide epigenetically drives differentiation and fusion of myotube, eventually promotes skeletal muscle regeneration. This should be a therapeutic treatment for skeletal muscle regeneration after muscle damage.
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http://dx.doi.org/10.1016/j.ejphar.2020.173470DOI Listing
December 2020

Targeting foam cell formation and macrophage polarization in atherosclerosis: The Therapeutic potential of rhubarb.

Biomed Pharmacother 2020 Sep 28;129:110433. Epub 2020 Jun 28.

Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, PR China. Electronic address:

Atherosclerosis, a chronic inflammatory disease associated with high morbidity and mortality, is characterized by the accumulation of foam cells in the arterial wall. It has long been acknowledged that the formation of foam cells is caused by excess lipid uptake and abnormal cholesterol metabolism function. And increasing evidence shows that inhibiting foam cell formation is a promising way to suppress the development of atherosclerotic lesions. In addition to excess foam cells accumulation, inflammation is another major contributor of atherosclerotic lesions. Recently, macrophage polarization has been demonstrated to play a vital role in the regulation of inflammatory response. Generally, macrophages mainly polarized into two phenotypes: either classically activated pro-inflammatory M1 or alternatively activated anti-inflammatory M2. And targeting macrophage polarization has been considered as a feasible approach to prevent the development of atherosclerosis. At present, the anti-atherosclerosis drugs mainly classified into two types: lipid-lowering drugs and anti-inflammatory drugs. A large part of those drugs belong to western medicine, and various side effects are unavoidable. Interestingly, in recent years, Traditional Chinese medicine has attracted growing attention because of its good efficacy and low negative effects. Rhubarb (called Da Huang in Chinese) is a famous folk medicine with a wide spectrum of pharmacological effects, such as lipid-lowering and anti-inflammatory effects. In this review, we summarized current findings about the regulatory effects of Rhubarb on foam cell formation and macrophage polarization, with emphasis on the molecular mechanisms of action that have been revealed during the past two decades, to better understand its pivotal role in the treatment and prevention of atherosclerosis.
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http://dx.doi.org/10.1016/j.biopha.2020.110433DOI Listing
September 2020

Salidroside as a potential neuroprotective agent for ischemic stroke: a review of sources, pharmacokinetics, mechanism and safety.

Biomed Pharmacother 2020 Sep 27;129:110458. Epub 2020 Jun 27.

Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China. Electronic address:

Salidroside (Sal) is a bioactive extract principally from traditional herbal medicine such as Rhodiola rosea L., which has been commonly used for hundreds of years in Asia countries. The excellent neuroprotective capacity of Sal has been illuminated in recent studies. This work focused on the source, pharmacokinetics, safety and anti-ischemic stroke (IS) effect of Sal, especially emphasizing its mechanism of action and BBB permeability. Extensive databases, including Pubmed, Web of science (WOS), Google Scholar and China National Knowledge Infrastructure (CNKI), were applied to obtain relevant online literatures. Sal exerts powerful therapeutic effects on IS in experimental models either in vitro or in vivo due to its neuroprotection, with significantly diminishing infarct size, preventing cerebral edema and improving neurological function. Also, the findings suggest the underlying mechanisms involve anti-oxidation, anti-inflammation and anti-apoptosis by regulating multiple signaling pathways and key molecules, such as NF-κB, TNF-α and PI3K/Akt pathway. In pharmacokinetics, although showing a rapid absorption and elimination, bioavailability of Sal is elevated under some non-physiological conditions. The component and its metabolite (tyrosol) are capable of distributing to brain tissue and the later keeps a higher level of concentration. Moreover, Sal scarcely has obvious toxicity or side effects in a variety of animal experiments and clinical trials, but combination of drugs and perinatal use of medicine should be taken more attentions. Finally, as an active ingredient, not only is Sal isolated from diverse plants with limited yield, but also large batches of the products can be harvested by biological and chemical synthesis. With higher efficacy and better safety profiles, Sal could sever as a promising neuroprotectant for preventing and treating IS. Nevertheless, further investigations are still required to explore the pharmacodynamic and pharmacokinetic properties of Sal in the treatment of IS.
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http://dx.doi.org/10.1016/j.biopha.2020.110458DOI Listing
September 2020

Phosphoproteomics and Proteomics Reveal Metabolism as a Key Node in LPS-Induced Acute Inflammation in RAW264.7.

