Small molecule inhibitors targeting m6A regulators.

As the most common form of epigenetic regulation by RNA, N6 methyladenosine (m6A) modification is closely involved in physiological processes, such as growth and development, stem cell renewal and differentiation, and DNA damage response. Meanwhile, its aberrant expression in cancer tissues promotes the development of malignant tumors, as well as plays important roles in proliferation, metastasis, drug resistance, immunity and prognosis. This close association between m6A and cancers has garnered substantial attention in recent years. An increasing number of small molecules have emerged as potential agents to target m6A regulators for cancer treatment. These molecules target the epigenetic level, enabling precise intervention in RNA modifications and efficiently disrupting the survival mechanisms of tumor cells, thus paving the way for novel approaches in cancer treatment. However, there is currently a lack of a comprehensive review on small molecules targeting m6A regulators for anti-tumor. Here, we have comprehensively summarized the classification and functions of m6A regulators, elucidating their interactions with the proliferation, metastasis, drug resistance, and immune responses in common cancers. Furthermore, we have provided a comprehensive overview on the development, mode of action, pharmacology and structure-activity relationships of small molecules targeting m6A regulators. Our aim is to offer insights for subsequent drug design and optimization, while also providing an outlook on future prospects for small molecule development targeting m6A.

Natural products and derivatives for breast cancer treatment: From drug discovery to molecular mechanism.

BACKGROUND: Breast cancer stands as the most common malignancy among women globally and a leading cause of cancer-related mortality. Conventional treatments, such as surgery, hormone therapy, radiotherapy, chemotherapy, and small-molecule targeted therapy, often fall short of addressing the complexity and heterogeneity of certain breast cancer subtypes, leading to drug resistance and metastatic progression. Thus, the search for novel therapeutic targets and agents is imperative. Given their low toxicity and abundant variety, natural products and their derivatives are increasingly considered valuable sources for small-molecule anticancer drugs. PURPOSE: This review aims to elucidate the pharmacological impacts and underlying mechanisms of active compounds found in select natural products and their derivatives, primarily focusing on breast cancer treatment. It intends to underscore the potential of these substances in combating breast cancer and guide future research directions for the development of natural product-based therapeutics. METHODS: We conducted comprehensive searches in electronic databases such as PubMed, Web of Science, and Scopus until October 2023, using keywords such as 'breast cancer', 'natural products', 'derivatives', 'mechanism', 'signaling pathways', and various keyword combinations. RESULTS: The review presents a spectrum of phytochemicals, including but not limited to flavonoids, polyphenols, and alkaloids, and examines their actions in various animal and cellular models of breast cancer. The anticancer effects of these natural products and derivatives are manifested through diverse mechanisms, including induction of cell death via apoptosis and autophagy, and suppression of tumor angiogenesis. CONCLUSION: An increasing array of natural products and their derivatives are proving effective against breast cancer. Future therapeutic strategies can benefit from strategic enhancement of the anticancer properties of natural compounds, optimization for targeted action, improved bioavailability, and minimized side effects. The forthcoming research on natural products should prioritize these facets to maximize their therapeutic potential.

Structure-Guided Discovery and Preclinical Assessment of Novel (Thiophen-3-yl)aminopyrimidine Derivatives as Potent ERK1/2 Inhibitors.

The RAS-RAF-MEK-ERK signaling cascade is abnormally activated in various tumors, playing a crucial role in mediating tumor progression. As the key component at the terminal stage of this cascade, ERK1/2 emerges as a potential antitumor target and offers a promising therapeutic strategy for tumors harboring BRAF or RAS mutations. Here, we identified 36c with a (thiophen-3-yl)aminopyrimidine scaffold as a potent ERK1/2 inhibitor through structure-guided optimization for hit 18. In preclinical studies, 36c showed powerful ERK1/2 inhibitory activities (ERK1/2 IC50 = 0.11/0.08 nM) and potent antitumor efficacy both in vitro and in vivo against triple-negative breast cancer and colorectal cancer models harboring BRAF and RAS mutations. 36c could directly inhibit ERK1/2, significantly block the phosphorylation expression of their downstream substrates p90RSK and c-Myc, and induce cell apoptosis and incomplete autophagy-related cell death. Taken together, this work provides a promising ERK1/2 lead compound for multiple tumor-treatment drug discovery.

Appraising the quality standard of clinical practice guidelines related to central venous catheter-related thrombosis prevention: a systematic review of clinical practice guidelines.

