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1.
Article in English | WPRIM | ID: wpr-1011013

ABSTRACT

NAD(P)H: quinone oxidoreductase 1 (NQO1) is a flavin protease highly expressed in various cancer cells. NQO1 catalyzes a futile redox cycle in substrates, leading to substantial reactive oxygen species (ROS) production. This ROS generation results in extensive DNA damage and elevated poly (ADP-ribose) polymerase 1 (PARP1)-mediated consumption of nicotinamide adenine dinucleotide (NAD+), ultimately causing cell death. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage synthesis pathway, emerges as a critical target in cancer therapy. The concurrent inhibition of NQO1 and NAMPT triggers hyperactivation of PARP1 and intensive NAD+ depletion. In this study, we designed, synthesized, and assessed a novel series of proqodine A derivatives targeting both NQO1 and NAMPT. Among these, compound T8 demonstrated potent antitumor properties. Specifically, T8 selectively inhibited the proliferation of MCF-7 cells and induced apoptosis through mechanisms dependent on both NQO1 and NAMPT. This discovery offers a promising new molecular entity for advancing anticancer research.


Subject(s)
Humans , NAD/metabolism , Cell Line, Tumor , Reactive Oxygen Species/metabolism , Nicotinamide Phosphoribosyltransferase/metabolism , Cytokines/metabolism , Quinones , Oxidoreductases
2.
Acta Pharmaceutica Sinica B ; (6): 113-127, 2023.
Article in English | WPRIM | ID: wpr-971696

ABSTRACT

Ischemic preconditioning (IPC) is a potential intervention known to protect the heart against ischemia/reperfusion injury, but its role in the no-reflow phenomenon that follows reperfusion is unclear. Dihydrotanshinone I (DT) is a natural compound and this study illustrates its role in cardiac ischemic injury from the aspect of IPC. Pretreatment with DT induced modest ROS production and protected cardiomyocytes against oxygen and glucose deprivation (OGD), but the protection was prevented by a ROS scavenger. In addition, DT administration protected the heart against isoprenaline challenge. Mechanistically, PKM2 reacted to transient ROS via oxidization at Cys423/Cys424, leading to glutathionylation and nuclear translocation in dimer form. In the nucleus, PKM2 served as a co-factor to promote HIF-1α-dependent gene induction, contributing to adaptive responses. In mice subjected to permanent coronary ligation, cardiac-specific knockdown of Pkm2 blocked DT-mediated preconditioning protection, which was rescued by overexpression of wild-type Pkm2, rather than Cys423/424-mutated Pkm2. In conclusion, PKM2 is sensitive to oxidation, and subsequent glutathionylation promotes its nuclear translocation. Although IPC has been viewed as a protective means against reperfusion injury, our study reveals its potential role in protection of the heart from no-reflow ischemia.

3.
Acta Pharmaceutica Sinica B ; (6): 559-576, 2023.
Article in English | WPRIM | ID: wpr-971732

ABSTRACT

Farnesoid X receptor (FXR) is widely accepted as a promising target for various liver diseases; however, panels of ligands in drug development show limited clinical benefits, without a clear mechanism. Here, we reveal that acetylation initiates and orchestrates FXR nucleocytoplasmic shuttling and then enhances degradation by the cytosolic E3 ligase CHIP under conditions of liver injury, which represents the major culprit that limits the clinical benefits of FXR agonists against liver diseases. Upon inflammatory and apoptotic stimulation, enhanced FXR acetylation at K217, closed to the nuclear location signal, blocks its recognition by importin KPNA3, thereby preventing its nuclear import. Concomitantly, reduced phosphorylation at T442 within the nuclear export signals promotes its recognition by exportin CRM1, and thereby facilitating FXR export to the cytosol. Acetylation governs nucleocytoplasmic shuttling of FXR, resulting in enhanced cytosolic retention of FXR that is amenable to degradation by CHIP. SIRT1 activators reduce FXR acetylation and prevent its cytosolic degradation. More importantly, SIRT1 activators synergize with FXR agonists in combating acute and chronic liver injuries. In conclusion, these findings innovate a promising strategy to develop therapeutics against liver diseases by combining SIRT1 activators and FXR agonists.

