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Background Massive occurrences of interstitial loss of heterozygosity (LOH) likely resulting from gene conversions were found by us in different cancers as a type of single-nucleotide variations (SNVs), comparable in abundance to the commonly investigated gain of heterozygosity (GOH) type of SNVs, raising the question of the relationships between these two opposing types of cancer mutations. Methods In the present study, SNVs in 12 tetra sample and 17 trio sample sets from four cancer types along with copy number variations (CNVs) were analyzed by AluScan sequencing, comparing tumor with white blood cells as well as tissues vicinal to the tumor. Four published “nontumor”-tumor metastasis trios and 246 pan-cancer pairs analyzed by whole-genome sequencing (WGS) and 67 trios by whole-exome sequencing (WES) were also examined. Results Widespread GOHs enriched with CG-to-TG changes and associated with nearby CNVs and LOHs enriched with TG-to-CG changes were observed. Occurrences of GOH were 1.9-fold higher than LOH in “nontumor” tissues more than 2 cm away from the tumors, and a majority of these GOHs and LOHs were reversed in “paratumor” tissues within 2 cm of the tumors, forming forward-reverse mutation cycles where the revertant LOHs displayed strong lineage effects that pointed to a sequential instead of parallel development from “nontumor” to “paratumor” and onto tumor cells, which was also supported by the relative frequencies of 26 distinct classes of CNVs between these three types of cell populations. Conclusions These findings suggest that developing cancer cells undergo sequential changes that enable the “nontumor” cells to acquire a wide range of forward mutations including ones that are essential for oncogenicity, followed by revertant mutations in the “paratumor” cells to avoid growth retardation by excessive mutation load. Such utilization of forward-reverse mutation cycles as an adaptive mechanism was also observed in cultured HeLa cells upon successive replatings. An understanding of forward-reverse mutation cycles in cancer development could provide a genomic basis for improved early diagnosis, staging, and treatment of cancers.

Earlier, prominent occurrences of interstitial loss-of-heterozygosities (LOHs) were found in different cancers as a type of single-nucleotide-variations (SNVs), at rates far exceeding those of the commonly investigated gain-of-heterozygosities (GOHs) type of SNVs. Herein, such co-occurrences of LOHs and GOHs were confirmed in 102 cases of four cancer types analyzed with three different next-generation sequencing platforms, comparing non-tumor, paratumor, and tumor tissues with white-blood-cell controls; and in 246 pan-cancer cases of whole-genome tumor-control pairs. Unexpectedly, large numbers of SNVs enriched with CG>TG GOHs and copy-number-variations (CNVs) proximal to these GOHs were detected in the non-tumor tissues, which were extensively reversed in paratumors showing prominent TG>CG LOHs with proximal CNVs, and less so in tumors to form forward-reverse mutation cycles. Lineage effects in the reversions, likely resulting from directional selection, supported a sequential rather than parallel mode of evolution as described in a 'Stage Specific Populations' model of cancer development.

Testicular dysfunction (TDF) is characterized by testosterone deficiency and is caused by oxidative stress injury in Leydig cells. A natural fatty amide named N-benzylhexadecanamide (NBH), derived from cruciferous maca, has been shown to promote testosterone production. Our study aims to reveal the anti-TDF effect of NBH and explore its potential mechanism in vitro. This study examined the effects of H2O2 on cell viability and testosterone levels in mouse Leydig cells (TM3) under oxidative stress. In addition, cell metabolomics analysis based on UPLC-Q-Exactive-MS/MS showed that NBH was mainly involved in arginine biosynthesis, aminoacyl-tRNA biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis, the TCA cycle and other metabolic pathways by affecting 23 differential metabolites, including arginine and phenylalanine. Furthermore, we also performed network pharmacological analysis to observe the key protein targets in NBH treatment. The results showed that its role was to up-regulate ALOX5, down-regulate CYP1A2, and play a role in promoting testicular activity by participating in the steroid hormone biosynthesis pathway. In summary, our study not only provides new insights into the biochemical mechanisms of natural compounds in the treatment of TDF, but also provides a research strategy that integrates cell metabolomics and network pharmacology in order to promote the screening of new drugs for the treatment of TDF.

