LdCyPA attenuates MAPK pathway to assist Leishmania donovani immune escape in host cells.

BACKGROUND: Visceral leishmaniasis is a neglected tropical disease affecting millions of people worldwide. Macrophages serve as the primary host cells for L. donovani, the immune response capability of these host cells is crucial for parasites' intracellular survival. L. donovani peptidyl-prolyl cis/trans isomerase Cyclophilin A (LdCypA) is a key protein for L. donovani intracellular proliferation, while the molecular mechanism conducive to intracellular survival of parasites remains elusive. METHODS: In this study, we generated a macrophage cell line overexpressing LdCyPA to investigate its role in controlling host immunity and promoting intracellular immune escape of L. donovani. RESULTS: It was discovered that the overexpression of the LdCyPA cell line regulated the host immune response following infection by downregulating the proportion of M1-type macrophages, promoting the secretion of the anti-inflammatory factor IL-4, and inhibiting the secretion of pro-inflammatory factors like IL-12, IFN-γ, TNF-α, and INOS. Transcriptome sequencing and mechanistic validation, meanwhile, demonstrated that cells overexpressing LdCyPA controlled the immune responses that followed infection by blocking the phosphorylation of P38 and JNK1/2 proteins in the MAPK signaling pathway and simultaneously increasing the phosphorylation of ERK proteins, which helped the L. donovani escape immune recognition. CONCLUSION: Our findings thus pave the way for the development of host-directed antiparasitic drugs by illuminating the pro-Leishmania survival mechanism of L. donovani cyclophilin A and exposing a novel immune escape strategy for L. donovani that targets host cellular immune regulation.

Efficient separation and production of high-quality rubber, lignin nanoparticles and fermentable sugars from Eucommia ulmoides pericarp via deep eutectic solvent pretreatment.

The natural barriers of lignocellulose hinder the separation of Eucommia ulmoides rubber (EUR) from Eucommia ulmoides pericarp (EUP), whereas traditional separation methods normally lead to the waste of Eucommia ulmoides lignocellulose resource and environmental pollution. In this study, an acidic deep eutectic solvent composed of lactic acid and ZnCl2 was developed as a pretreatment medium to reduce the separation barriers of EUR while producing lignin nanoparticles and fermentable sugars. Results showed that DES pretreatment could accelerate the extraction efficiency (91.0 %) and purity (>99 %) of EUR and maintain its chemical structure compared to the traditional alkaline and mechanical methods. Meanwhile, the regenerated nano-lignin showed excellent antioxidant activity (IC50 = 46.3 µg/mL) comparable to commercial antioxidant BHA. Besides, the enzymatic hydrolysis efficiency of EUP with DES pretreatment was significantly enhanced about 9 times than the control groups. Overall, the acidic DES pretreatment could be considered a promising pretreatment method for separation of high-quality EUR and valorization of lignocellulosic components.

Analysis of a heterogeneous SEIRS patch model with asymmetric mobility kernel.

In this paper, we establish a spatial heterogeneous SEIRS patch model with asymmetric mobility kernel. The basic reproduction ratio $ \mathcal{R}_{0} $ is defined, and threshold-type results on global dynamics are investigated in terms of $ \mathcal{R}_{0} $. In certain cases, the monotonicity of $ \mathcal{R}_{0} $ with respect to the heterogeneous diffusion coefficients is established, but this is not true in all cases. Finally, when the diffusion rate of susceptible individuals approaches zero, the long-term behavior of the endemic equilibrium is explored. In contrast to most prior studies, which focused primarily on the mobility of susceptible and symptomatic infected individuals, our findings indicate the significance of the mobility of exposed and recovered persons in disease dynamics.

Optimal control by deep learning techniques and its applications on epidemic models.

We represent the optimal control functions by neural networks and solve optimal control problems by deep learning techniques. Adjoint sensitivity analysis is applied to train the neural networks embedded in differential equations. This method can not only be applied in classic epidemic control problems, but also in epidemic forecasting, discovering unknown mechanisms, and the ideas behind can give new insights to traditional mathematical epidemiological problems.