4.
Article in Chinese | WPRIM | ID: wpr-1019646

ABSTRACT

Objective To investigate the role and existing dilemmas of policies related to traditional Chinese medicine talents in China in terms of their growth paths and attitudes towards existing policies.Methods A questionnaire survey was conducted to investigate the current situation of the development of traditional Chinese medicine talents and their views on the existing policies.Results 278 valid questionnaires were collected.In general,traditional Chinese medicine talents are quite satisfied with the current talent policy,the interviewees with senior professional titles have a better understanding of the talent policy,and the young members and members of the Chinese society of traditional Chinese medicine have a more positive and urgent attitude towards building a talent policy and evaluation index system with traditional Chinese medicine characteristics.Respondents generally believe that the current financial support for talent projects of traditional Chinese medicine is average,but it can stimulate the growth of young scholars.The title of talents and the achievements of scholars'scientific research complement each other.Conclusion In the process of the development of the field of traditional Chinese medicine,we should speed up the training of innovative talents of traditional Chinese medicine,establish talent evaluation indicators with traditional Chinese medicine characteristics,improve the evaluation and project management system of traditional Chinese medicine talents,and reasonably optimize the incentive mechanism brought by the title of talents.

5.
Article in Chinese | WPRIM | ID: wpr-1003571

ABSTRACT

@#Lysine acylation is a ubiquitous protein modification that controls various aspects of protein function. However, it can be challenging to decipher the biological function of site-specific acylation modifications in living cells.The recently developed genetic code expansion (GCE) technology has enabled site-specific incorporation of unnatural amino acids (UAAs) that are structurally consistent with the natural acylation modifications in vivo through orthogonal aminoacyl-tRNA synthetase/tRNA pairs, thus facilitating the study of physicochemical properties and biological behaviors of homogeneously acylated proteins.Besides, GCE technology allows for the targeted introduction of UAAs that mimic acylation modifications but cannot be recognized by deacylases, which improves the stability of lysine acylation modification products.Moreover, the insertion of photo-crosslinked UAAs at specific sites of the target protein has been used to elucidate the reciprocal proteome of acylated modified proteins.Based on the introduction of different structural and functional acylation modifications, we described the novel design of GCE technology combined with three types of UAAs, and their application in studying the functional effects of protein acylation modifications on the enzyme activity, protein stability, cellular localization, protein-DNA interactions and protein-protein interactions of target proteins, with a description of the limitations and prospects of GCE technology in studying protein acylation modification.

6.
Article in English | WPRIM | ID: wpr-1010987

ABSTRACT

Depression is a mental disorder with high morbidity, disability and relapse rates. Ginkgo biloba extract (GBE), a traditional Chinese medicine, has a long history of clinical application in the treatment of cerebral and mental disorders, but the key mechanism remains incompletely understood. Here we showed that GEB exerted anti-depressant effect in mice through regulating gut microbial metabolism. GBE protected against unpredictable mild stress (UMS)-induced despair, anxiety-like and social avoidance behavior in mice without sufficient brain distribution. Fecal microbiome transplantation transmitted, while antibiotic cocktail abrogated the protective effect of GBE. Spatiotemporal bacterial profiling and metabolomics assay revealed a potential involvement of Parasutterella excrementihominis and the bile acid metabolite ursodeoxycholic acid (UDCA) in the effect of GBE. UDCA administration induced depression-like behavior in mice. Together, these findings suggest that GBE acts on gut microbiome-modulated bile acid metabolism to alleviate stress-induced depression.


