Deep Learning and Random Forest Approach for Finding the Optimal Traditional Chinese Medicine Formula for Treatment of Alzheimer's Disease.

It has demonstrated that glycogen synthase kinase 3ß (GSK3ß) is related to Alzheimer's disease (AD). On the basis of the world largest traditional Chinese medicine (TCM) database, a network-pharmacology-based approach was utilized to investigate TCM candidates that can dock well with multiple targets. Support vector machine (SVM) and multiple linear regression (MLR) methods were utilized to obtain predicted models. In particular, the deep learning method and the random forest (RF) algorithm were adopted. We achieved R2 values of 0.927 on the training set and 0.862 on the test set with deep learning and 0.869 on the training set and 0.890 on the test set with RF. Besides, comparative molecular similarity indices analysis (CoMSIA) was performed to get a predicted model. All of the training models achieved good results on the test set. The stability of GSK3ß protein-ligand complexes was evaluated using 100 ns of MD simulation. Methyl 3- O-feruloylquinate and cynanogenin A induced both more compactness to the GSK3ß complex and stable conditions at all simulation times, and the GSK3ß complex also had no substantial fluctuations after a simulation time of 5 ns. For TCM molecules, we used the trained models to calculate predicted bioactivity values, and the optimum TCM candidates were obtained by ranking the predicted values. The results showed that methyl 3- O-feruloylquinate contained in Phellodendron amurense and cynanogenin A contained in Cynanchum atratum are capable of forming stable interactions with GSK3ß.

Direct Decarboxylative-Decarbonylative Alkylation of α-Oxo Acids with Electrophilic Olefins via Visible-Light Photoredox Catalysis.

The decarbonylation of primary, secondary, and tertiary alkyl-substituted acyl radicals has been investigated through photoredox catalysis. A series of quaternary carbons and γ-ketoesters have been directly constructed by the photoredox 1,4-conjugate addition of the corresponding alkyl ketoacids with electrophilic alkenes. And, the tertiary alkyl ketoacids have proved to be good precursors of tertiary alkyl radicals.

Photoredox-Induced Functionalization of Alkenes for the Synthesis of Substituted Imidazolines and Oxazolidines.

A one-pot, three-component cascade reaction combining photoredox catalyzed radical addition and formal [3 + 2] annulation was developed. With this approach, highly concise syntheses of imidazoline and oxazolidine derivatives have been achieved. The advantages of this transformation are good to excellent yields, mild reaction conditions, operational simplicity, and easy accessibility of raw materials.

Effects of Aquaporin 4 Knockdown on Brain Edema of the Uninjured Side After Traumatic Brain Injury in Rats.

BACKGROUND Traumatic brain injury (TBI) induces edema on the uninjured side (i.e., contralateral brain tissue; CBT). We evaluated the role of AQP4 in CBT edema formation following TBI. MATERIAL AND METHODS Mild or severe TBI was induced using a controlled cortical impact model in rats, immediately followed by intraventricular siRNA infusions. The effects of AQP4 siRNA on CBT edema were assessed at up to 168 h. RESULTS Mild or severe TBI induced different patterns of CBT edema. Furthermore, following mild TBI, brain water content (BWC) was increased at 72 h thereafter and AQP4 expression was increased after 168 h, relative to non-injured rats (i.e., sham). AQP4 interference reduced AQP4 expression 48 h thereafter and BWC 72 h thereafter, relative to control siRNA. In contrast, following severe TBI, BWC was increased 1 h thereafter and AQP4 expression was transiently enhanced after 1 h, relative to sham. However, AQP4 interference reduced AQP4 expression after 1 h and BWC 24 h thereafter, relative to control siRNA. Finally, apparent diffusion coefficient (ADC) value in CBT was positively correlated with AQP4 expression level following severe, but not mild, TBI. AQP4 interference disrupted this correlation. CONCLUSIONS AQP4 interference reduces CBT edema formation, and ADC value may predict TBI severity.

