Failure Analysis for Overall Overturning of Concrete Single-Column Pier Bridges Induced by Temperature and Overloaded Vehicles.

Several overloaded-induced overturning incidents of girder bridges with single-column piers have occurred in recent years, resulting in significant casualties and economic losses. Temperature, in addition to overloading, may also play a role in exacerbating bridge overturning. To investigate the association between temperature and bridge overturning, an explicit finite element model (EFEM) of a three-span concrete curved continuous bridge considering nonlinearities was developed to simulate overall collapse. The effects of uniform and gradient temperatures on the overall overturning stability of curved and straight bridges were evaluated based on the EFEMs. Furthermore, the temperature-bridge coupling model and temperature-vehicle-bridge coupling model were utilized to examine how gradient temperature influences bridge overturning. The results show that the overall overturning collapse of a bridge follows four stages: stabilization, transition, risk and overturning. Variations in uniform temperature from -30 °C to 60 °C had a negligible effect on the ultimate vehicle weight for bridge overturning, with a variation of less than 1%. As the gradient temperature ranged from -30 °C to 60 °C, curved bridges show less than a 2% variation in ultimate vehicle weights, compared to a range of -6.1% to 11.7% for straight bridges. The torsion caused by positive gradient temperature in curved bridges can exacerbate bridge overturning, while negative gradient temperature in straight bridges can lead the girder to 'upward warping', facilitating girder separation from bearings. Monitoring the girder rotation angle and vertical reaction force of bearings can serve as important indicators for comparing the stability of bridges.

Risk factors for incident venous thromboembolism in patients with renal tumor and inferior vena cava tumor thrombus: a retrospective case-control study.

BACKGROUND: Venous thromboembolism (VTE) is a principal cause of mortality and adverse oncologic outcomes in patients with renal tumor and inferior vena cava tumor thrombus (RT-IVCTT). However, the preoperative thrombotic risk factors in these patients remain not fully characterized. OBJECTIVES: To identify preoperative thrombotic risk factors in patients with RT-IVCTT. PATIENTS/METHODS: Two hundred fifty-seven consecutive postsurgical patients with RT-IVCTT aged 18-86 years were enrolled between January 2008 and September 2022. Clinicopathological variables were retrospectively reviewed. A multivariate logistic regression model was performed. Preoperative hemoglobin, neutrophils, and serum albumin levels were analyzed as both continuous and categorical variables. RESULTS: VTE was identified in 63 patients (24.5%). On both continuously and categorically coded variables, advanced IVC thrombus (OR 3.2, 95% CI: 1.4-7.0; OR 2.7, 95% CI: 1.2-6.1), renal sinus fat invasion (OR 3.4, 95% CI: 1.6-7.0; OR 3.7, 95% CI: 1.8-7.7), IVC wall invasion (OR 3.6, 95% CI: 1.6-7.9; OR 4.3, 95% CI: 1.9-10.0), IVC blockage status of greater than 75% (OR 5.2, 95% CI: 1.7-15.8; OR 6.1, 95% CI: 1.9-19.7), and higher neutrophils (OR 1.3, 95% CI: 1.0-1.7; OR 2.4, 95% CI: 1.1-5.4) were significantly associated with increased VTE risk in patients with RT-IVCTT. Except hemoglobin, categorically coded serum albumin (OR 0.36, 95% CI: 0.17-0.75) was validated as an independent risk factor for VTE. CONCLUSIONS: This study provided an insight of risk factors contributing to preoperative VTE in patients with RT-IVCTT, which may be beneficial for optimizing strategies to manage VTE in clinical practice.

Management of Class III Malocclusion and Maxillary Transverse Deficiency with Microimplant-Assisted Rapid Palatal Expansion (MARPE): A Case Report.