OBJECTIVE: To evaluate the quality and analyse the content of clinical practice guidelines regarding central venous catheter-related thrombosis (CRT) to provide evidence for formulating an evidence-based practice protocol and a risk assessment scale to prevent it. DESIGN: Scoring and analysis of the guidelines using the AGREE II and AGREE REX scales. DATA SOURCES: Pubmed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang, VIP, and the Chinese Biomedical Literature, and the relevant websites of the guideline, were searched from 1 January 2017 to 26 March 2022. ELIGIBILITY CRITERIA: Guidelines covering CRT treatment, prevention, or management were included from 1 January 2017 to 26 March 2022. DATA EXTRACTION AND SYNTHESIS: Three independent reviewers systematically trained in using the AGREE II and AGREE REX scales were selected to evaluate these guidelines. RESULTS: Nine guidelines were included, and the quality grade results showed that three were at A-level and six were at B-level. The included guidelines mainly recommended the prevention measure of central venous CRT from three aspects: risk screening, prevention strategies, and knowledge training, with a total of 22 suggestions being recommended. CONCLUSION: The overall quality of the guidelines is high, but there are few preventive measures for central venous CRT involved in the guidelines. All preventive measures have yet to be systematically integrated and evaluated, and no risk assessment scale dedicated to this field has been recommended. Therefore, developing an evidence-based practice protocol and a risk assessment scale to prevent it is urgent.

Selective autophagy in cancer: mechanisms, therapeutic implications, and future perspectives.

Eukaryotic cells engage in autophagy, an internal process of self-degradation through lysosomes. Autophagy can be classified as selective or non-selective depending on the way it chooses to degrade substrates. During the process of selective autophagy, damaged and/or redundant organelles like mitochondria, peroxisomes, ribosomes, endoplasmic reticulum (ER), lysosomes, nuclei, proteasomes, and lipid droplets are selectively recycled. Specific cargo is delivered to autophagosomes by specific receptors, isolated and engulfed. Selective autophagy dysfunction is closely linked with cancers, neurodegenerative diseases, metabolic disorders, heart failure, etc. Through reviewing latest research, this review summarized molecular markers and important signaling pathways for selective autophagy, and its significant role in cancers. Moreover, we conducted a comprehensive analysis of small-molecule compounds targeting selective autophagy for their potential application in anti-tumor therapy, elucidating the underlying mechanisms involved. This review aims to supply important scientific references and development directions for the biological mechanisms and drug discovery of anti-tumor targeting selective autophagy in the future.

Targeted therapy for non-small-cell lung cancer: New insights into regulated cell death combined with immunotherapy.

Non-small-cell lung cancer (NSCLC), which has a high rate of metastatic spread and drug resistance, is the most common subtype of lung cancer. Therefore, NSCLC patients have a very poor prognosis and a very low chance of survival. Human cancers are closely linked to regulated cell death (RCD), such as apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis. Currently, small-molecule compounds targeting various types of RCD have shown potential as anticancer treatments. Moreover, RCD appears to be a specific part of the antitumor immune response; hence, the combination of RCD and immunotherapy might increase the inhibitory effect of therapy on tumor growth. In this review, we summarize small-molecule compounds used for the treatment of NSCLC by focusing on RCD and pharmacological systems. In addition, we describe the current research status of an immunotherapy combined with an RCD-based regimen for NSCLC, providing new ideas for targeting RCD pathways in combination with immunotherapy for patients with NSCLC in the future.

Targeted regulated cell death with small molecule compounds in colorectal cancer: Current perspectives of targeted therapy and molecular mechanisms.

Colorectal cancer (CRC), a tumor of the digestive system, is characterized by high malignancy and poor prognosis. Currently, targeted therapy of CRC is far away from satisfying. The molecular mechanisms of regulated cell death (RCD) have been clearly elucidated, which can be intervened by drug or genetic modification. Numerous studies have provided substantial evidence linking these mechanisms to the progression and treatment of CRC. The RCD includes apoptosis, autophagy-dependent cell death (ADCD), ferroptosis, necroptosis, and pyroptosis, and immunogenic cell death, etc, which provide potential targets for anti-cancer treatment. For the last several years, small-molecule compounds targeting RCD have been a well concerned therapeutic strategy for CRC. This present review aims to describe the function of small-molecule compounds in the targeted therapy of CRC via targeting apoptosis, ADCD, ferroptosis, necroptosis, immunogenic dell death and pyroptosis, and their mechanisms. In addition, we prospect the application of newly discovered cuproptosis and disulfidptosis in CRC. Our review may provide references for the targeted therapy of CRC using small-molecule compounds targeting RCD, including the potential targets and candidate compounds.

Quercetin ameliorates ferroptosis of rat cardiomyocytes via activation of the SIRT1/p53/SLC7A11 signaling pathway to alleviate sepsis­induced cardiomyopathy.

Sepsis­induced cardiomyopathy (SIC) is a manifestation of multiple organ failure as a result of sepsis and is a serious threat to life. Here, the effect and mechanisms of quercetin (QUE) in SIC were assessed. It was found that patients with SIC expressed lower serum levels of glutathione peroxidase 4 (GPX4) and SIRT1 but higher levels of CK­MB, cTnI, TNF­α, and IL­6 compared with healthy individuals. A dose of 80 µM QUE increased the viability and reduced the ferroptosis of H9C2 cells treated with 1.0 µg/ml LPS in vitro. The administration of QUE decreased the levels of MDA, NADPH, lipid peroxidation and cytoplasmic cytochrome C and upregulated the levels of GSH and TOM 20, thus exerting an anti­oxidative effect via mediating SIRT1 expression. It also activated the SIRT1/p53/SLC7A11 signaling pathway to reduce cellular Fe2+ and PTGS2 levels, decreased cell apoptosis rate, and upregulated the levels of GPX4 and ferritin to inhibit ferroptosis of H9C2 cells in vitro. Injection of QUE into rats activated the SIRT1/p53/SLC7A11 signaling pathway, reduced the levels of CK­MB, cTnI, inflammatory cell infiltration, MDA, NADPH, cytoplasmic cytochrome C, cellular Fe2+, and PTGS2 but upregulated the levels of GSH, TOM 20, GPX4, and ferritin to alleviate SIC in a dose­dependent manner in vivo. To conclude, QUE exerted an anti­ferroptotic effect via activation of the SIRT1/p53/SLC7A11 signaling pathway to dampen SIC both in vivo and in vitro. These findings highlighted a potential therapeutic strategy for the management of SIC.