Molecular and biological characteristics of a novel chrysovirus infecting the fungus phytopathogenic Setosphaeria turcica f.sp. sorghi.

A new double-stranded RNA (dsRNA) virus has been identified in the filamentous fungus Setosphaeria turcica f.sp. sorghi, whose genome consists of four segments (dsRNA1-4). Each dsRNA carries single open reading frame (ORF) flanked by 5' and 3' untranslated regions (UTRs) containing strictly conserved termini. The putative protein encoded by dsRNA1 showed 80.50% identity to the RNA-dependent RNA polymerase (RdRp) of the most closely related virus, Alternaria alternata chrysovirus 1 (AaCV1), belonging to the Chrysoviridae. dsRNA2 encodes the putative coat protein, while dsRNA3 and dsRNA4 respectively encode the hypothetical proteins of unknown functions. Phylogenetic analysis based on the RdRp protein indicated the virus clustered with members of the genus Betachrysovirus in the family Chrysoviridae. Based on the dsRNA profile, amino acid sequence comparisons, and phylogenetic analyses, the mycovirus is thought to be a new member of the family Chrysoviridae and designated as Setosphaeria turcica chrysovirus 1 (StCV1). Moreover, obvious differences were observed in the colony, mycelial and spore morphology between StCV1-infected and virus-cured strains of S. turcica f.sp. sorghi. StCV1 infection strongly reduced colony growth rate, spore production ability and virulence on host fungus. To our knowledge, this is the first report about mycovirus infecting S. turcica f.sp. sorghi and also the first chrysovirus infecting S. turcica.

Genetic risk, metabolic syndrome, and gastrointestinal cancer risk: A prospective cohort study.

BACKGROUND: Gastrointestinal (GI) cancer risk has been associated with metabolic syndrome (MetS), a surrogate indicator for unhealthy lifestyles, and a number of genetic loci, but the combined effect of MetS and genetic variants on GI cancer risk is uncertain. METHODS: We included 430,036 participants with available MetS and genotype data from UK Biobank. During the follow-up time, 5494 incident GI cancer cases, including esophageal cancer, gastric cancer, and colorectal cancer, were identified. We created a GI polygenic risk score (GI-PRS) for overall GI cancer derived from three site-specific cancer PRSs. Cox proportional hazards regression was used to estimate the associations of MetS and GI-PRS with the risk of GI cancer. RESULTS: MetS was significantly associated with 28% increment in GI cancer risk (hazard ratio [HR]MetS vs. non-MetS : 1.28, 95% confidence interval [CI]: 1.21-1.35, p < 0.0001), whereas a high GI-PRS (top quintile) was associated with 2.28-fold increase in risk (HRhigh vs. low : 2.28, 95% CI: 2.09-2.49, p < 0.0001). Compared with participants without MetS and at low genetic risk (bottom quintile of GI-PRS), those with MetS and at high genetic risk had 2.75-fold increase in GI cancer risk (HR: 2.75, 95% CI: 2.43-3.12, p < 0.0001). Additionally, MetS in comparison with no MetS had 1.49‰, 2.75‰, and 3.37‰ absolute risk increases in 5 years among participants at low, intermediate (quintiles 2-4 of GI-PRS) and high genetic risk, respectively, representing the number of subjects diagnosed as MetS causing a new GI cancer case in 5 years were 669, 364, and 296, respectively. CONCLUSIONS: Metabolic and genetic factors may jointly contribute to GI cancer risk and may serve as predictors by quantitative measurements to identify high-risk populations of GI cancer for precise prevention.

Polyphenols as potential metabolism mechanisms regulators in liver protection and liver cancer prevention.