Microimplant-assisted rapid palatal expansion (MARPE) has been demonstrated successfully in maxillary expansion in late adolescence and adulthood. The maxillary advancement accompanied by expansion is frequently anticipated, which is beneficial for the treatment of class III malocclusion. Airway volume increase can also be noted in some cases from the measurement of cone beam computerized tomography (CBCT) after expansion. The objective of this case report is to demonstrate the feasibility of applying MARPE on late adolescence patients with maxillary transverse deficiency and to present the changes in transverse and anteroposterior dimensions as well as the volume increase in velopharyngeal airway after MARPE. A 15-year-old female presented class III skeletal pattern. She had maxillary transverse deficiency with moderate crowding and posterior/anterior crossbites. Maxillary Skeletal Expander (MSE; Biomaterials Korea Inc.) type-2 was used as a MARPE device in this case. After four weeks of maxillary expansion, a significant amount of expansion was achieved and the anterior crossbite was spontaneously corrected. Fixed appliance treatment was commenced four weeks after MARPE with 0.022-slot preadjusted brackets (MBT prescription). Temporary anchorage devices (TADs) were placed over the mandibular buccal shelves for posterior teeth distalization and crowding relief. After 25 months of treatment, the facial profile was improved with maxillary advancement (SNA: 83° to 83.5°) and mandibular backward rotation (SNB: 83° to 82°; SN-MP: 34.5° to 35°). In this case, MARPE not only engenders significant transverse correction but also aids in anteroposterior change. The treatment effects of maxillary advancement and mandibular backward rotation can lead to a more esthetic profile in skeletal class III cases.

VSIG4 overexpression alleviates acute kidney injury of mice via inhibition of M1-macrophages activation.

Background: The infiltration and activation of M1-macrophages can promote renal tubular interstitial damage. The study aimed to investigate the effect of V-set and immunoglobulin domain containing 4 (VSIG4) on M1-macrophages activation and acute kidney injury (AKI) mice. Methods: The M1-macrophage markers cluster of differentiation 86 (CD86) and inducible nitric oxide synthase (iNOS) were detected via flow cytometry. Cell viability and expression of inflammatory factors were analyzed through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), as well as quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) assays. Moreover, HK-2 cells stimulated with lipopolysaccharide (LPS) and RAW264.7 cells overexpressing VSIG4 were co-cultured to analyze the effect of VSIG4 suppressing M1-macrophage activation on HK-2 cells via detecting cell proliferation and apoptosis levels. Furthermore, the pathological changes and iNOS expression of kidney tissue in VSIG4 knockout mice with renal ischemia-reperfusion injury (IRI) were detected by hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining. Results: Overexpression of VSIG4 partially reversed the phenomenon of M1-macrophageactivation caused by LPS-upregulated CD86 and iNOS expression, reduced cell viability, and induced the expression levels of interleukin 1ß (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) in RAW264.7. In addition, RAW264.7 cells overexpressing VSIG4 could also alleviate the low proliferation and high apoptotic level of HK-2 cells stimulated with LPS. After VSIG4 knockout, the kidney tissue of AKI mice showed obvious lesions and iNOS expression, indicating that VSIG4 knockout promoted the infiltration of M1-macrophages in the damaged kidney tissue and accelerated kidney tissue lesions. Conclusions: Overexpression of VSIG4 might alleviate the lesions of kidney tissue in AKI mice via inhibition of the secretion of inflammatory factors in M1-macrophages.

Research on Knee Joint Load and Influencing Factors of Typical Tai Chi Movements.

