Recent advances in the managements of type 2 diabetes mellitus and natural hypoglycemic substances

Diabetes has become a global concern at present,among which type 2 diabetes mellitus(T2DM)accounts for approximately 90%-95%of patients.T2DM is a type of metabolic disorder syndrome that results from a genetic defect,and it is based on insulin resistance and an insulin secretion disorder.The occurrence of T2DM is usually the outcome of both genetic and environmental factors and their interactions.The etiology and pathogenesis of diabetes have not been fully elucidated,and no radical therapeutic cure has been found.Patients with T2DM suffer from complications such as the development of a chronic hyperglycemic condition and even serious metabolic disorders and organ damage in the body and depression and dementia,in addition to other chronic complications.Many studies have suggested that diet is crucial in the development of diabetes and the control of blood glucose.Natural substances have the characteristics of low toxicity and few side effects and may be key to the development of diabetic health products and preventive treatments.This paper reviews the etiology,pathogenesis,risks,treatments and diets related to T2DM to summarize the types of recently available natural products,from both local and foreign sources,for lowering blood glucose at home and their application in supplementary hypoglycemic foods.The key findings and conclusions suggest that there are various known T2DM-inducing factors,including genetic and environmental factors and three types of hybrid factors.

A robust luminescent assay for screening alkyladenine DNA glycosylase inhibitors to overcome DNA repair and temozolomide drug resistance

Temozolomide(TMZ)is an anticancer agent used to treat glioblastoma,typically following radiation therapy and/or surgical resection.However,despite its effectiveness,at least 50%of patients do not respond to TMZ,which is associated with repair and/or tolerance of TMZ-induced DNA lesions.Studies have demonstrated that alkyladenine DNA glycosylase(AAG),an enzyme that triggers the base excision repair(BER)pathway by excising TMZ-induced N3-methyladenine(3meA)and N7-methylguanine lesions,is overexpressed in glioblastoma tissues compared to normal tissues.Therefore,it is essential to develop a rapid and efficient screening method for AAG inhibitors to overcome TMZ resistance in glioblastomas.Herein,we report a robust time-resolved photoluminescence platform for identifying AAG inhibitors with improved sensitivity compared to conventional steady-state spectroscopic methods.As a proof-of-concept,this assay was used to screen 1440 food and drug administration-approved drugs against AAG,resulting in the repurposing of sunitinib as a potential AAG inhibitor.Sunitinib restored glioblastoma(GBM)cancer cell sensitivity to TMZ,inhibited GBM cell proliferation and stem cell characteristics,and induced GBM cell cycle arrest.Overall,this strategy offers a new method for the rapid identification of small-molecule inhibitors of BER enzyme activities that can prevent false negatives due to a fluorescent background.

Inhibition of the CDK9-cyclin T1 protein-protein interaction as a new approach against triple-negative breast cancer

Cyclin-dependent kinase 9(CDK9) activity is correlated with worse outcomes of triplenegative breast cancer(TNBC) patients. The heterodimer between CDK9 with cyclin T1 is essential for maintaining the active state of the kinase and targeting this protein-protein interaction(PPI) may offer promising avenues for selective CDK9 inhibition. Herein, we designed and generated a library of metal complexes bearing the 7-chloro-2-phenylquinoline CN ligand and tested their activity against the CDK9cyclin T1 PPI. Complex 1 bound to CDK9 via an enthalpically-driven binding mode, leading to disruption of the CDK9-cyclin T1 interaction in vitro and in cellulo. Importantly, complex 1 showed promising anti-metastatic activity against TNBC allografts in mice and was comparably active compared to cisplatin. To our knowledge, 1 is the first CDK9-cyclin T1 PPI inhibitor with anti-metastatic activity against TNBC. Complex 1 could serve as a new platform for the future design of more efficacious kinase inhibitors against cancer, including TNBC.