BACKGROUND: Liver cancer is one of the common malignancies. The dysregulation of metabolism is a driver of accelerated tumourigenesis. Metabolic changes are well documented to maintain tumour growth, proliferation and survival. Recently, a variety of polyphenols have been shown to have a crucial role both in liver disease prevention and metabolism regulation. METHODS: We conducted a literature search and combined recent data with systematic analysis to comprehensively describe the molecular mechanisms that link polyphenols to metabolic regulation and their contribution in liver protection and liver cancer prevention. RESULTS: Targeting metabolic dysregulation in organisms prevents and resists the development of liver cancer, which has important implications for identifying new therapeutic strategies for the management and treatment of cancer. Polyphenols are a class of complex compounds composed of multiple phenolic hydroxyl groups and are the main active ingredients of many natural plants. They mediate a broad spectrum of biological and pharmacological functions containing complex lipid metabolism, glucose metabolism, iron metabolism, intestinal flora imbalance, as well as the direct interaction of their metabolites with key cell-signalling proteins. A large number of studies have found that polyphenols affect the metabolism of organisms by interfering with a variety of intracellular signals, thereby protecting the liver and reducing the risk of liver cancer. CONCLUSION: This review systematically illustrates that various polyphenols, including resveratrol, chlorogenic acid, caffeic acid, dihydromyricetin, quercetin, catechins, curcumin, etc., improve metabolic disorders through direct or indirect pathways to protect the liver and fight liver cancer.

Screening Novel Vaccine Candidates for Leishmania Donovani by Combining Differential Proteomics and Immunoinformatics Analysis.

Visceral leishmaniasis (VL), also known as kala-azar, is the most dangerous form of leishmaniasis. Currently no effective vaccine is available for clinical use. Since the pathogenicity of different Leishmania strains is inconsistent, the differentially expressed proteins in Leishmania strains may play an important role as virulence factors in pathogenesis. Therefore, effective vaccine candidate targets may exist in the differentially expressed proteins. In this study, we used differential proteomics analysis to find the differentially expressed proteins in two Leishmania donovani strains, and combined with immunoinformatics analysis to find new vaccine candidates. The differentially expressed proteins from L. DD8 (low virulent) and L. 9044 (virulent) strains were analyzed by LC-MS/MS, and preliminarily screened by antigenicity, allergenicity and homology evaluation. The binding peptides of MHC II, IFN-γ and MHC I from differentially expressed proteins were then predicted and calculated for the second screening. IFN-γ/IL-10 ratios and conserved domain prediction were performed to choose more desirable differentially expressed proteins. Finally, the 3D structures of three vaccine candidate proteins were produced and submitted for molecular dynamics simulation and molecular docking interaction with TLR4/MD2. The results showed that 396 differentially expressed proteins were identified by LC-MS/MS, and 155 differentially expressed proteins were selected through antigenicity, allergenicity and homology evaluation. Finally, 16 proteins whose percentages of MHC II, IFN-γ and MHC I binding peptides were greater than those of control groups (TSA, LmSTI1, LeIF, Leish-111f) were considered to be suitable vaccine candidates. Among the 16 candidates, amino acid permease, amastin-like protein and the hypothetical protein (XP_003865405.1) simultaneously had the large ratios of IFN-γ/IL-10 and high percentages of MHC II, IFN-γ and MHC I, which should be focused on. In conclusion, our comprehensive work provided a methodological basis to screen new vaccine candidates for a better intervention against VL and associated diseases.

Anti-tumor pharmacology of natural products targeting mitosis.

Cancer has been an insurmountable problem in the history of medical science. The uncontrollable proliferation of cancer cells is one of cancer's main characteristics, which is closely associated with abnormal mitosis. Targeting mitosis is an effective method for cancer treatment. This review summarizes several natural products with anti-tumor effects related to mitosis, focusing on targeting microtubulin, inducing DNA damage, and modulating mitosis-associated kinases. Furthermore, the main disadvantages of several typical compounds, including drug resistance, toxicity to non-tumor tissues, and poor aqueous solubility and pharmacokinetic properties, are also discussed, together with strategies to address them. Improved understanding of cancer cell mitosis and natural products may pave the way to drug development for the treatment of cancer.

Stachydrine hydrochloride inhibits hepatocellular carcinoma progression via LIF/AMPK axis.

