In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment

Synthetic lethality describes situations in which defects in two different genes or pathways together result in cell death. This concept has been applied to drug development for cancer treatment, as represented by Poly (ADP-ribose) polymerase (PARPs) inhibitors. In the current study, we performed a computational screening to discover new PARP inhibitors. Among the 11,247 compounds analyzed, one natural product, ZINC67913374, stood out by its superior performance in the simulation analyses. Compared with the FDA approved PARP1 inhibitor, olaparib, our results demonstrated that the ZINC67913374 compound achieved a better grid score (−86.8) and amber score (−51.42). Molecular dynamics simulations suggested that the PARP1-ZINC67913374 complex was more stable than olaparib. The binding free energy for ZINC67913374 was −177.28 kJ/mol while that of olaparib was −159.16 kJ/mol. These results indicated ZINC67913374 bound to PARP1 with a higher affinity, which suggest ZINC67913374 has promising potential for cancer drug development

Moderate Hyperglycemia-Preventive Effect and Mechanism of Action of <i>Periplaneta americana</i> Oligosaccharides in Streptozotocin-Induced Diabetic Mice

Periplaneta americana is a kind of medicinal and edible insect, and its oligosaccharides (PAOS) have been reported to exert anti-inflammatory effects by regulating immunity, reducing oxidative stress, and meliorating gut microbiota. We hypothesized PAOS might benefit experimental diabetes mellitus (DM), an inflammatory disease coordinated by both innate and adaptive immunity. This study aimed to evaluate the effect of PAOS on glycemia and its potential mechanisms. Mice model of diabetes was established, and then the potential effects of PAOS was tested in vivo. Here, we found that PAOS triggered a moderate hyperglycemia-preventive effect on DM mice, showing markedly alleviated symptoms of DM, reduced blood glucose, and meliorated functions of liver and pancreas β cell. Deciphering the underlying mechanism of PAOS-improving diabetes, the results revealed that PAOS downregulated the blood glucose level by activating PI3K/AKT/mTOR and Keap/Nrf2/HO-1 pathways, meanwhile inhibiting TLR4/MAPK/NF-κB, Beclin1/LC3, and NLRP3/caspase1 pathways in vivo. Furthermore, analyses of the microbial community intriguingly exhibited that PAOS promoted the communities of bacteria producing short-chain fatty acids (SCFAs), whereas attenuating lipopolysaccharides (LPS)-producing ones that favored inflammatory tolerance. Collectively, balancing the intestinal bacterial communities by PAOS, which favored anabolism but suppressed inflammatory responses, contributed substantially to the glycemia improvement of PAOS in DM mice. Accordingly, PAOS might function as complementary and alternative medicine for DM

Discovery of a Potential HER2 Inhibitor from Natural Products for the Treatment of HER2-Positive Breast Cancer

Breast cancer is one of the most lethal types of cancer in women worldwide due to the late stage detection and resistance to traditional chemotherapy. The human epidermal growth factor receptor 2 (HER2) is considered as a validated target in breast cancer therapy. Even though a substantial effort has been made to develop HER2 inhibitors, only lapatinib has been approved by the U.S. Food and Drug Administration (FDA). Side effects were observed in a majority of the patients within one year of treatment initiation. Here, we took advantage of bioinformatics tools to identify novel effective HER2 inhibitors. The structure-based virtual screening combined with ADMET (absorption, distribution, metabolism, excretion and toxicity) prediction was explored. In total, 11,247 natural compounds were screened. The top hits were evaluated by an in vitro HER2 kinase inhibition assay. The cell proliferation inhibition effect of identified inhibitors was evaluated in HER2-overexpressing SKBR3 and BT474 cell lines. We found that ZINC15122021 showed favorable ADMET properties and attained high binding affinity against HER2. Moreover, ZINC15122021 showed high kinase inhibition activity against HER2 and presented outstanding cell proliferation inhibition activity against both SKBR3 and BT474 cell lines. Results reveal that ZINC15122021 can be a potential HER2 inhibitor

Periplaneta americana Oligosaccharides Exert Anti-Inflammatory Activity through Immunoregulation and Modulation of Gut Microbiota in Acute Colitis Mice Model