Background: Tai chi is recognized worldwide for its rehabilitation abilities and healthcare benefits. However, in recent years, some movements associated with tai chi have been shown to damage the lower limb joints. The purpose of this study was to investigate and compare the effects of different movements, postures, center of mass (COM) movements, and range of knee movement of tai chi exercises on knee joint load. Methods: Fourteen professional tai chi practitioners in two postures (high and low) were enrolled to perform the following four typical tai chi movements: wild horse's mane (WHM), repulse monkey (RM), wave-hand in cloud (WHIC), and grasp the bird's tail (GBT). Kinematic and kinetics data were synchronously collected using the Vicon infrared high-speed motion capture system and a three-dimensional (3D) force measurement platform. Variance analysis and partial correlation analysis were performed to investigate factors influencing peak knee joint moment and vertical ground reaction force (VGRF). Results: The results showed that the peak knee extension and abduction moment were larger in WHM and RM than those in WHIC and GBT (p < 0.05). WHM was associated with greater rotation moment than the other typical movements (p < 0.05). VGRF and joint moment among different poses were significantly different. Low-pose tai chi typical movements were associated with greater VGRF, knee joint extension and abduction, and rotation moments than high-pose movements (p < 0.05). The anteroposterior and mediolateral COM displacements were strongly and positively associated with VGRF (p < 0.001), while the mediolateral COM displacement was negatively associated with knee extension moment (p < 0.001). The knee internal-external rotation ROM and anteroposterior and mediolateral COM displacements were positively associated with knee abduction moment (p < 0.01). Conclusion: For long-term tai chi exercises, choosing a suitable posture based on an individual exercise level and reasonable control of knee ROM and COM displacement can reduce the risk of knee injury during exercise.

Treatment of Liver Cancer: Role of the Traditional Mongolian Medicine.

Liver cancer is an extraordinarily heterogeneous malignancy with relatively high mortality and increasing incidence rate among the so far identified cancers. Improvements in liver cancer therapy have been made in the past decades, but therapeutics against liver cancer are still limited. Traditional Mongolian Medicine, formed and developed by the Mongolian people to maintain health in the medical practice of fighting against diseases, has been recognized as one of the key components of the world healthcare system. Traditional Mongolian Medicine has been used to treat various malignancies, including liver cancer, for a long time in Asia and its advantages have become more and more apparent. Herein, this review made a comprehensive summary of Traditional Mongolian Medicine, including the ideas in the liver cancer treatment, sources of medicines or prescriptions, traditional applications, modern pharmacological research, chemical structure and mechanisms of several monomer compounds isolated from Traditional Mongolian Medicine, with a view to finding promising drugs against liver cancer and expanding the clinical application of Traditional Mongolian Medicine in liver cancer therapy.

Vertically Ordered Mesoporous Silica-Nanochannel Film-Equipped Three-Dimensional Macroporous Graphene as Sensitive Electrochemiluminescence Platform.

Three-dimensional (3D) electrochemiluminescence (ECL) platform with high sensitivity and good anti-fouling is highly desirable for direct and sensitive analysis of complex samples. Herein, a novel ECL-sensing platform is demonstrated based on the equipment of vertically ordered mesoporous silica-nanochannel films (VMSF) on monolithic and macroporous 3D graphene (3DG). Through electrografting of 3-aminopropyltriethoxysilane (APTES) onto 3DG as molecular glue, VMSF grown by electrochemically assisted self-assembly (EASA) method fully covers 3DG surface and displays high stability. The developed VMSF/APTES/3DG sensor exhibits highly sensitized ECL response of tris(2,2'-bipyridyl) ruthenium (Ru (bpy)3 2+) taking advantages of the unique characteristics of 3DG (high active area and conductivity) and VMSF nanochannels (strong electrostatic enrichment). The VMSF/APTES/3DG sensor is applied to sensitively detect an important environmental pollutant (4-chlorophenol, with limit of detection or LOD of 30.3 nM) in term of its quenching effect (ECL signal-off mode) toward ECL of Ru (bpy)3 2+/tri-n-propylamine (TPrA). The VMSF/APTES/3DG sensor can also sensitively detect the most effective antihistamines chlorpheniramine (with LOD of 430 nM) using ECL signal-on mode because it acts as co-reactant to promote the ECL of Ru (bpy)3 2+. Combined with the excellent antifouling ability of VMSF, the sensor can also realize the analysis of actual environmental (lake water) and pharmaceutical (pharmacy tablet) samples. The proposed 3D ECL sensor may open new avenues to develop highly sensitive ECL-sensing platform.