Visible-Light-Induced 1,7-Enyne Dicyclization: Synthesis of Ester-Substituted Benzo[j]phenanthridines.

A novel alkoxycarbonyl-radical-triggered cascade cyclization of 1,7-enynes, with alkyloxalyl chlorides as the ester units, for the synthesis of benzo[j]phenanthridines is described. The reaction conditions exhibit excellent compatibility with a broad range of alkoxycarbonyl radical sources and realize the installation of an ester group in the polycyclic compound. This radical cascade cyclization reaction features excellent functional group tolerance, mild reaction conditions, and good to excellent yields.

Synthesis of Ester-Substituted Indolo[2,1-a]isoquinolines via Photocatalyzed Alkoxycarbonylation/Cyclization Reactions.

A direct alkoxycarbonylation/cyclization reaction is accomplished under visible light-induced photoredox catalysis. With this approach, a variety of ester-substituted indolo[2,1-a]isoquinolines are prepared in good to excellent yields. It is worth noting that this method not only can afford the synthesis of indolo[2,1-a]isoquinolines but also can provide an alternative route for generating complex target structures bearing carboxylic esters.

[Case-control study on carpal canal endoscopy and arthroscopy for the treatment of plantar fasciopathy].

OBJECTIVE: To explore clinical effects of carpal canal endoscopy in treating patients with plantar fasciopathy who failed by conservative treatment. METHODS: From August 2018 to August 2019, 50 patients with plantar fascia were divided into two groups and 25 patients in each group. In carpal canal endoscopy group, included 11 males and 14 females, aged from 39 to 67 years old with an average of(57.7±6.4) years old;carpal canal endoscopy was used to plantar fascia release. In arthroscopy group, included 9 males and 16 females, aged from 41 to 73 years old with an average of (58.1±7.2) years old;conventional 4.0 mm arthroscopy Instruments was used to plantar fascia release. Operation time, hospitalization expense and postoperative complications between two groups were observed and compared. Postoperative visual analogue scale(VAS) and American Orthopedic Foot Ankle Society (AOFAS) score were used to evaluate clinical function. RESULTS: All patients were followed up from 12 to 18 months with an average of (14.3±2.1) months. There were significant differentces in operation time and hospitalization expense between two groups (P<0.05). Surgical incision healed well in carpal canal endoscopy group, and 2 patients delayed union in arthroscopy group, and no difference between two groups (P>0.05). There were no statistical differences in VAS, AOFAS and grading between two groups at 12 months after operation(P>0.05). CONCLUSION: The outcome of carpal canal endoscopy and arthroscopy has similar effects in treating plantar fascia. While carpal canal endoscopy has advantages of need not perfusion during opertaion, protect soft tissue well, less operation time, and lower cost.

The fission yeast inhibitor of growth (ING) protein Png1p functions in response to DNA damage.

In budding yeast and human cells, ING (inhibitor of growth) tumor suppressor proteins play important roles in response to DNA damage by modulating chromatin structure through collaborating with histone acetyltransferase or histone deacetylase complexes. However, the biological functions of ING family proteins in fission yeast are poorly defined. Here, we report that Png1p, a fission yeast ING homolog protein, is required for cell growth under normal and DNA-damaged conditions. Png1p was further confirmed to regulate histone H4 acetylation through collaboration with the MYST family histone acetyltransferase 1 (Mst1). Additionally, both fission yeast PNG1 and MST1 can functionally complement their budding yeast correspondence homologs YNG2 and ESA1, respectively. These results suggest that ING proteins in fission yeast might also conserve function, similar to ING proteins in budding yeast and human cells. We also showed that decreased acetylation in Deltapng1 cells resulted in genome-wide down-regulation of 756 open reading frames, including the central DNA repair gene RAD22. Overexpression of RAD22 partially rescued the png1 mutant phenotype under both normal and DNA-damaged conditions. Furthermore, decreased expression of RAD22 in Deltapng1 cells was confirmed to be caused by decreased H4 acetylation at its promoter. Altogether, these results indicate that Png1p is required for histone H4 acetylation and functions upstream of RAD22 in the DNA damage response pathway.