Subject(s)
Humans , Mice , Animals , Depression/drug therapy , Gastrointestinal Microbiome , Plant Extracts , Ginkgo biloba
7.
Acta Pharmaceutica Sinica B ; (6): 558-580, 2022.
Article in English | WPRIM | ID: wpr-929314

ABSTRACT

Hepatocellular carcinoma (HCC) is an aggressive human cancer with increasing incidence worldwide. Multiple efforts have been made to explore pharmaceutical therapies to treat HCC, such as targeted tyrosine kinase inhibitors, immune based therapies and combination of chemotherapy. However, limitations exist in current strategies including chemoresistance for instance. Tumor initiation and progression is driven by reprogramming of metabolism, in particular during HCC development. Recently, metabolic associated fatty liver disease (MAFLD), a reappraisal of new nomenclature for non-alcoholic fatty liver disease (NAFLD), indicates growing appreciation of metabolism in the pathogenesis of liver disease, including HCC, thereby suggesting new strategies by targeting abnormal metabolism for HCC treatment. In this review, we introduce directions by highlighting the metabolic targets in glucose, fatty acid, amino acid and glutamine metabolism, which are suitable for HCC pharmaceutical intervention. We also summarize and discuss current pharmaceutical agents and studies targeting deregulated metabolism during HCC treatment. Furthermore, opportunities and challenges in the discovery and development of HCC therapy targeting metabolism are discussed.

8.
Acta Pharmaceutica Sinica B ; (6): 1473-1486, 2022.
Article in English | WPRIM | ID: wpr-929350

ABSTRACT

The development of nanomedicine has recently achieved several breakthroughs in the field of cancer treatment; however, biocompatibility and targeted penetration of these nanomaterials remain as limitations, which lead to serious side effects and significantly narrow the scope of their application. The self-assembly of intermediate filaments with arginine-glycine-aspartate (RGD) peptide (RGD-IFP) was triggered by the hydrophobic cationic molecule 7-amino actinomycin D (7-AAD) to synthesize a bifunctional nanoparticle that could serve as a fluorescent imaging probe to visualize tumor treatment. The designed RGD-IFP peptide possessed the ability to encapsulate 7-AAD molecules through the formation of hydrogen bonds and hydrophobic interactions by a one-step method. This fluorescent nanoprobe with RGD peptide could be targeted for delivery into tumor cells and released in acidic environments such as endosomes/lysosomes, ultimately inducing cytotoxicity by arresting tumor cell cycling with inserted DNA. It is noteworthy that the RGD-IFP/7-AAD nanoprobe tail-vein injection approach demonstrated not only high tumor-targeted imaging potential, but also potent antitumor therapeutic effects in vivo. The proposed strategy may be used in peptide-driven bifunctional nanoparticles for precise imaging and cancer therapy.

9.
Acta Pharmaceutica Sinica B ; (6): 2129-2149, 2022.
Article in English | WPRIM | ID: wpr-929399

ABSTRACT

Cardiometabolic disease (CMD), characterized with metabolic disorder triggered cardiovascular events, is a leading cause of death and disability. Metabolic disorders trigger chronic low-grade inflammation, and actually, a new concept of metaflammation has been proposed to define the state of metabolism connected with immunological adaptations. Amongst the continuously increased list of systemic metabolites in regulation of immune system, bile acids (BAs) represent a distinct class of metabolites implicated in the whole process of CMD development because of its multifaceted roles in shaping systemic immunometabolism. BAs can directly modulate the immune system by either boosting or inhibiting inflammatory responses via diverse mechanisms. Moreover, BAs are key determinants in maintaining the dynamic communication between the host and microbiota. Importantly, BAs via targeting Farnesoid X receptor (FXR) and diverse other nuclear receptors play key roles in regulating metabolic homeostasis of lipids, glucose, and amino acids. Moreover, BAs axis per se is susceptible to inflammatory and metabolic intervention, and thereby BAs axis may constitute a reciprocal regulatory loop in metaflammation. We thus propose that BAs axis represents a core coordinator in integrating systemic immunometabolism implicated in the process of CMD. We provide an updated summary and an intensive discussion about how BAs shape both the innate and adaptive immune system, and how BAs axis function as a core coordinator in integrating metabolic disorder to chronic inflammation in conditions of CMD.