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.

One-Step Preparation of Nitrogen-Doped Graphene Quantum Dots With Anodic Electrochemiluminescence for Sensitive Detection of Hydrogen Peroxide and Glucose.

Simple and efficient synthesis of graphene quantum dots (GQDs) with anodic electrochemiluminescence (ECL) remains a great challenge. Herein, we present an anodic ECL-sensing platform based on nitrogen-doped GQDs (N-GQDs), which enables sensitive detection of hydrogen peroxide (H2O2) and glucose. N-GQDs are easily prepared using one-step molecular fusion between carbon precursor and a dopant in an alkaline hydrothermal process. The synthesis is simple, green, and has high production yield. The as-prepared N-GQDs exhibit a single graphene-layered structure, uniform size, and good crystalline. In the presence of H2O2, N-GQDs possess high anodic ECL activity owing to the functional hydrazide groups. With N-GQDs being ECL probes, sensitive detection of H2O2 in the range of 0.3-100.0 µM with a limit of detection or LOD of 63 nM is achieved. As the oxidation of glucose catalyzed by glucose oxidase (GOx) produces H2O2, sensitive detection of glucose is also realized in the range of 0.7-90.0 µM (LOD of 96 nM).

Clinicopathological features, risk factors, and outcomes of immunoglobulin A nephropathy associated with hepatitis B virus infection.

BACKGROUND: Hepatitis B virus (HBV) infections are associated with an increased risk of kidney diseases. However, the effects of HBV infection on the prognosis of immunoglobulin A nephropathy (IgAN) are unclear. METHODS: A total of 838 patients with biopsy-confirmed IgAN were enrolled in this retrospective cohort study. The patients were categorized into either affected by IgAN and HBV infection (HBsAg-IgAN) or by primary IgAN with no sign of HBV infection (P-IgAN). A 1:1 propensity-score matching was performed between the two groups, followed by a Kaplan-Meier survival analysis, to compare the prognoses, and a Cox regression analysis, to identify factors influencing the HBsAg-IgAN outcomes. RESULTS: A total of 176 pairs of patients were successfully matched. A significant difference in the systolic blood pressure and urea, serum creatinine, uric acid, and 24-h urine protein levels was observed between the groups. A renal pathological analysis also revealed a significant difference in the mesangial hypercellularity between the groups. During a median follow-up period of 2.4 years, Kaplan-Meier analysis also revealed a significant difference in the renal survival between the groups. Furthermore, multivariate Cox analysis confirmed that HBV infection is an independent risk factor for IgAN progression (hazard ratio [HR] 2.096; 95% confidence interval [CI] 1.091-4.026). Finally, the HBsAg-IgAN patients who received treatment with renin-angiotensin-aldosterone system inhibitors had a better overall prognosis than those who received immunosuppressive therapy and antiviral treatment. CONCLUSION: Our results indicate that the clinicopathological features and outcomes of patients with IgAN differ significantly between those with and without HBV infection, and that HBV is an independent risk factor for IgAN progression.

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.

Effect of Massage on the TLR4 Signalling Pathway in Rats with Neuropathic Pain.

