Work-related factors and risk of amyotrophic lateral sclerosis: A multivariable Mendelian randomization study.

BACKGROUND: The causal relationship between work-related factors and amyotrophic lateral sclerosis (ALS) is unclear. We used a Mendelian randomization (MR) analysis to investigate the unconfounded association between work-related factors and ALS. METHODS: Univariable MR analyses were conducted to evaluate the causal effects of work-related factors on ALS. Instrumental variables from the UK Biobank on work-related factors (n = 263,615) were used as proxies. The outcome dataset used ALS (n case = 20,806, n control = 59,804) summary-level data from a large-scale genome-wide association study based on European ancestry. MR analysis used inverse variance weighted (IVW), MR-Egger, and weighted median (WM) to assess causal effects and other methods of MR for sensitivity analysis. Further multivariable MR analyses were performed to explore potential mediating effects. RESULTS: In univariable MR, IVW methods support evidence that genetically determined job involves heavy manual or physical work (OR = 2.04, 95% CI: 1.26-3.31; p = .004) was associated with an increased risk of ALS, and the WM methods also confirm this result (OR = 2.36, 95% CI: 1.30-4.28; p = .005). No evidence of heterogeneity or horizontal pleiotropy was found in the results. In multivariable MR, the association was absent after adjusting for smoking and blood pressure. CONCLUSIONS: Our MR analysis results demonstrate the potential causal relationship between jobs that involve heavy manual or physical work and ALS, which might be mediated by smoking and high systolic blood pressure.

The signaling pathways and targets of natural products from traditional Chinese medicine treating gastric cancer provide new candidate therapeutic strategies.

Gastric cancer (GC) is one of the severe malignancies with high incidence and mortality, especially in Eastern Asian countries. Significant advancements have been made in diagnosing and treating GC over the past few decades, resulting in tremendous improvements in patient survival. In recent years, traditional Chinese medicine (TCM) has garnered considerable attention as an alternative therapeutic approach for GC due to its multicomponent and multitarget characteristics. Consequently, natural products found in TCM have attracted researchers' attention, as growing evidence suggests that these natural products can impede GC progression by regulating various biological processes. Nevertheless, their molecular mechanisms are not systematically uncovered. Here, we review the major signaling pathways involved in GC development. Additionally, clinical GC samples were analyzed. Moreover, the anti-GC effects of natural products, their underlying mechanisms and potential targets were summarized. These summaries are intended to facilitate further relevant research, and accelerate the clinical applications of natural products in GC treatment.

A large-scale transcriptional analysis reveals herb-derived ginsenoside F2 suppressing hepatocellular carcinoma via inhibiting STAT3.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common type of cancer that shows great morbidity and mortality rates. However, there are limited available drugs to treat HCC. AIM: The present work focused on discovering the potential anti-HCC compounds from traditional Chinese medicine (TCM) by employing high-throughput sequencing-based high-throughput screening (HTS2) together with the liver cancer pathway-associated gene signature. METHODS: HTS2 assay was adopted for identifying herbs. Protein-protein interaction (PPI) network analysis and computer-aided drug design (CADD) were used to identify key targets and screen the candidate natural products of herbs. Molecular docking, network pharmacology analysis, western blotting, immunofluorescent staining, subcellular fractionation experiment, dual-luciferase reporter gene assay, surface plasmon resonance (SPR) as well as nuclear magnetic resonance (NMR) were performed to validate the ability of compound binding with key target and inhibiting its function. Moreover, cell viability, colony-forming, cell cycle assay and animal experiments were performed to examine the inhibitory effect of compound on HCC. RESULTS: We examined the perturbation of 578 herb extracts on the expression of 84 genes from the liver cancer pathway, and identified the top 20 herbs significantly reverting the gene expression of this pathway. Signal transducer and activator of transcription 3  (STAT3)  was identified as one of the key targets of the liver cancer pathway by PPI network analysis. Then, by analyzing compounds from top 20 herbs utilizing CADD, we found ginsenoside F2 (GF2) binds to STAT3 with high affinity, which was further validated by the results from molecular docking, SPR and NMR. Additionally, our results showed that GF2 suppresses the phosphorylation of Y705 of STAT3, inhibits its nuclear translocation, decreases its transcriptional activity and inhibits the growth of HCC in vitro and in vivo. CONCLUSION: Based on this large-scale transcriptional study, a number of anti-HCC herbs were identified. GF2, a compound derived from TCM, was found to be a chemical basis of these herbs in treating HCC. The present work also discovered that GF2 is a new STAT3 inhibitor, which is able to suppress HCC. As such, GF2 represents a new potential anti-HCC therapeutic strategy.