The incidence and prevalence of inflammatory bowel disorders (IBD) are increasing around the world due to bacterial infection, abnormal immune response, etc. The conventional medicines for IBD treatment possess serious side effects. Periplaneta americana (P. americana), a traditional Chinese medicine, has been used to treat arthritis, fever, aches, inflammation, and other diseases. This study aimed to evaluate the anti-inflammatory effects of oligosaccharides from P. Americana (OPA) and its possible mechanisms in vivo. OPA were purified and biochemical characterization was analyzed by HPGPC, HPLC, FT-IR, and GC–MS. Acute colitis mice model was established, the acute toxicity and anti-inflammatory activity were tested in vivo. The results showed OPA with molecular mass of 1.0 kDa were composed of 83% glucose, 6% galactose, 11% xylose, and the backbone was (1→4)-Glcp. OPA had potent antioxidant activities in vitro and significantly alleviated the clinical symptoms of colitis, relieved colon damage without toxic side effects in vivo. OPA exhibited anti-inflammatory activity by regulating Th1/Th2, reducing oxidative stress, preserving intestinal barrier integrity, and inhibiting TLR4/MAPK/NF-κB pathway. Moreover, OPA protected gut by increasing microbial diversity and beneficial bacteria, and reducing pathogenic bacteria in feces. OPA might be the candidate of complementary and alternative medicines of IBD with low-cost and high safety

Analyses of artificial morel soil bacterial community structure and mineral element contents in ascocarp and the cultivated soil

This study explored the differences among different artificial morel cultivations and the influential factors, including soil bacterial community structure, yield, and mineral element contents of ascocarp and the cultivated soil. High-throughput sequencing results revealed that the dominant bacterial phyla in all the samples, including Proteobacteria, Acidobacteria, Chloroflexi, Bacteroides and Gemmatimonadetes, were found not only in morel soils (experimental group) but also in wheat soil (control group), while the highest richness and diversity in the soil bacteria were observed during the primordial differentiation stage. M6 group exhibited the highest yield (271.8g/m2) and had an unexpectedly high proportion of Pseudomonas (25.30%) during the primordial differentiation stage, which was 1.77ď˝ 194.62 times more than the proportion of Pseudomonas in other samples. Pseudomonas may influence the growth of morel. Mineral element contents of the varied soil groups and ascocarp were determined using electro thermal digestion and inductively coupled plasma mass spectrometry. The results revealed that morel had high enrichment effects on Phosphorus (P, Bioconcentration factor = 16.83), Potassium (K, 2.18), Boron (B, 1.47), Zinc (Zn, 1.36), Copper (Cu, 1.15) and Selenium (Se, 2.27). P levels were the highest followed by Se and K, and the mineral element contents in ascocarp were positively correlated with the soil element contents.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

In Silico Discovery of Potential VEGFR-2 Inhibitors from Natural Derivatives for Anti-Angiogenesis Therapy

Angiogenesis is the growth of new capillaries from existing blood vessels that supply oxygen and nutrients and provide gateways for immune surveillance. Abnormal vessel growth in term of excessive angiogenesis is a hallmark of cancer, inflammatory and eye diseases. VEGFR-2 (vascular endothelial growth factor receptor 2) dominating the process of angiogenesis has led to approval of therapeutic inhibitors and is becoming a promising target for anti-angiogenic drugs. Notwithstanding these successes, the clinical use of current VEGFR-2 blockers is more challenging than anticipated. Taking axitinib as a reference drug, in our study we found three potent VEGFR-2 inhibitors (ZINC08254217, ZINC08254138, and ZINC03838680) from natural derivatives. Each of the three inhibitors acquired a better grid score than axitinib (−62.11) when docked to VEGFR-2. Molecular dynamics simulations demonstrated that ZINC08254217– and ZINC08254138–VEGFR-2 complexes were more stable than axitinib. Similar to bind free energy for axitinib (−54.68 kcal/mol), such for ZINC03838680, ZINC08254217, and ZINC08254138 was −49.37, −43.32, and −32.73 kcal/mol respectively. These results suggested these three compounds could be candidate drugs against angiogenesis, with comparable VEGFR-2 binding affinity of axitinib. Hence findings in our study are able to provide valuable information on discovery of effective anti-angiogenesis therapy

L1198F Mutation Resensitizes Crizotinib to ALK by Altering the Conformation of Inhibitor and ATP Binding Sites

The efficacy of anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) treatment with small molecule inhibitors is greatly challenged by acquired resistance. A recent study reported the newest generation inhibitor resistant mutation L1198F led to the resensitization to crizotinib, which is the first Food and Drug Administration (FDA) approved drug for the treatment of ALK-positive NSCLC. It is of great importance to understand how this extremely rare event occurred for the purpose of overcoming the acquired resistance of such inhibitors. In this study, we exploited molecular dynamics (MD) simulation to dissect the molecular mechanisms. Our MD results revealed that L1198F mutation of ALK resulted in the conformational change at the inhibitor site and altered the binding affinity of ALK to crizotinib and lorlatinib. L1198F mutation also affected the autoactivation of ALK as supported by the identification of His1124 and Tyr1278 as critical amino acids involved in ATP binding and phosphorylation. Our findings are valuable for designing more specific and potent inhibitors for the treatment of ALK-positive NSCLC and other types of cancer