This study set out to investigate the effect of massage on the Toll-like receptor 4 (TLR4) signalling pathway in the dorsal root ganglia of rats that had undergone spinal nerve ligation (SNL), with the hypothesis that massage could be used as an analgesic. Forty female SD rats were randomly divided into 5 groups: the control group, sham-operated group, model group, sham massage group, and massage group. There were 8 rats in each group. SNL rat models were established in the model group, sham massage group, and massage group. Rats in the sham-operated group underwent surgery to expose the vertebral nerves, but no further procedures were performed. The control group consisted of intact animals. The rats in the massage group underwent massage using a massage simulation machine once a day for 14 d in succession; the hind limbs of the rats in the sham massage group were gently touched with a cloth bag once a day for 14 continuous days. The rats in the control group, the sham-operated group, and the model group did not receive any intervention and were observed for 14 d. Paw withdrawal thermal latency (PWTL) and paw withdrawal mechanical threshold (PWMT) of rats in each group were detected 1 d before modelling and at 1, 3, 7, and 14 d after modelling. Fourteen days after modelling, the expression levels of TLR4, IRAK1, TRAF6, TNF-α, and IL-6 were detected in all rats. The PWTL and PWMT of SNL rats were decreased, while these parameters were elevated after massage. SNL rats showed higher levels of TLR4, IRAK1, TRAF6, IL-6, and TNF-α, and massage effectively lowered the expression levels of these molecules. Inhibiting activation of the TLR4 signalling pathway, which can reduce the release of inflammatory factors, may be one mechanism by which massage treats neuropathic pain.

Cellular senescence and cancer: Focusing on traditional Chinese medicine and natural products.

Cancer is the principal cause of death and a dominant public health problem which seriously threatening human life. Among various ways to treat cancer, traditional Chinese medicine (TCM) and natural products have outstanding anti-cancer effects with their unique advantages of high efficiency and minimal side effects. Cell senescence is a physiological process of cell growth stagnation triggered by stress, which is an important line of defence against tumour development. In recent years, active ingredients of TCM and natural products, as an interesting research hotspot, can induce cell senescence to suppress the occurrence and development of tumours, by inhibiting telomerase activity, triggering DNA damage, inducing SASP, and activating or inactivating oncogenes. In this paper, the recent research progress on the main compounds derived from TCM and natural products that play anti-cancer roles by inducing cell senescence is systematically reviewed, aiming to provide a reference for the clinical treatment of pro-senescent cancer.

IRF1-mediated downregulation of PGC1α contributes to cardiorenal syndrome type 4.

Cardiorenal syndrome type 4 (CRS4) is a common complication of chronic kidney disease (CKD), but the pathogenic mechanisms remain elusive. Here we report that morphological and functional changes in myocardial mitochondria are observed in CKD mice, especially decreases in oxidative phosphorylation and fatty acid metabolism. High phosphate (HP), a hallmark of CKD, contributes to myocardial energy metabolism dysfunction by downregulating peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α). Furthermore, the transcriptional factor interferon regulatory factor 1 (IRF1) is revealed as the key molecule upregulated by HP through histone H3K9 acetylation, and responsible for the HP-mediated transcriptional inhibition of PGC1α by directly binding to its promoter region. Conversely, restoration of PGC1α expression or genetic knockdown of IRF1 significantly attenuates HP-induced alterations in vitro and in vivo. These findings demonstrate that IRF1-PGC1α axis-mediated myocardial energy metabolism remodeling plays a crucial role in the pathogenesis of CRS4.

Klotho is regulated by transcription factor Sp1 in renal tubular epithelial cells.

BACKGROUND: Klotho is a multifunctional protein, which exists both in a membrane bound and a soluble form. In renal tubules, Klotho is involved in cell senescence, anti-oxidant response, and renal fibrosis, thus regulation of its expression is critical to understand its roles in renal diseases. Indeed, reduced expression was observed in various renal disease. However, the mechanisms underlying transcriptional regulation of the human klotho gene (KL) largely remain unknown. RESULTS: Here we demonstrated that the Klotho expression in human renal tubular epithelial cells (RTECs) was enhanced by overexpression of the transcription factor Sp1. On the contrary, Klotho expression was decreased by Sp1 knockdown. Besides, increased expression of Sp1 alleviated TGF-ß1-induced fibrosis in HK-2 cells by inducing Klotho expression. Luciferase reporter assays and chromatin immunoprecipitation assays further identified the binding site of Sp1 was located in - 394 to - 289 nt of the KL promoter, which was further confirmed by mutation analysis. CONCLUSIONS: These data demonstrate that KL is a transcriptional target of Sp1 and TGF-ß1-induced fibrosis was alleviated by Sp1 in human RTECs by directly modulating Klotho expression, which help to further understand the transcriptional regulation of Klotho in renal disease models.