BACKGROUND: Hepatocellular carcinoma (HCC) is not only one of the four highest malignancies, but also the principal reason of cancer-related death worldwide, yet no effective medication for anti-HCC is available. Stachydrine hydrochloride (SH), an alkaloid component in Panzeria alaschanica Kupr, exhibits potent antitumor activity in breast cancer. However, the anti-HCC effects of SH remain unknown. PURPOSE: Our study assessed the therapeutic effect of SH on HCC and tried to clarify the mechanisms by which it ameliorates HCC. No studies involving using SH for anti-HCC activity and molecular mechanism have been reported yet. STUDY DESIGN/METHODS: We examined the cell viability of SH on HCC cells by MTT assay. The effect of SH on cell autophagy in HCC cells was verified by Western blot and Immunofluorescence test. Flow cytometry was performed to assess cell-cycle arrest effects. Cell senescence was detected using ß-Gal staining and Western blot, respectively. An inhibitor or siRNA of autophagy, i.e., CQ and si LC-3B, were applied to confirm the role of autophagy acted in the anti-cancer function of SH. Protein expression in signaling pathways was detected by Western blot. Besides, molecular docking combined with cellular thermal shift assay (CETSA) was used for analysis. Patient-derived xenograft (PDX) model were built to explore the inhibitory effect of SH in HCC in vivo. RESULTS: In vitro studies showed that SH possessed an anti-HCC effect by inducing autophagy, cell-cycle arrest and promoting cell senescence. Specifically, SH induced autophagy with p62 and LC-3B expression. Flow cytometry analysis revealed that SH caused an obvious cell-cycle arrest, accompanied by the decrease and increase in Cyclin D1 and p27 levels, respectively. Additionally, SH induced cell senescence with the induction of p21 in HCC cell lines. Mechanistically, SH treatment down-regulated the LIF and up-regulated p-AMPK. Moreover, PDX model in NSG mice was conducted to support the results in vitro. CONCLUSION: This study is the first to report the inhibitory function of SH in HCC, which may be due to the induction of autophagy and senescence. This study provides novel insights into the anti-HCC efficacy of SH and it might be a potential lead compound for further development of drug candidates for HCC.

Solamargine induces hepatocellular carcinoma cell apoptosis and autophagy via inhibiting LIF/miR-192-5p/CYR61/Akt signaling pathways and eliciting immunostimulatory tumor microenvironment.

Hepatocellular carcinoma (HCC) is well-known to be a highly prevalent malignant tumor, but the treatment of this pathological state has been still challenging. Solamargine (SM), a traditional Chinese herb-derived compound, has been widely reported to possess multiple antitumor properties. However, whether SM plays a vital role in HCC therapy and how it exerts an antitumor effect remains unclear. Thus, in this study, we demonstrated that SM inhibited the proliferation of HCC and effectively induced HCC cell apoptosis and autophagy in vitro and in vivo. Mechanistically, the oncogenic factor LIF was aberrantly elevated in HCC tissues and down-regulated by SM in HCC cells, as well as subsequently the overexpression of LIF could restore the anti-HCC effects of SM via miR-192-5p/CYR61/Akt signaling pathways. Additionally, SM could repolarize tumor associated macrophages by LIF/p-Stat3 to inhibit the growth and epithelial-mesenchymal transition of HCC, and simultaneously affected other immune cell populations in the immune (tumor) microenvironment by regulating macrophages, such as MDSCs, DCs and T cell populations. Together, these findings exploit the potential use of SM against HCC and shed light on exploring SM as a potent candidate drug for the future HCC therapeutics.

Mutation Characteristics and Phylogenetic Analysis of Five Leishmania Clinical Isolates.