Aurone derivatives as Vps34 inhibitors that modulate autophagy

We report in this study the identification of a natural product-like antagonist(1a) of Vps34 as a potent autophagy modulator via structure-based virtual screening. Aurone derivative 1a strongly inhibited Vps34 activity in cell-free and cell-based assays. Significantly, 1a prevents autophagy in human cells induced either by starvation or by an mT OR inhibitor. In silico modeling and kinetic data revealed that 1a could function as an ATP-competitive inhibitor of Vps34. Moreover, it suppressed autophagy in vivo and without inducing heart or liver damage in mice. 1a could be utilized as a new motif for more selective and efficacious antagonists of Vps34 for the potential treatment of autophagy-related human diseases.

Discovery of a tetrahydroisoquinoline-based CDK9-cyclin T1 proteineprotein interaction inhibitor as an anti-proliferative and anti-migration agent against triple-negative breast cancer cells

Triple-negative breast cancer(TNBC)is a highly aggressive and metastasizing cancer that has the worst prognosis out of all breast cancer subtypes.The epithelial emesenchymal transition(EMT)and cancer stem cells(CSCs)have been proposed as important mechanisms underlying TNBC metastasis.CDK9 is highly expressed in breast cancer,including TNBC,where it promotes EMT and induces cancer cell stemness.In this study,we have identified a tetrahydroisoquinoline derivative(compound 1)as a potent and selective CDK9-cyclin T1 inhibitor via virtual screening.Interestingly,by targeting the ATP binding site,compound 1 not only inhibited CDK9 activity but also disrupted the CDK9-cyclin T1 proteineprotein interaction(PPI).Mechanistically,compound 1 reversed EMT and reduced the ratio of CSCs by blocking the CDK9-cyclin T1 interaction,leading to reduced TNBC cell proliferation and migration.To date,compound 1 is the first reported tetrahydroisoquinoline-based CDK9-cyclin T1 ATP-competitive inhibitor that also interferes with the interaction between CDK9 and cyclin T1.Compound 1 may serve as a promising scaffold for developing more selective and potent anti-TNBC agents.Our work also provides insight into the role of the CDK9-cyclin T1 PPI on EMT and CSCs and highlights the feasibility and significance of targeting CDK9 for the treatment of TNBC.

Artificial intelligence-aided discovery of prolyl hydroxylase 2 inhibitors to stabilize hypoxia inducible factor-1α and promote angiogenesis

From ZINC database with a total of 1.8 million small molecules, four compounds are identified as prolyl hydroxylase 2 inhibitors through a virtual screening workflow that sequentially incorporates machine learning, molecular docking, and molecular dynamics. Among them, compound 103,(E)-5-(5-((2-(1Htetrazol-5-yl)hydrazineylidene)methyl)furan-2-yl)isoindoline-1,3-dione, promotes the migration and capillary tube formation capacity of human umbilical vein endothelial cells through enhancing the stability of hypoxia inducible factor-1α and increasing the level of vascular endothelial growth factor.

Development of an orally bioavailable selective inhibitor of the menin-MLL

The protein–protein interaction between menin and mixed lineage leukemia(MLL)plays an important role in the development of human hepatocellular carcinogenesis(HCC)and is associated with poor prognosis of HCC patients.1,2 Hence,interrupting the menin-MLL interaction is an attractive strategy in cancer treatment,particularly for liver cancer.3,4 In this study,we identified complex C1 as the first rhodium(III)-based orally bioavailable selective inhibitor of the menin-MLL interaction for HCC.

Development of a dual targeting scaffold of SET7/MLL inhibitor for castration-resistant prostate cancer treatment

Histone methyltransferase enzyme SET7 and mixed-lineage leukemia protein(MLL)complex are crucial co-activators of androgen receptor(AR)and have recently emerged as potential therapeutic targets for advanced castration-resistant prostate cancer(CRPC).In this study,we described the identification of a rhodium-based hybrid complex(SM_1)as a potent blocker of AR activity via simultaneously inhibiting SET7 and MLL complex activity,which makes it a potential lead scaffold for CPRC drug development.