Ethyl acetate extract of Antenoron Filiforme inhibits the proliferation of triple negative breast cancer cells via suppressing Skp2/p21 signaling axis.

BACKGROUND: Triple negative breast cancer (TNBC) has the worst prognosis of the any breast cancer subtype, and the efficient therapeutical treatment is extremely limited. Antenoron filiforme (Thunb.) Roberty & Vautier (AF) is a Traditional Chinese Medicine (TCM), which is well-known for a diverse array of pharmacological activities, including but not limited to anti-inflammatory, antioxidant and anti-tumors properties. Clinically, AF is commonly prescribed for the treatment of gynecological diseases. PURPOSE: Since TNBC is one of the worst gynecological diseases, the objective of this research is to study the anti-TNBC function of the ethyl acetate extract (EAE) of AF (AF-EAE) and disclose its mechanism of action. MATERIALS AND METHODS: With the aim of elucidating the underlying molecular mechanism and possible chemical basis of AF-EAE in the treatment of TNBC, a comprehensive approach combining system pharmacology and transcriptomic analysis, functional experimental validation, and computational modeling was implemented. Firstly, the potential therapeutic targets of AF-EAE treating TNBC were analyzed by systemic pharmacology and transcriptome sequencing. Subsequently, cell viability assays, cell cycle assays, and transplantation tumor assays were employed to detect the inhibitory effect of AF-EAE on TNBC. Apart from that, the western blot and RT-qPCR assays were adopted to verify its mechanism of action. Finally, the potential chemical basis of anti-TNBC function of AF-EAE was screened through molecular docking and validated by molecular dynamics. RESULTS: This study analyzed the differentially expressed genes after AF-EAE treatment by RNA-sequencing (RNA-seq). It was found that most of the genes were abundant in the gene set termed "cell cycle". Besides, AF-EAE could suppress the proliferation of TNBC cells in vitro and in vivo by inhibiting the function of Skp2 protein. AF-EAE could also lead to the accumulation of p21 and a decrease of CDK6/CCND1 protein, thereby stalling the cycle of cell in the G1/S stage. Notably, clinical data survival analysis clearly demonstrated that Skp2 overexpression has been negatively correlated with survival rates in breast cancer (BC) patients. Further, as suggested by molecular docking and molecular dynamics, the quercetin and its analogues of AF-EAE might bind to Skp2 protein. CONCLUSION: In summary, AF-EAE inhibits the growth of TNBC in vitro and in vivo through targeting Skp2/p21 signaling pathway. While providing a novel potential drug for treating TNBC, this study might establish a method to delve into the action mechanism of TCM.

N-Acetyldopamine Dimer Attenuates DSS-Induced Ulcerative Colitis by Suppressing NF-κB and MAPK Pathways.

Ulcerative Colitis (UC) is a major form of chronic inflammatory bowel disease of the colonic mucosa and exhibits progressive morbidity. There is still a substantial need of small molecules with greater efficacy and safety for UC treatment. Here, we report a N-acetyldopamine dimer (NADD) elucidated (2R,3S)-2-(3',4'-dihydroxyphenyl)-3-acetylamino-7-(N-acetyl-2″-aminoethyl)-1,4-benzodioxane, which is derived from traditional Chinese medicine Isaria cicadae, exhibits significant therapeutic efficacy against dextran sulfate sodium (DSS)-induced UC. Functionally, NADD treatment effectively relieves UC symptoms, including weight loss, colon length shortening, colonic tissue damage and expression of pro-inflammatory factors in pre-clinical models. Mechanistically, NADD treatment significantly inhibits the expression of genes in inflammation related NF-κB and MAPK signaling pathways by transcriptome analysis and western blot, which indicates that NADD inhibits the inflammation in UC might through these two pathways. Overall, this study identifies an effective small molecule for UC therapy.