10.
Article in Chinese | WPRIM | ID: wpr-939963

ABSTRACT

@#Proteins in the human body are usually made of 20 natural amino acids.Through different amino acid combinations and isomerization, proteins of diverse functions are built.An emerging genetic code expansion technology can introduce unnatural amino acids into specific sites of target protein, endowing the protein with new biological characteristics including covalently binding with proximal proteins, carrying fluorescence, and mimicking specific protein post-translational modifications.In this paper, based on the structure and function of unnatural amino acids, the applications of different types of unnatural amino acids in regulating protein''s stability, studying protein''s conformation, expression level, and localization, and uncovering heretofore unknown protein-protein interactions were reviewed.Besides, genetic code expansion of unnatural amino acids is anticipated to find broad utilities in biomedicine by bringing new ideas and methods to the design and optimization of biologics.

11.
Article in Chinese | WPRIM | ID: wpr-959232

ABSTRACT

@#After the integration of Yangtze River Delta was elevated and developed into a national strategy, few domestic studies have been conducted to explore the integrated and collaborative development of biopharmaceutical industry in the Yangtze River Delta region, which, as an important region of biopharmaceutical industry in China, has initially formed the development mode of industrial clusters. In this study, based on the industry-university-research model of patent and fund project cooperation, the social network analysis (SNA) method is used to analyze and study the cooperation of patent and Major Projects of National Natural Science Foundation of China in the biopharmaceutical industry in the Yangtze River Delta region. The study shows that the industry-university-research cooperation in the biomedical field in the Yangtze River Delta region is still in the development stage and the degree of integration needs to be improved. Universities and research institutes are more inclined to cooperate with enterprises for invention patents and with other universities for fund project research.It is suggested that the Yangtze River Delta region should adopt the deep integration mode of industry-university-research, relevant leading scientific research institutions should establish open innovation platforms, and pharmaceutical universities should cultivate innovative talents with the advantages of their disciplines, and adopt "Revealing the List and Taking Command" or other ways to tackle key core technologies.

12.
Acta Pharmaceutica Sinica B ; (6): 3553-3566, 2021.
Article in English | WPRIM | ID: wpr-922424

ABSTRACT

Rescuing cells from stress damage emerges a potential therapeutic strategy to combat myocardial infarction. Protocatechuic aldehyde (PCA) is a major phenolic acid in Chinese herb Danshen (

13.
Article in Chinese | WPRIM | ID: wpr-886696

ABSTRACT

@#This paper aims to explore the feasibility of establishing a representative work screening method based on the academic recognition of the paper. Through comparative analysis of the strong and weak points of representative method, h-index core method, the subjective selection results by faculty applying for higher professional titles, and the academic recognition method established in this research (Q1 Journal-Percentile in Subject Area-Category Normalized Citation Impact, Q1-PSA-CNCI), representative works were introduced into the Z-index to form the Zh, Zr and Zq-index, and the correlations between the indicators were analyzed. Compared with other methods, the number of representative works obtained by the Q1-PSA-CNCI method is more reasonable. There was significant correlation among the indicators (P < 0.05), with no significant difference in the Zq-index among faculty evaluated for different professional titles (P > 0.05). Studies have shown that the Q1-PSA-CNCI method could help to screen representative works and was more reasonable than the number of representative works selected based on the other two methods, so Zq-index could be used as an indicator for representative work evaluation to provide reference for the qualitative evaluation of papers. It is more reasonable to improve the review process with the participation of "small peers".