Inflammation 2020 Oct;43(5):1667-1679

College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People's Republic of China.

To better understand the acute inflammatory mechanisms, the modulation, and to investigate the key node in predicting inflammatory diseases, high-sensitivity LC-MS/MS-based proteomics and phosphoproteomics approaches were used to identify differential proteins in RAW264.7 macrophages with lipopolysaccharide (LPS). Furthermore, differential proteins and their main biological process, as well as signaling pathways, were analyzed through bioinformatics techniques. The biological process comparison revealed 219 differential proteins and 405 differential phosphorylation proteins, including major regulatory factors of metabolism (PFKL, PGK1, GYS1, ACC, HSL, LDHA, RAB14, PRKAA1), inflammatory signaling transduction (IKKs, NF-κB, IRAK, IKBkb, PI3K, AKT), and apoptosis (MCL-1, BID, NOXA, SQSTM1). Label-free proteome demonstrated canonical inflammation signaling pathways such as the TNF signaling pathway, NF-κB signaling pathway, and NOD-like receptor signaling pathway. Meanwhile, phosphoproteome revealed new areas of acute inflammation. Phosphoproteomics profiled that glycolysis was enhanced and lipid synthesis was increased. Overall, the AMPK signaling pathway is the key regulatory part in macrophages. These revealed that the early initiation phase of acute inflammation primarily regulated the phosphoproteins of glucose metabolic pathway and lipid synthesis to generate energy and molecules, along with the enhancement of pro-inflammatory factors, and further induced apoptosis. Phosphoproteomics provides new evidence for a complex network of specific but synergistically acting mechanisms confirming that metabolism has a key role in acute inflammation.
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http://dx.doi.org/10.1007/s10753-020-01240-xDOI Listing
October 2020

The multiple organs insult and compensation mechanism in mice exposed to hypobaric hypoxia.

Cell Stress Chaperones 2020 09 19;25(5):779-791. Epub 2020 May 19.

School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.

This study was first and systematically conducted to evaluate the hypoxia response of the brain, heart, lung, liver, and kidney of mice exposed to an animal hypobaric chamber. First, we examined the pathological damage of the above tissues by Hematoxylin & eosin (H&E) staining. Secondly, biochemical assays were used to detect oxidative stress indicators such as superoxide dismutase (SOD), malondialdehyde (MDA), reduced glutathione (GSH), and oxidized glutathione (GSSG). Finally, the hypoxia compensation mechanism of tissues was evaluated by expression levels of hypoxia-inducible factor 1 alpha (HIF-1α), erythropoietin (EPO), and vascular endothelial growth factor (VEGF). During the experiment, the mice lost weight gradually on the first 3 days, and then, the weight loss tended to remain stable, and feed consumption showed the inverse trend. H&E staining results showed that there were sparse and atrophic neurons and dissolved chromatin in the hypoxia group. And hyperemia occurred in the myocardium, lung, liver, and kidney. Meanwhile, hypoxia stimulated the enlargement of myocardial space, the infiltration of inflammatory cells in lung tissue, the swelling of epithelial cells in hepatic lobules and renal tubules, and the separation of basal cells. Moreover, hypoxia markedly inhibited the activity of SOD and GSH and exacerbated the levels of MDA and GSSG in the serum and five organs. In addition, hypoxia induced the expression of HIF-1α, EPO, and VEGF in five organs. These results suggest hypoxia leads to oxidative damage and compensation mechanism of the brain, heart, lung, liver, and kidney in varying degrees of mice.
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http://dx.doi.org/10.1007/s12192-020-01117-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479670PMC
September 2020

Mitochondrial MPTP: A Novel Target of Ethnomedicine for Stroke Treatment by Apoptosis Inhibition.

Front Pharmacol 2020 25;11:352. Epub 2020 Mar 25.

Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China.