The neuroprotective properties of ginsenosides have been found to reverse the neurological damage caused by oxidation in many neurodegenerative diseases. However, the distribution of ginsenosides in different tissues of the main root, which was regarded as the primary medicinal portion in clinical practice was different, the specific parts and specific components against neural oxidative damage were not clear. The present study aims to screen and determine the potential compounds in different parts of the main root in ginseng. Comparison of the protective effects in the main root, phloem and xylem of ginseng on hydrogen peroxide-induced cell death of SH-SY5Y neurons was investigated. UPLC-Q-Exactive-MS/MS was used to quickly and comprehensively characterize the chemical compositions of the active parts. Network pharmacology combined with a molecular docking approach was employed to virtually screen for disease-related targets and potential active compounds. By comparing the changes before and after Content-Effect weighting, the compounds with stronger anti-nerve oxidative damage activity were screened out more accurately. Finally, the activity of the selected monomer components was verified. The results suggested that the phloem of ginseng was the most effective part. There were 19 effective compounds and 14 core targets, and enriched signaling pathway and biological functions were predicted. After Content-Effect weighting, compounds Ginsenosides F1, Ginsenosides Rf, Ginsenosides Rg1 and Ginsenosides Rd were screened out as potential active compounds against neural oxidative damage. The activity verification study indicated that all four predicted ginsenosides were effective in protecting SH-SY5Y cells from oxidative injury. The four compounds can be further investigated as potential lead compounds for neurodegenerative diseases. This also provides a combined virtual and practical method for the simple and rapid screening of active ingredients in natural products.

Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor worldwide and is associated with a poor prognosis. Oxidative stress is a key factor in the occurrence and progression of HCC. KHK-A, a key protein in the oxidative stress pathway, plays an important role in various cancers. This study aimed to discover small-molecule inhibitors targeting KHK-A through structure-based virtual screening, evaluate their therapeutic effects on HCC, and explore the potential of KHK-A as a therapeutic target for HCC. Based on the crystal structure of KHK-A, potential small-molecule inhibitors (HK1 to HK-24) were screened from the SPECS database using the Discovery Studio (DS) 2019 software. The effects of these compounds were evaluated through molecular docking and cellular experiments. The screened compound HK-4 significantly inhibited HCC cell proliferation, migration, and invasion ex vivo. The half-maximal inhibitory concentrations (IC ) of HK-4 in HepG2, PLC/PRF/5, and HuH7 cells were 22.54 µM, 23.91 µM, and 23.38 µM, respectively. HK-4 induced G1 phase arrest and apoptosis, and reduced the protein levels of p-AKT and p-mTOR in the PI3K-AKT signaling pathway. Through structure-based virtual screening, this study identified HK-4, a small-molecule inhibitor of KHK-A with anti-HCC activity. Its mechanism of action is closely related to the regulation of the PI3K-AKT signaling pathway. This finding provides experimental evidence supporting KHK-A as a therapeutic target for HCC and offers a new direction for the development of novel anti-HCC drugs.

Melanoma is the most common malignant skin tumor, characterized by complexity, invasiveness, and heterogeneity. Conventional therapies often yield poor outcomes, posing significant clinical challenges. Here, a microneedle (MN) patch that integrates nanozyme and traditional Chinese medicine (TCM) for ferroptosis pathway‐dependent combined therapy of melanoma is designed. To amplify therapeutic activity, a novel Au@MoS2 bimetallic plasmonic nanozyme (BPNzyme) is prepared through a simple aqueous synthesis strategy involving a two‐step process. Owing to the synergy between heterostructures, this rationally designed BPNzyme exhibits significantly enhanced therapeutic characteristics, including near‐infrared (NIR) photothermal effect, peroxidase‐like activity, and glutathione peroxidase‐like property, which can effectively reshape the tumor microenvironment and disrupt the redox homeostasis. Under the combined action of the TCM β‐elemene (β‐ELE) and NIR light, further enhancement of oxidative damage, lipid peroxidation, and glutathione peroxidase 4 expression downregulation are observed for skin tumor cells, validating the synergistic amplification of ferroptosis. Moreover, the transdermal delivery of BPNzyme and β‐ELE using the soluble hyaluronic acid MN patch effectively achieves 99.8% tumor growth suppression without significant systemic toxicity in vivo. These findings highlight the potential of the rationally designed BPNzyme‐based MN system as a promising innovative strategy for non‐invasive, efficient, and safe combination therapy of melanoma. A microneedle (MN) patch that integrates novel bimetallic plasmonic nanozyme (BPNzyme) and traditional Chinese medicine β‐elemene (β‐ELE) has been rationally designed for ferroptosis pathway‐dependent combined therapy of melanoma.