14.
Article in Chinese | WPRIM | ID: wpr-1014990

ABSTRACT

Metabolic regulation is an important mechanism by which organisms adapt to changes in the internal and external environment. Metabolic small molecules function as versatile messengers involved in signaling networks and organ crosstalk, which carries great implications for understanding physiological processes, revealing disease mechanisms and discovering drug targets. In this review, we present an overview of the main progresses in metabolic regulation and drug target discovery researches in China, and look forward to its future direction, which may provide a reference for the drug development endeavor based on metabolic regulation.

15.
Acta Pharmaceutica Sinica B ; (6): 30-54, 2021.
Article in English | WPRIM | ID: wpr-881123

ABSTRACT

The sustained cell proliferation resulting from dysregulation of the cell cycle and activation of cyclin-dependent kinases (CDKs) is a hallmark of cancer. The inhibition of CDKs is a highly promising and attractive strategy for the development of anticancer drugs. In particular, third-generation CDK inhibitors can selectively inhibit CDK4/6 and regulate the cell cycle by suppressing the G1 to S phase transition, exhibiting a perfect balance between anticancer efficacy and general toxicity. To date, three selective CDK4/6 inhibitors have received approval from the U.S. Food and Drug Administration (FDA), and 15 CDK4/6 inhibitors are in clinical trials for the treatment of cancers. In this perspective, we discuss the crucial roles of CDK4/6 in regulating the cell cycle and cancer cells, analyze the rationale for selectively inhibiting CDK4/6 for cancer treatment, review the latest advances in highly selective CDK4/6 inhibitors with different chemical scaffolds, explain the mechanisms associated with CDK4/6 inhibitor resistance and describe solutions to overcome this issue, and briefly introduce proteolysis targeting chimera (PROTAC), a new and revolutionary technique used to degrade CDK4/6.

16.
Article in English | WPRIM | ID: wpr-781553

ABSTRACT

Few medications are available for meeting the increasing disease burden of nonalcoholic fatty liver disease (NAFLD) and its progressive stage, nonalcoholic steatohepatitis (NASH). Traditional herbal medicines (THM) have been used for centuries to treat indigenous people with various symptoms but without clarified modern-defined disease types and mechanisms. In modern times, NAFLD was defined as a common chronic disease leading to more studies to understand NAFLD/NASH pathology and progression. THM have garnered increased attention for providing therapeutic candidates for treating NAFLD. In this review, a new model called "multiple organs-multiple hits" is proposed to explain mechanisms of NASH progression. Against this proposed model, the effects and mechanisms of the frequently-studied THM-yielded single anti-NAFLD drug candidates and multiple herb medicines are reviewed, among which silymarin and berberine are already under U.S. FDA-sanctioned phase 4 clinical studies. Furthermore, experimental designs for anti-NAFLD drug discovery from THM in treating NAFLD are discussed. The opportunities and challenges of reverse pharmacology and reverse pharmacokinetic concepts-guided strategies for THM modernization and its global recognition to treat NAFLD are highlighted. Increasing mechanistic evidence is being generated to support the beneficial role of THM in treating NAFLD and anti-NAFLD drug discovery.

17.
Article in Chinese | WPRIM | ID: wpr-823996

ABSTRACT

Amyloid fibrils are found in systemic amyloidosis diseases such as Alzheimer's disease, Parkinson's disease, and type II diabetes. Currently, these diseases are diagnosed by observation of fibrils or plaques, which is an ineffective method for early diagnosis and treatment of disease. The goal of this study was to develop a simple and quick method to predict the possibility and speed of fibril formation before its occurrence. Oligomers generated from seven representative peptide segments were first isolated and detected by ion-mobility mass spectrometry (IM-MS). Then, their assemblies were disrupted using formic acid (FA). Interestingly, oligomers that showed small ion intensity changes upon FA addition had rapid fibril formation. By contrast, oligomers that had large ion intensity changes generated fibrils slowly. Two control peptides (aggregation/no fibrils and no aggregation/no fibrils) did not show changes in their ion intensities, which confirmed the ability of this method to predict amyloid formation. In summary, the developed method correlated MS intensity ratio changes of peptide oligomers on FA addition with their amyloid propensities. This method will be useful for monitoring peptide/protein aggregation behavior and essential for their mechanism studies.