Mammalian mitochondrial permeability transition pore (MPTP), across the inner and outer membranes of mitochondria, is a nonspecific channel for signal transduction or material transfer between mitochondrial matrix and cytoplasm such as maintenance of Ca homeostasis, regulation of oxidative stress signals, and protein translocation evoked by some of stimuli. Continuous MPTP opening has been proved to stimulate neuronal apoptosis in ischemic stroke. Meanwhile, inhibition of MPTP overopening-induced apoptosis has shown excellent efficacy in the treatment of ischemic stroke. Among of which, the potential molecular mechanisms of drug therapy for stroke has also been gradually revealed by researchers. The characteristics of multi-components or multi-targets for ethnic drugs also provide the possibility to treat stroke from the perspective of mitochondrial MPTP. The advantages mentioned above make it necessary for us to explore and clarify the new perspective of ethnic medicine in treating stroke and to determine the specific molecular mechanisms through advanced technologies as much as possible. In this review, we attempt to uncover the relationship between abnormal MPTP opening and neuronal apoptosis in ischemic stroke. We further summarized currently authorized drugs, ethnic medicine prescriptions, herbs, and identified monomer compounds for inhibition of MPTP overopening-induced ischemic neuron apoptosis. Finally, we strive to provide a new perspective and enlightenment for ethnic medicine in the prevention and treatment of stroke by inhibition of MPTP overopening-induced neuronal apoptosis.
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http://dx.doi.org/10.3389/fphar.2020.00352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109312PMC
March 2020

Novel small-molecule fluorophores for in vivo NIR-IIa and NIR-IIb imaging.

Chem Commun (Camb) 2020 Mar;56(22):3289-3292

State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE), Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China. and College of Science, Innovation Center for Traditional Tibetan Medicine Modernization and Quality Control, Medical College, Tibet University, Lasa, 850000, China.

Near-infrared fluorescence imaging in the 1000-1700 nm-wavelength window (NIR-II) has exhibited great potential for deep-tissue bioimaging due to its diminished auto-fluorescence, suppressed photo-scattering, deep penetration, and high spatial and temporal resolutions. Various kinds of inorganic nanomaterials have been extensively developed for NIR-IIa (1300-1400 nm) and NIR-IIb (1500-1700 nm) bioimaging. However, the development of small-molecule NIR-IIa and NIR-IIb fluorophores is still in its infancy. Herein, we designed and synthesized a novel NIR-II organic aggregation-induced emission (AIE) fluorophore (HQL2) with a fluorescence tail extending into the NIR-IIa and NIR-IIb region based on our previous reported skeleton Q4. The encapsulated NIR-II AIE nanoparticles (HQL2 dots) exhibited water solubility and biocompatibility, and high brightness for NIR-IIa and NIR-IIb vascular imaging in vivo, a first for NIR-II AIE dots.
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http://dx.doi.org/10.1039/c9cc09865hDOI Listing
March 2020

The Status quo and way forwards on the development of Tibetan medicine and the pharmacological research of tibetan materia Medica.

Pharmacol Res 2020 05 13;155:104688. Epub 2020 Feb 13.

College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.

Tibetan medicine (TM), the second largest traditional Chinese medicine system in China, boasts a long history and an integrated theoretical system. It abounds with classical medical works constituing a unique corpus of Tibetan materia medica (TMM). China has now conceived a modern education system of TM, and Tibetan medical hospitals at different levels have been set up. Many enterprises are granted the privileges to produce preparations of TM in compliance with Good Manufacturing Practices (GMP) regulations. However, there still exist unsolved issuess in TMM research as to the mechanism of action and the active constituents of TMM which are now been tackled through pharmacology and modern science and technology. Up till now, the mechanism of action and the active constituents of 141 medicines as well as 230 preparations of TM have been preliminarily revealed. This paper reviews in detail the development of TM and the status quo of TM's pharmacological research, in hope of serving a reference value for the promotion of the modernization of TM and understanding of TM among the medical scholars.
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http://dx.doi.org/10.1016/j.phrs.2020.104688DOI Listing
May 2020

Molecular Simulation Elaborating the Mechanism of 1β-Hydroxy Alantolactone Inhibiting Ubiquitin-Conjugating Enzyme UbcH5s.

Sci Rep 2020 01 10;10(1):141. Epub 2020 Jan 10.

College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, P.R. China.