Efficient access to aliphatic esters by photocatalyzed alkoxycarbonylation of alkenes with alkyloxalyl chlorides.

Aliphatic esters are essential constituents of biologically active compounds and versatile chemical intermediates for the synthesis of drugs. However, their preparation from readily available olefins remains challenging. Here, we report a strategy to access aliphatic esters from olefins through a photocatalyzed alkoxycarbonylation reaction. Alkyloxalyl chlorides, generated in situ from the corresponding alcohols and oxalyl chloride, are engaged as alkoxycarbonyl radical fragments under photoredox catalysis. This transformation tolerates a broad scope of electron-rich and electron-deficient olefins and provides the corresponding ß-chloro esters in good yields. Additionally, a formal ß-selective alkene alkoxycarbonylation is developed. Moreover, a variety of oxindole-3-acetates and furoindolines are prepared in good to excellent yields. A more concise formal synthesis of (±)-physovenine is accomplished as well. With these strategies, a wide range of natural-product-derived olefins and alkyloxalyl chlorides are also successfully employed.

Piperlongumine inhibits migration and proliferation of castration-resistant prostate cancer cells via triggering persistent DNA damage.

BACKGROUND: Metastatic castration-resistant prostate cancer (CRPC) is the leading cause of death among men diagnosed with prostate cancer. Piperlongumine (PL) is a novel potential anticancer agent that has been demonstrated to exhibit anticancer efficacy against prostate cancer cells. However, the effects of PL on DNA damage and repair against CRPC have remained unclear. The aim of this study was to further explore the anticancer activity and mechanisms of action of PL against CRPC in terms of DNA damage and repair processes. METHODS: The effect of PL on CRPC was evaluated by MTT assay, long-term cell proliferation, reactive oxygen species assay, western blot assay, flow cytometry assay (annexin V/PI staining), ß-gal staining assay and DAPI staining assay. The capacity of PL to inhibit the invasion and migration of CRPC cells was assessed by scratch-wound assay, cell adhesion assay, transwell assay and immunofluorescence (IF) assay. The effect of PL on DNA damage and repair was determined via IF assay and comet assay. RESULTS: The results showed that PL exhibited stronger anticancer activity against CRPC compared to that of taxol, cisplatin (DDP), doxorubicin (Dox), or 5-Fluorouracil (5-FU), with fewer side effects in normal cells. Importantly, PL treatment significantly decreased cell adhesion to the extracellular matrix and inhibited the migration of CRPC cells through affecting the expression and distribution of focal adhesion kinase (FAK), leading to concentration-dependent inhibition of CRPC cell proliferation and concomitantly increased cell death. Moreover, PL treatment triggered persistent DNA damage and provoked strong DNA damage responses in CRPC cells. CONCLUSION: Collectively, our findings demonstrate that PL potently inhibited proliferation, migration, and invasion of CRPC cells and that these potent anticancer effects were potentially achieved via triggering persistent DNA damage in CRPC cells.

[Research progress on genomic integrity regulated by epigenetics using yeast as a model.].

Genomic integrity is crucial for normal cell replication, proliferation and differentiation. DNA lesions resulted from exogenous and endogenous factors will lead to genomic instability, and consequently the cause for various diseases. Epigenetic regulation (including DNA methylation, histone modifications and non-coding RNA) plays important roles in DNA lesion repair and cell cycle regulation as well as maintaining the genetic integrity. The yeast, a type of single cell eukaryotic organism, is an ideal model for the researches of epigenetics, especially in the area of DNA lesion repair and the formation of heterochromatin. Previous researches on epigenetics were mainly focus on histone modifications. Recent re-searches have observed that non-coding RNAs are able to direct the cytosine methylation and histone modifications that are related to gene expression regulation. This paper discuss the mechanism, research progress and future development of epi-genetics in maintaining the genomic integrity, using the yeast as a model.