18.
Acta Pharmaceutica Sinica B ; (6): 526-536, 2019.
Article in English | WPRIM | ID: wpr-774969

ABSTRACT

Obeticholic acid (OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possibly due to the lower dosage to reduce the incidence of the side-effect of pruritus. Here we propose a combinatory therapeutic strategy of OCA and apoptosis inhibitor for combating against liver fibrosis. CCl-injured mice, d-galactosamine/LPS (GalN/LPS)-treated mice and cycloheximide/TNF (CHX/TNF)-treated HepG2 cells were employed to assess the effects of OCA, or together with IDN-6556, an apoptosis inhibitor. OCA treatment significantly inhibited hepatic stellate cell (HSC) activation/proliferation and prevented fibrosis. Elevated bile acid (BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs. OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis. An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556. Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs. The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.

19.
Article in Chinese | WPRIM | ID: wpr-811742

ABSTRACT

@#A qualitative analysis was developed to identify different ingredients from three Ginkgo biloba preparations(including Yinxingye Diwan, extract of Ginkgo biloba leaves tablets and Yinxingtongzhi Diwan)based on high resolution mass spectrometry and metabolomics technology. An XSELECT HSS T3(4. 6 mm×150 mm, 3. 5 μm)column was used for separation, with the mobile phases consisting of acetonitrile and water containing 0. 1% formic acid. The column temperature was set at 40 °C. Negative ion mode was used for mass spectrometric data acquisition. Through partial least squares projection to latent structure-discriminant analysis(PLS-DA), we firstly found the different compounds among different Ginkgo biloba preparations. Subsequently, the compounds displaying different abundance levels via database searching and literature matching were identified. Finally, we identified 21 different compounds between the extract of Ginkgo biloba leaves tablets and Yinxingye Diwan, which mostly belong to the organic acids and flavonols families. Quantitative analysis showed that the ingredients which had higher abundance in extract of Ginkgo biloba leaves tablets were mainly organic acids, whereas those exhibiting higher levels in Yinxingye Diwan are flavonols. We also identified 12 different ingredients between the Yinxingye Diwan and Yinxingtongzhi Diwan, which were flavonols, sciadopitysin and organic acids. The results of this study are useful for studying different chemical constituents from distinct Ginkgo biloba preparations.

20.
Article in Chinese | WPRIM | ID: wpr-491911

ABSTRACT

This study was to investigate the regulation of lipopolysaccharides(LPS)-induced sepsis in mice by preadministration of Shenmai injection (SMI)and the therapeutic differences between male and female.The females and males were randomly grouped by weight,including control group,LPS-induced sepsis model group and SMI administration group.After preadministration of SMI for 14 days,10 mg/kg LPS were intraperitoneally injected subsequently to induce sepsis.The survival rate of mice,level of serum cytokines and the mRNA expres-sion of proinflammatory cytokines in main tissues were detected to evaluate the impact of SMI in LPS-induced sepsis mice.From the survival rate,which is considered as a gold standard of improvement in sepsis,significant protective effect can be observed after SMI pretreatment in LPS-induced sepsis mice,a more significant effect was shown in the females.Consisting with the serum cytokines levels,SMI significantly inhibited proinflammatory cyto-kines including IL-6,IL-1βand TNF-αmRNA expression in tissues and the regulation of IL-6 was most signifi-cant,which was consistent with the results of ELISA in serum.Moreover,the liver tissue acquired a more evident impact than any other tissues,which fits with the ratio of dry/wet weight.SMI can significantly inhibit inflammato-ry response by delivery in advance in LPS-induced septic mice,providing strong evidence for elaborating mecha-nism in the treatment of cardiovascular disease related inflammation and shock.

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