1β-hydroxy alantolactone, a sesquiterpene lactone, exhibits potent anti-inflammatory and anticancer activities. Recently, it has been found to target UbcH5s by covalently bonding with Cys85 specifically, but the exact molecular basis remains unclear. Here, we analyzed the structural specificity of the catalytic site of UbcH5s by comparing them with other E2 proteins. Molecular dynamics was performed to detect the structural stability of the catalytic site. Docking method was then used to predict conformations of ligand docked at the catalytic site of UbcH5s. The electrostatic surface and charge distribution of ligand and proteins were analyzed by quantitative calculation. Molecular dynamics was used to detect the stability of docking complexes of 1β-hydroxy alantolactone and UbcH5s, the covalently bonded intermediates and the products. The QM/MM methodology was used to calculate the free energy barrier of hydrogen transfer and formation of covalent bond between 15-position carbon of ligand and Cys85. Results revealed that the structure of the catalytic site is stable, and 1β-hydroxy alantolactone can dock at the catalytic site with correct conformation. Molecular dynamics further demonstrates that 1β-hydroxy alantolactone can steadily combine with UbcH5s. Intermediate and product of catalytic reaction are also certified to be stable. Besides, Asp112 and Asn114 function as anchors to fix ligand, ensuring it steadily docked at catalytic site to complete covalent reaction. More importantly, we have found that Cys85 of UbcH5c is more efficient to form a covalent bond with the ligand in comparison with UbcH5a and UbcH5b. Our results successfully explained the mechanism of 1β-hydroxy alantolactone covalently bonding with UbcH5s. Such molecular mechanism may provide a better insight into the molecular development or modification for ubiquitin-related drugs.
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http://dx.doi.org/10.1038/s41598-019-57104-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954291PMC
January 2020

Tibetan Medical informatics: An emerging field in Sowa Rigpa pharmacological & clinical research.

J Ethnopharmacol 2020 03 17;250:112481. Epub 2019 Dec 17.

Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People's Republic of China. Electronic address:

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http://dx.doi.org/10.1016/j.jep.2019.112481DOI Listing
March 2020

To Elucidate the Inhibition of Excessive Autophagy of Rhodiola crenulata on Exhaustive Exercise-Induced Skeletal Muscle Injury by Combined Network Pharmacology and Molecular Docking.

Biol Pharm Bull 2020 Feb 29;43(2):296-305. Epub 2019 Nov 29.

Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine.

Autophagy can remodel skeletal muscle in response to exercise. However, excessive autophagy can have adverse effects on skeletal muscle. Although Rhodiola crenulata (R. crenulata) is thought to regulate autophagy, its active ingredients and mechanisms of action remain unclear. In this study, molecular docking and network pharmacology were used to screen for autophagy-related targets of R. crenulata. Subsequently, protein-protein interaction (PPI) analysis was used to find the relationships between the inverse docking targets and autophagy-related targets and therefore highlight the key targets. And then the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database was recruited to explain the functions and enrichment pathways of the target proteins. Finally, the potential targets were validated by immunohistochemistry of a mouse model of exhaustive exercise-induced skeletal muscle injury. We found a network of 15 major constituents of R. crenulata with 30 autophagy-related and 105 inverse-docking targets by molecular docking and network pharmacology. The results of PPI analysis indicated that 16 inverse-docking targets interacted 8 autophagy-related proteins. Further pathway analysis showed that R. crenulata could regulate exercise-induced skeletal muscle autophagy through mammalian target of rapamycin (mTOR), AMP activated protein kinase (AMPK) and Forkhead box protein O (FoxO). The results of our animal experiments indicated that R. crenulata could suppress the expression of Ubiquitin-like protein ATG12 (ATG12), Beclin-1 (BECN1), and Serine/threonine-protein kinase ULK1 (ULK1), while increasing the expression of MTOR, NAD-dependent protein deacetylase sirtuin-1 (SIRT1), and Microtubule-associated protein tau (MAPT). In conclusion, this study demonstrated that R. crenulata may protect skeletal muscle injury induced by exhaustive exercise via regulating the mTOR, AMPK, and FoxO singling pathway.
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http://dx.doi.org/10.1248/bpb.b19-00627DOI Listing
February 2020

Longzhibu disease and its therapeutic effects by traditional Tibetan medicine: Ershi-wei Chenxiang pills.

J Ethnopharmacol 2020 Mar 24;249:112426. Epub 2019 Nov 24.

Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. Electronic address:

Ethnopharmacological Relevance: Ershi-wei Chenxiang pills (ECP) or Aga Nixiu wan (ཨ་གར་ཉི་ཤུ།), composed of 20 Tibetan medicines, has the effect of promoting blood circulation to remove blood stasis. As a common and frequent prescription used by traditional Tibetan medicine in clinical treatment of Longzhibu disease (cerebral ischemia sequelae), it has a significant effect. However, its anti-cerebral ischemia mechanism is still unclear.