Leishmaniasis is a neglected tropical disease threatening millions of people worldwide. The emergence of antimony-resistant Leishmania strains have brought difficulties to the treatment and elimination of leishmaniasis. This study performed genome sequencing, phylogenetic analysis and mutation analysis of five Leishmania clinical isolates, especially the Leishmania strain L_HCZ isolated in 2016, which shows strong virulence and antimony resistance. By phylogenetic analysis, four isolates (L_DD8, L_801, L_Liu and L_9044) were identified as Leishmania donovani, the isolate L_HCZ was identified as Leishmania infantum and the isolate L_DD8 as a standard strain of L.donovani. Genome-wide mutation analysis was applied to identify mutations related to the drug resistance and virulence of the newly isolated L_HCZ. Compared with the other four Leishmania isolates, L_HCZ had the most mutations in genes associated with antimony resistance, including the ABC transporter, ascorbate-dependent peroxidase, gamma-glutamylcysteine synthetase, glucose-6-phosphate 1-dehydrogenase, ATP-binding cassette protein subfamily A and multi-drug resistance protein-like genes. Among the genes associated with virulence, L_HCZ had the most mutations in cysteine peptidase A, cysteine peptidase B, cysteine peptidase C, heat-shock protein 70, gp63, acid phosphatase, kinesin k39, kinesin, phosphoglycan beta 1, amastin-like surface protein and amastin-like proteins. The mutations in L_HCZ might possibly contribute to its antimony resistance and strong virulence in clinical patients. Whole-genome resequencing has exhibited broad application prospects and may be put into clinical use in the future for parasite identifying and epidemiological investigations.

Cyclin-dependent kinase 1 as a potential target for lycorine against hepatocellular carcinoma.

The pathological changes and possible underlying molecular mechanisms of hepatocellular carcinoma (HCC) are currently unclear. Effective treatment of this pathological state remains a challenge. The purpose of this study is to obtain some key genes with diagnostic and prognostic meaning and to identify potential therapeutic agents for HCC treatment. Here, CDK1, CCNB1 and CCNB2 were found to be highly expressed in HCC patients and accompanied by poor prognosis, and knockdown of them by siRNA drastically induced autophagy and senescence in hepatoma cells. Simultaneously, the anti-HCC effect of lycorine was comparable to that of interfering with these three genes, and lycorine significantly promoted the decrease both in protein and mRNA expression of CDK1. Molecular validation mechanistically demonstrated that lycorine might attenuate the degradation rate of CDK1 via interaction with it, which had been confirmed by cellular thermal shift assay and drug affinity responsive targets stability assay. Taken together, these findings suggested that CDK1, CCNB1 and CCNB2 could be regarded as potential diagnostic and prognostic biomarkers for HCC, and CDK1 might serve as a promising therapeutic target for lycorine against HCC.

Tumor microenvironment: a prospective target of natural alkaloids for cancer treatment.

Malignant tumor has become one of the major diseases that seriously endangers human health. Numerous studies have demonstrated that tumor microenvironment (TME) is closely associated with patient prognosis. Tumor growth and progression are strongly dependent on its surrounding tumor microenvironment, because the optimal conditions originated from stromal elements are required for cancer cell proliferation, invasion, metastasis and drug resistance. The tumor microenvironment is an environment rich in immune/inflammatory cells and accompanied by a continuous, gradient of hypoxia and pH. Overcoming immunosuppressive environment and boosting anti-tumor immunity may be the key to the prevention and treatment of cancer. Most traditional Chinese medicine have been proved to have good anti-tumor activity, and they have the advantages of better therapeutic effect and few side effects in the treatment of malignant tumors. An increasing number of studies are giving evidence that alkaloids extracted from traditional Chinese medicine possess a significant anticancer efficiency via regulating a variety of tumor-related genes, pathways and other mechanisms. This paper reviews the anti-tumor effect of alkaloids targeting tumor microenvironment, and further reveals its anti-tumor mechanism through the effects of alkaloids on different components in tumor microenvironment.

Quantitative assessment of the effectiveness of joint measures led by Fangcang shelter hospitals in response to COVID-19 epidemic in Wuhan, China.