Synthesis of indolo[2,1-a]isoquinoline derivatives via visible-light-induced radical cascade cyclization reactions.

We describe a photocatalyzed transformation for the synthesis of the indolo[2,1-a]isoquinoline core structure. This redox neutral reaction features mild reaction conditions and exceptional functional group tolerance. A series of valuable indolo[2,1-a]isoquinoline derivatives bearing various functional groups were synthesized using this method in good to excellent yields.

Visible Light-Mediated Direct C-H Aroylation and Alkylation of Heteroarenes.

Herein, we describe the photocatalytic generation of nucleophilic aroyl radicals from simple aroyl chlorides as a universal and efficient cross-coupling strategy for the direct aroylation of heteroarenes. Furthermore, visible light-mediated direct alkylation of heteroarenes has also been achieved using unactivated bromoalkanes as radical precursors. These two strategies feature high functional group tolerance, exclusive regioselectivity for reaction at the more electrophilic position of heteroarenes, easily accessible substrates, and mild reaction conditions. Moreover, mechanism studies of two reactions are carried out to support our hypotheses.

Artificial Intelligence Approach to Find Lead Compounds for Treating Tumors.

It has been demonstrated that MMP13 enzyme is related to most cancer cell tumors. The world's largest traditional Chinese medicine database was applied to screen for structure-based drug design and ligand-based drug design. To predict drug activity, machine learning models (Random Forest (RF), AdaBoost Regressor (ABR), Gradient Boosting Regressor (GBR)), and Deep Learning models were utilized to validate the Docking results, and we obtained an R2 of 0.922 on the training set and 0.804 on the test set in the RF algorithm. For the Deep Learning algorithm, R2 of the training set is 0.90, and R2 of the test set is 0.810. However, these TCM compounds fly away during the molecular dynamics (MD) simulation. We seek another method: peptide design. All peptide database were screened by the Docking process. Modification peptides were optimized the interaction modes, and the affinities were assessed with ZDOCK protocol and Refine Docked protein protocol. The 300 ns MD simulation evaluated the stability of receptor-peptide complexes. The double-site effect appeared on S2, a designed peptide based on a known inhibitor, when complexed with BCL2. S3, a designed peptide referred from endogenous inhibitor P16, competed against cyclin when binding with CDK6. The MDM2 inhibitors S5 and S6 were derived from the P53 structure and stable binding with MDM2. A flexible region of peptides S5 and S6 may enhance the binding ability by changing its own conformation, which was unforeseen. These peptides (S2, S3, S5, and S6) are potentially interesting to treat cancer; however, these findings need to be affirmed by biological testing, which will be conducted in the near future.

Over-expression of OsDREB genes lead to enhanced drought tolerance in rice.

The DREB transcription factors, which specifically interact with C-repeat/DRE (A/GCCGAC), play an important role in plant abiotic stress tolerance by controlling the expression of many cold or/and drought-inducible genes in an ABA-independent pathway. We have isolated three novel rice DREB genes, OsDREB1E, OsDREB1G, and OsDREB2B, which are homologous to Arabidopsis DREB genes. The yeast one-hybrid assay indicated that OsDREB1E, OsDREB1G, and OsDREB2B can specifically bind to the C-repeat/DRE element. To elucidate the function of respective OsDREB genes, we have stably introduced these to rice by Agrobacterium-mediated transformation. Transgenic rice plants analysis revealed that over-expression of OsDREB1G and OsDREB2B in rice significantly improved their tolerance to water deficit stress, while over-expression of OsDREB1E could only slightly improved the tolerance to water deficit stress, suggesting that the OsDREBs might participate in the stress response pathway in different manners.

Regiospecific Three-Component Aminofluorination of Olefins via Photoredox Catalysis.