Semiconductor nanocrystals in sol-gel derived matrices.

Wet-chemically synthesized colloidal semiconductor nanocrystals are unique chromophores which possess properties such as size-dependent absorption and emission, large action cross-sections and flexible surface chemistry. This Perspective summarizes efforts in the field to incorporate these nanocrystals into sol-gel derived matrices, thereby harnessing their salient material properties to enhance or create new avenues for research in applications such as biological imaging, diagnostics and optical amplifiers. A description of the basic chemistry involved in making the semiconductor nanocrystals compatible with the sol-gel process is given, as well as the different strategies developed to localize various types of nanocrystals within the sol-gel network. As the field of semiconductor nanocrystals evolves towards structurally complex multifunctional architectures, the physicochemical attributes of composites of nanocrystals in sol-gel matrices are also dramatically improved. A number of examples from the most recent reports on such structures will be highlighted, along with a brief discussion on the future outlook of such materials.

Ultralow-threshold two-photon pumped amplified spontaneous emission and lasing from seeded CdSe/CdS nanorod heterostructures.

Ultralow-threshold two-photon pumped amplified spontaneous emission (2ASE) and lasing in seeded CdSe/CdS nanodot/nanorod heterostructures is demonstrated for the first time. Such heterostructures allow the independent tunability of the two-photon absorption (2PA) cross-section (σ(2)) through varying the CdS rod size, and that of the emission wavelength through varying the CdSe dot size. With an enhanced σ(2), 2ASE in these heterostructures is achieved with an ultralow threshold fluence of ~1.5 mJ/cm(2), which is as much as one order less than that required for spherical semiconductor NCs. Importantly, by exploiting this unique property of the seeded nanorods exhibiting strong quantum confinement even at relatively large rod sizes, a near reciprocal relation between the 2ASE threshold and the 2PA action cross-section (σ(2)η) (where η is the quantum yield) was found and validated over a wide volume range for II-VI semiconductor nanostructures. Ultrafast optical spectroscopy verified that while the Auger processes in these heterostructures are indeed suppressed, ASE in these samples could also be strongly affected by a fast hole-trapping process to the NR surface states. Lastly, to exemplify the potential of these seeded CdSe/CdS nanodot/nanorod heterostructures as a viable gain media for achieving two-photon lasing, a highly photostable microsphere laser with an ultralow pump threshold is showcased.

Linear cyclen-based polyamine as a novel and efficient reagent in gene delivery.

Linear cyclen-based polyamine (LCPA, M(w) = 7392, M(w)/M(n) = 1.19) as a novel non-viral gene vector was designed and synthesized from 1,7-diprotected 1,4,7,10-tetraazacyclododecane (cyclen), bis(beta-hydroxylethyl)amine and epichlorohydrin. Agarose gel retardation and fluorescent titration using ethidium bromide showed the good DNA-binding ability of LCPA. It could retard pDNA at an N/P ratio of 4 and form polyplexes with sizes around 250-300 nm from an N/P ratio of 10 to 60 and relatively lower zeta-potential values (< +3 mV) even at the N/P ratio of 60. The cytotoxicity of LCPA assayed by MTT is much lower than that of 25 kDa PEI. In vitro transfection against A549 and 293 cells showed that the transfection efficiency of LCPA/DNA polyplexes is close to that of 25 kDa PEI at an N/P ratio of 10-15, indicating that the new material could be a promising non-viral polycationic reagent for gene delivery.

Linear disulfide-containing low polymer as efficient DNA cleavage reagent.

A novel linear poly[1,7-bis(mercaptoacetyl)-1,4,7,10-tetraazacyclododecane] (PBMAC) containing macrocyclic polyamine was synthesized through oxidation of 1,7-bis(mercaptoacetyl)-1,4,7,10-tetraazacyclododecane (BMAC) and characterized. Gel electrophoresis experiments showed that PBMAC can promote the DNA cleavage more efficiently than its monomer under physiological conditions without any thiol additives. Fluorescence quenching and DNA melting experiments demonstrated that PBMAC has stronger binding ability with DNA than that of monomer.