OBJECTIVE: To quantitatively evaluate the effectiveness of Fangcang shelter hospitals, designated hospitals, and the time interval from illness onset to diagnosis toward the prevention and control of the COVID-19 epidemic. METHODS: We used SEIAR and SEIA-CQFH warehouse models to simulate the two-period epidemic in Wuhan and calculate the time dependent basic reproduction numbers (BRNs) of symptomatic infected individuals, asymptomatic infected individuals, exposed individuals, and community-isolated infected individuals. Scenarios that varied in terms of the maximum numbers of open beds in Fangcang shelter hospitals and designated hospitals, and the time intervals from illness onset to hospitals visit and diagnosis were considered to quantitatively assess the optimal measures. RESULTS: The BRN decreased from 4.50 on Jan 22, 2020 to 0.18 on March 18, 2020. Without Fangcang shelter hospitals, the cumulative numbers of cases and deaths would increase by 18.58 and 51.73%, respectively. If the number of beds in the designated hospitals decreased by 1/2 and 1/4, the number of cumulative cases would increase by 178.04 and 92.1%, respectively. If the time interval from illness onset to hospital visit was 4 days, the number of cumulative cases and deaths would increase by 2.79 and 6.19%, respectively. If Fangcang shelter hospitals were not established, the number of beds in designated hospitals reduced 1/4, and the time interval from visiting hospitals to diagnosis became 4 days, the cumulative number of cases would increase by 268.97%. CONCLUSION: The declining BRNs indicate the high effectiveness of the joint measures. The joint measures led by Fangcang shelter hospitals are crucial and need to be rolled out globally, especially when medical resources are limited.

Reverse wedge effect following intramedullary nail fixation of trochanteric fracture, what does it imply?

Lag screw cut-out is the most common cause of fixation failure of trochanteric fractures. Intraoperative assessment of fracture reduction and fixation quality is vital to avoid fracture reduction and achieve good functional outcomes. In a recent study, Zhang et al. reported the occurrence of a reverse wedge effect after intraoperative nail insertion based on a new computed tomography(CT)-guided fracture classification system, which specifically happened to the basicervical facture type and resulted in valgus deformity with gapping at the medial inferior fracture line. Impingement between the reamer/nail and superolateral cortex of the femoral neck has been regarded as the main cause. Based on these findings, together with an extensive literature review, the practicality of the new fracture classification system, the definition of basicervical trochanteric fracture, and the mechanisms underlying the reverse wedge effect have been deeply discussed. More studies should be carried out in the future to analyse pre- and intraoperative related factors that could affect the intraoperative fragment migration effects and determine highly specific measures to address them.

Anticancer activities of TCM and their active components against tumor metastasis.

Traditional Chinese Medicine (TCM) has the characteristics of multiple targets, slight side effects and good therapeutic effects. Good anti-tumor effects are shown by Traditional Chinese Medicine prescription, Chinese patent medicine, single Traditional Chinese Medicine and Traditional Chinese medicine monomer compound. Clinically, TCM prolonged the survival time of patients and improved the life quality of patients, due to less side effects. Cancer metastasis is a complex process involving numerous steps, multiple genes and their products. During the process of tumor metastasis, firstly, cancer cell increases its proliferative capacity by reducing autophagy and apoptosis, and then the cancer cell capacity is stimulated by increasing the ability of tumors to absorb nutrients from the outside through angiogenesis. Both of the two steps can increase tumor migration and invasion. Finally, the purpose of tumor metastasis is achieved. By inhibiting autophagy and apoptosis of tumor cells, angiogenesis and EMT outside the tumor can inhibit the invasion and migration of cancer, and consequently achieve the purpose of inhibiting tumor metastasis. This review explores the research achievements of Traditional Chinese Medicine on breast cancer, lung cancer, hepatic carcinoma, colorectal cancer, gastric cancer and other cancer metastasis in the past five years, summarizes the development direction of TCM on cancer metastasis research in the past five years and makes a prospect for the future.

HTBPI, an active phenanthroindolizidine alkaloid, inhibits liver tumorigenesis by targeting Akt.