Cancer therapy faces significant challenges due to the resistance of traditional apoptosis-based treatments. Ferroptosis, an iron-dependent, lipid peroxidation-driven form of programmed cell death, has emerged as a novel therapeutic strategy owing to its unique metabolic regulation mechanisms. However, conventional small-molecule ferroptosis inducers suffer from poor targeting and rapid metabolism. The integration of nanotechnology provides innovative solutions for precise ferroptosis modulation. Among various nanomaterials, two-dimensional (2D) nanomaterials stand out due to their distinctive physicochemical properties and multifunctionality, making them widely studied in ferroptosis-mediated cancer therapy. In this review, we first outline the development, physiological mechanisms, detection markers, and common methodologies of ferroptosis, while highlighting the current challenges in ferroptosis-related cancer therapies. Second, we discuss the general principles of 2D materials in inducing ferroptosis, emphasizing how these platforms enhance ferroptosis efficacy. Third, we classify and elaborate on different types of 2D materials that induce ferroptosis in tumor cells. Finally, we present future perspectives in this field. We hope this review will facilitate the rational design of 2D materials for ferroptosis induction and pave the way for broader biomedical applications.

In this perspective, we outline that a space borne gravitational wave detector network combining LISA and Taiji can be used to measure the Hubble constant with an uncertainty less than 0.5% in ten years, compared with the network of the ground based gravitational wave detectors which can measure the Hubble constant within a 2% uncertainty in the next five years by the standard siren method. Taiji is a Chinese space borne gravitational wave detection mission planned for launch in the early 2030 s. The pilot satellite mission Taiji-1 has been launched in August 2019 to verify the feasibility of Taiji. The results of a few technologies tested on Taiji-1 are presented in this paper. Gravitational wave astronomy has opened the door to test general relativity and the effect of gravity in the Universe. The authors present the capabilities of an overlap between space gravitational wave detectors LISA and Taiji to constrain the Hubble constant to 0.5%, in 10 years, and what can be learned from the satellite pilot Taiji-1 launched in 2019.

Asthenozoospermia is a common cause of decreased male fertility, and several factors can inhibit or prevent sperm motility, including ultrastructural defects of the sperm flagellum） An ultrastructural defect leading to severe asthenozoospermia is a syndrome called dysplasia of the fibrous sheath （DFS）.

Homocysteine is an independent risk factor for various cardiovascular diseases. There are two ways to remove homocysteine from embryonic cardiac cells： remethylation to form methionine or transsolfuration to form cysteine. Cystathionine β-synthase （CBS） catalyzes the first step of homocysteine transsulfuration as a rate-limiting enzyme. In this study, we identified a functional variant -4673C〉G （rs2850144） in the CBS gene promoter region that significant- ly reduces the susceptibility to congenital heart disease （CHD） in a Han Chinese population consisting of 2 340 CHD patients and 2 270 controls. Individuals carrying the heterozygous CG and homozygous GG genotypes had a 15% （odds ratio （OR） = 0.85, 95% confidence interval （CI） = 0.75-0.96, P = 0.011） and 40% （OR = 0.60, 95% CI = 0.49-0.73, P = 1.78 ×10^-7） reduced risk to develop CHD than the wild-type CC genotype carriers in the combined samples, respec-tively. Additional stratified analyses demonstrated that CBS -4673C〉G is significantly related to septation defects and conotruncal defects. In vivo detection of CBS mRNA levels in human cardiac tissues and in vitro luciferase assays consistently showed that the minor G allele significantly increased CBS transcription. A functional analysis revealed that both the attenuated transcription suppressor SP1 binding affinity and the CBS promoter hypomethylation spe-cifically linked with the minor G allele contributed to the remarkably upregulated CBS expression. Consequently, the carriers with genetically increased CBS expression would benefit from the protection due to the low homocysteine levels maintained by CBS in certain cells during the critical heart development stages. These results shed light on un-expected role of CBS and highlight the importance of homocysteine removal in cardiac development.