Coherent phonon dynamics in spatially separated graphene mechanical resonators.

Vibrational modes in mechanical resonators provide a promising candidate to interface and manipulate classical and quantum information. The observation of coherent dynamics between distant mechanical resonators can be a key step toward scalable phonon-based applications. Here we report tunable coherent phonon dynamics with an architecture comprising three graphene mechanical resonators coupled in series, where all resonators can be manipulated by electrical signals on control gates. We demonstrate coherent Rabi oscillations between spatially separated resonators indirectly coupled via an intermediate resonator serving as a phonon cavity. The Rabi frequency fits well with the microwave burst power on the control gate. We also observe Ramsey interference, where the oscillation frequency corresponds to the indirect coupling strength between these resonators. Such coherent processes indicate that information encoded in vibrational modes can be transferred and stored between spatially separated resonators, which can open the venue of on-demand phonon-based information processing.

IRF-1 promotes renal fibrosis by downregulation of Klotho.

Although the key role of renal fibrosis in the progression of chronic kidney disease (CKD) is well known, the causes of renal fibrosis are not fully clarified. In this study, interferon regulatory factor 1 (IRF-1), a mammalian transcription factor, was highly expressed in fibrotic kidney of CKD patients. Concordantly, the expression level of IRF-1 was significantly elevated in the kidney of unilateral ureteral obstruction (UUO) and Adriamycin nephropathy (ADR) mice. In tubular epithelial cells, overexpression of IRF-1 could induce profibrotic markers expression, which accompanied by dramatic downregulation of Klotho, an important inhibitor of renal fibrosis. Luciferase reporter analysis and ChIP assay revealed that IRF-1 repressed Klotho expression by downregulation of C/EBP-ß, which regulates Klotho gene transcription via directly binding to its promoter. Further investigation showed that tumor necrosis factor-alpha may be an important inducement for the increase of IRF-1 in tubular epithelial cells after UUO and genetic deletion of IRF-1 attenuated renal fibrosis in UUO mice. Hence, these findings demonstrate that IRF-1 contributes to the pathogenesis of renal fibrosis by downregulation of Klotho, and suppresses IRF-1 may be a potential therapeutic target for CKD.

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.

Alkaloids from Traditional Chinese Medicine against hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has become one of the major diseases that are threatening human health in the 21st century. Currently there are many approaches to treat liver cancer, but each has its own advantages and disadvantages. Among various methods of treating liver cancer, natural medicine treatment has achieved promising results because of their superiorities of high efficiency and availability, as well as low side effects. Alkaloids, as a class of natural ingredients derived from traditional Chinese medicines, have previously been shown to exert prominent anti-hepatocarcinogenic effects, through various mechanisms including inhibition of proliferation, metastasis and angiogenesis, changing cell morphology, promoting apoptosis and autophagy, triggering cell cycle arrest, regulating various cancer-related genes as well as pathways and so on. As a consequence, alkaloids suppress the development and progression of liver cancer. In this study, the mechanisms of representative alkaloids against hepatocarcinoma in each class are described systematically according to the structure classification, which mainly divides alkaloids into piperidine alkaloids, isoquinoline alkaloids, indole alkaloids, terpenoids alkaloids, steroidal alkaloids and other alkaloids. Besides using them alone, synergistic effects created together with other chemotherapy drugs and some special preparation methods also have been demonstrated. In this review, we have summarized the potential roles of several common alkaloids in the prevention and treatment of HCC, by revising the preclinical studies, highlighting the potential applications of alkaloids when they function as a therapeutic choice for HCC treatment, and integrating them into clinical practices.

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.