Akt, a crucial protein involved in a variety of signaling pathways in cancer, acts as an important regulator of survival in hepatocellular carcinoma (HCC), and provides curative option for the related drugs development. We have found an active phenanthroindolizidine alkaloid, (13aR,14R)-9,11,12,13,13a,14-hexahydro-3,6,7-trimethoxydibenzo[f,h]pyrrolo[1,2-b]isoquinolin-14-ol (HTBPI), is a promising Akt inhibitor effective in the suppression of HCC cells proliferation through stimulating apoptotic and autophagic capability in vivo and in vitro. Treatment of HTBPI combined with a classical autophagy-lysosomal inhibitor (bafilomycin A1), could enhance stimulation effects of apoptosis on HCC cell lines. In addition, we confirmed HTBPI targeting Akt, occupied the kinase binding domain (Thr 308) of Akt to inactivate its function by CETSA and DARTS assay. In contrast, ectopic Akt-induced overexpression significantly abrogated inhibitory effects of HTBPI on cell viability and proliferation. Furthermore, high p-Akt (Thr 308) expression is collated with liver tumor formation and poor survival in HCC patients. In conclusions, HTBPI impeded HCC progress through regulation of apoptosis and autophagy machinery via interaction with p-Akt (Thr 308). This may provide potential molecular candidate by targeting Akt for the therapy of HCC patients.

Sophoridine Inhibits Human Colorectal Cancer Progression via Targeting MAPKAPK2.

Radian Sophorae flavescentis is a traditional Chinese medicine commonly used to treat cancer in China. However, its active components and underlying mechanism remain ambiguous. In this study, we have screened the pharmacokinetic parameters of the main chemical constituents of Radian Sophorae flavescentis by Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database and Analysis Platform and have found that Sophoridine is one of the best antitumor active ingredients. We have found that MAPKAPK2 is a potential target for Sophoridine by the PharmMapper and KEGG databXase analysis. Moreover, we have found that Sophoridine selectively inactivates phospho-MAPKAPK2 (Thr222) and directly binds into the ATP site of MAPKAPK2 by molecular docking. Furthermore, we have found out a direct binding between MAPKAPK2 and Sophoridine by cellular thermal shift assay and drug affinity responsive targets stability assay. The inhibition effects are further confirmed by Western blot: Sophoridine significantly decreases phospho-MAPKAPK2 (Thr222) in a time-dependent manner, but there is no obvious change in its total expression in colorectal cancer cells. Clinical studies have shown that a higher level of MAPKAPK2 is associated with a poorer percent survival rate (prognosis). Furthermore, a higher level of MAPKAPK2 is positively associated with the enrichment of downregulation of apoptosis and autophagy by gene set enrichment analysis, as well as upregulation of proliferation and cell-cycle arrest. Taken together, our results suggest that the MAPKAPK2 plays a key role in Sophoridine-inhibited growth and invasion in colorectal cancers. IMPLICATIONS: These studies show that Sophoridine may be a promising therapeutic strategy that blocks tumorigenesis in colorectal cancers.

7-Deoxynarciclasine shows promising antitumor efficacy by targeting Akt against hepatocellular carcinoma.

Akt is a promising therapeutic target for cancer treatment. In our study, we have identified that 7-deoxynarciclasine (7-DONCS) is a potential inhibitor of Akt, which results in the repression of multiple oncogenic processes in hepatocellular carcinoma (HCC). We have found that 7-DONCS suppresses the growth of HCC by inducing the apoptotic and autophagic capacities, as well as by inhibiting epithelial-mesenchymal transition (EMT) in vitro and in vivo. Pretreatment of cells with specific autophagy inhibitor (Bafilomycin A1) or knockdown of endogenous LC­3B by siRNA strongly enhences 7­DONCS­regulated apoptosis and EMT. Consequently, we have found that 7-DONCS selectively inhibits phospho-Akt (Ser473), and subsequent molecular docking reveals that 7-DONCS directly binds to the C-terminal domain of Akt. Overexpressing Akt significantly blocks these effects via 7-DONCS in HCC cells. Furthermore, 7-DONCS, by targeting Akt, exhibits a promising therapeutic effect in orthotopic hepatocellular tumors. Finally, higher p-Akt expression is associated with poor prognosis, and higher level of Akt was positively correlated with the enrichment of both apoptosis and autophagy downregulation, and EMT upregulation in HCC patients. These studies suggest that 7-DONCS serves as an attractive drug candidate by targeting Akt for future HCC therapy.