Direct visible-light-mediated aminofluorination of styrenes has been developed with high regioselectivity. Shelf-stable N-Ts-protected 1-aminopyridine salt was used as the nitrogen-radical precursor, and the commercially available hydrogen fluoride-pyridine was used as the nucleophilic fluoride source. The synthesis of an analogue of LY503430 was performed to demonstrate the synthetic value of this strategy.

Alkene functionalization for the stereospecific synthesis of substituted aziridines by visible-light photoredox catalysis.

A novel strategy involving visible-light-induced functionalization of alkenes for the synthesis of substituted aziridines was developed. The readily prepared N-protected 1-aminopyridinium salts were used for the generation of N-centered radicals. This approach allowed the synthesis of aziridines bearing various functional groups with excellent diastereoselectivity under mild conditions. Moreover, this protocol was successfully applied to prepare structurally diverse nitrogen-containing frameworks.

Photoredox-Induced Intramolecular 1,5-H Transfer Reaction of Aryl Iodides for the Synthesis of Spirocyclic γ-Lactams.

This work develops a photocatalysis method for the synthesis of γ-spirolactams through a tandem intramolecular 1,5-HAT reaction-cyclization process. A variety of novel γ-spirolactams are prepared in good to excellent yields with this method. This transformation features mild reaction conditions and exceptional functional group tolerance. Additionally, γ-terpinene is applied to this transformation as a hydrogen atom donor for the first time.

The relationship between fractional anisotropy value and tumor microarchitecture in late-stage rat glioma.

OBJECTIVE: To explore the magnetic resonance diffusion tensor imaging (MR-DTI) features of in the late stage of Wistar rat C6 brain glioma, and the relationship between fractional anisotropy value and tumor microarchitecture. METHODS: The concentration of more than 1.0 × 106/10 µL glioma cells and complete medium were injected stereotactically into the right caudate nucleus of the experimental group (n = 35) and control group (n = 10), respectively. Conventional MRI, DTI, and enhanced T1WI scans were Performed using the GE Signa HD × 3.0T MRI scanner about 3-4 weeks after implantation for the rats. Postprocessing was done using the DTI specific software Function Tool to gain FA image. Many ROIs were drawn avoiding hemorrhage, necrosis areas in tumor parenchyma, the value of FA was recorded. Each surviving rat brain was examined histologically using HE and immunohistochemical staining for VEGF and CD34. Pearson correlation analysis was used to determine the relationships between FA values and VEGF, MVD, cell density, respectively. RESULTS: A total of 35 tumor-bearing rats were confirmed the tumor formation by the subsequent MRI and pathological examination. The mean FA values of the tumor and the contralateral brain tissue were 0.17 ± 0.03 and 0.31 ± 0.05 respectively, and the difference was statistically significant (t = 12.80, P < 0.05). The mean FA value of grade III glioma (n = 12) was 0.16 ± 0.03, and the average FA value of grade IV glioma (n = 23) was about 0.18 ± 0.04. There was no significant difference between the two groups (t = 1.92, P > 0.05). FA value in the late stage of Wistar rat C6 brain glioma has significant positive correlation to VEGF, MVD, cell density. The correlation coefficients between FA and VEGF, MVD, and cell density were 0.67, 0.65 and 0.71 (P < 0.05), respectively. CONCLUSIONS: The FA value of rat glioma tumor in the late stage can preoperatively provide an accurate, reliable and noninvasive imaging monitoring method to evaluate the microstructure of glioma (cell density, the extent of angiogenesis, fiber bundle integrity and tumor cell infiltration and so on), predict the biological behavior of the tumor and make out surgical plan.

Intramolecular 1,5-H transfer reaction of aryl iodides through visible-light photoredox catalysis: a concise method for the synthesis of natural product scaffolds.

The intramolecular 1,5-H transfer reaction of the aryl radicals generated from unactivated aryl iodides by photocatalysis is described. The features of this transformation are operational simplicity, excellent yields, mild reaction conditions, and good functional group tolerance. With this approach, a more concise formal synthesis of (±)-coerulescine and (±)-physovenine is accomplished.