Materials And Methods: The chemical components of ECP were determined by high-performance liquid chromatography and gas chromatography-mass spectrometry. SD rats were randomly divided into Sham, MCAO, Nim (20.00 mg/kg), and ECP (1.33 and 2.00 g/kg) groups, with 13 animals in each group. After 14 days of oral administration, we established a model of cerebral ischemia reperfusion injury by blocking the middle cerebral artery of rats. After 24 h of reperfusion injury, we evaluated the protective effect of ECP on ischemic brain by neural function score, TTC, H&E and Nissl staining. TUNEL fluorescence, western blot and immunohistochemistry were used to detect the phenomenon of apoptosis and the expression of apoptosis-related proteins Bax, Bcl-2, Cyto-c and activated Caspase-3. Furthermore, western blot, qRT-PCR and immunohistochemistry were employed to detect CaMKⅡ, ATF4 and c-Jun gene and protein expression.

Results: ECP contains agarotetrol, eugenol, oleanolic acid, ursolic acid, dehydrodiisoeugenol, hydroxysafflor yellow A, kaempferide, gallic acid, alantolactone, isoalantolactone, costunolide, dehydrocostus lactone, brucine, strychnine, echinacoside, bilirubin and cholic acid. Compared with MCAO group, ECP can significantly ameliorate the neurological deficit of cerebral ischemia in rats and reduce the volume of cerebral infarction. Pathological and Nissl staining results showed that ECP sharply inhibited the inflammatory infiltration injury of neurons and increased the activity of neurons in comparation with the MCAO group. TUNEL fluorescence apoptosis results confirmed that ECP obviously inhibited the apoptosis of neurons. Meanwhile, the results of immunohistochemistry and western blot demonstrated that EPC can dramatically inhibit the expression of pro-apoptotic proteins Bax, Cyto-c and activated Caspase-3, while increase the level of anti-apoptotic protein Bcl-2. In addition, compared with MCAO group, CaMK Ⅱ gene and protein expression were improved significantly by ECP administration. while, the expression of ATF4 and c-Jun genes and proteins were decreased.

Conclusions: In conclusion, this study preliminarily demonstrated that the protective effect of ECP on ischemic brain is related to the improvement of neurological deficit, reducing the size of cerebral infarction, improving the activity of neurons, inhibiting the mitochondrial apoptosis pathway by regulating the protein expression of CaMKⅡ, ATF4 and c-Jun. However, further in vivo and in vitro investigations are still needed to clarify the underlying mechanism of ECP in treating cerebral ischemia sequelae.
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http://dx.doi.org/10.1016/j.jep.2019.112426DOI Listing
March 2020

Coptisine from Coptis chinensis exerts diverse beneficial properties: A concise review.

J Cell Mol Med 2019 12 17;23(12):7946-7960. Epub 2019 Oct 17.

College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.

Coptisine is a natural small-molecular compound extracted from Coptis chinensis (CC) with a history of using for thousands of years. This work aimed at summarizing coptisine's activity and providing advice for its clinical use. We analysed the online papers in the database of SciFinder, Web of Science, PubMed, Google scholar and CNKI by setting keywords as 'coptisine' in combination of 'each pivotal pathway target'. Based on the existing literatures, we find (a) coptisine exerted potential to be an anti-cancer, anti-inflammatory, CAD ameliorating or anti-bacterial drug through regulating the signalling transduction of pathways such as NF-κB, MAPK, PI3K/Akt, NLRP3 inflammasome, RANKL/RANK and Beclin 1/Sirt1. However, we also (b) observe that the plasma concentration of coptisine demonstrates obvious non-liner relationship with dosage, and even the highest dosage used in animal study actually cannot reach the minimum concentration level used in cell experiments owing to the poor absorption and low availability of coptisine. We conclude (a) further investigations can focus on coptisine's effect on caspase-1-involved inflammasome assembling and pyroptosis activation, as well as autophagy. (b) Under circumstance of promoting coptisine availability by pursuing nano- or microrods strategies or applying salt-forming process to coptisine, can it be introduced to clinical trial.
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http://dx.doi.org/10.1111/jcmm.14725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850926PMC
December 2019