Quercetin inhibits the NOX2/ROS-mediated NF-κB/TXNIP signaling pathway to ameliorate pyroptosis of cardiomyocytes to relieve sepsis-induced cardiomyopathy.

Sepsis-induced cardiomyopathy (SIC) has high morbidity and mortality. Quercetin (QUE) has been used to treat many inflammatory diseases related to pyroptosis. However, its effect on SIC has not been reported before. We aimed to explore the therapeutic mechanism of QUE on SIC. We found that the expression levels of NOX2, markers of myocardial injury and inflammatory factors related to pyroptosis were upregulated in the serum of SIC patients. QUE improved the viability and reduced the death rate of LPS-treated H9C2 cells. It could downregulate the expression level of NOX2 and alleviate NOX2-induced mitochondrial damage to inhibit the ROS-mediated NF-κB/TXNIP pathway thus ameliorating cell pyroptosis. Overexpression of NOX2 partially attenuated the anti-pyroptotic effects of QUE on LPS-treated H9C2 cells in vitro. Besides, the results of animal experiments reported that the mitochondrial damage was reduced by QUE treatment, which subsequently inhibited the ROS-mediated NF-κB/TXNIP pathway to ameliorate cell pyroptosis to further alleviate myocardial injury in CLP-induced rats in vivo. To conclude, QUE suppressed the NOX2/ROS-mediated NF-κB/TXNIP signaling pathway to ameliorate pyroptosis of cardiomyocytes to relieve SIC.

Discovery of Novel Indazole Chemotypes as Isoform-Selective JNK3 Inhibitors for the Treatment of Parkinson's Disease.

c-Jun N-terminal kinases (JNKs) are involved in the pathogenesis of various diseases. In particular, JNK3 and not JNK1/2 is primarily expressed in the brain and plays a key role in mediating neurodegenerative diseases like Parkinson's disease (PD). Due to the sequence similarity of JNK isoforms, developing isoform-selective JNK3 inhibitors to evaluate their biological functions and therapeutic potential in PD has become a challenge. Herein, docking-based virtual screening and structure-activity relationship studies identified 25c with excellent inhibitory activity against JNK3 (IC50 = 85.21 nM) and exhibited an over 100-fold isoform selectivity for JNK3 over JNK1/2 and remarkable kinase selectivity. 25c showed neuroprotective effects on in vitro and in vivo PD models by selectively inhibiting JNK3. Meanwhile, 25c showed an ideal blood-brain barrier permeability and low toxicity. Overall, this study provided a valuable molecular tool for investigating the role of JNK3 in PD and a solid foundation for developing JNK3-targeted drugs in PD treatment.

Recent advances of ß-catenin small molecule inhibitors for cancer therapy: Current development and future perspectives.

The Wnt/ß-catenin signaling pathway is involved in many cellular physiological processes, including embryonic development, cell proliferation and differentiation, tissue homeostasis and regeneration, etc. Aberrant activation of Wnt/ß-catenin signaling is one of the most typical features in the development and progression of cancer. Abnormal accumulation of ß-catenin, a core component of the Wnt/ß-catenin signaling pathway, is one of the main factors leading to abnormal activation of the Wnt/ß-catenin signaling pathway. Therefore, ß-catenin has become an important target for the development of anticancer drugs. Some ß-catenin small molecule inhibitors have been shown to have the potential to treat cancer, such as the specific ß-catenin/CBP antagonist PRI-724, which has entered phase I/II clinical trials. However, the development and application of ß-catenin inhibitors are still challenging due to their selectivity, specificity and physicochemical properties, etc. This review introduces the Wnt/ß-catenin signaling pathway, focuses on the research progress of ß-catenin small molecule inhibitors, and prospects for the development of drug in the future.

Factors Influencing Post-Stroke Cognitive Impairment in Patients with Type 2 Diabetes Mellitus.

Objective: Type 2 diabetes mellitus (T2DM) and ischemic stroke, which are common diseases among older people, are closely related to cognitive impairment. This study aims to investigate the influencing factors of post-stroke cognitive impairment (PSCI) in patients with T2DM. Methods: We enrolled 161 patients with T2DM who experienced acute ischemic stroke and were hospitalized in the Department of Neurology, Jinan Central Hospital, Shandong, China. Cognitive function was evaluated with the Montreal Cognitive Assessment scale. According to the results, patients were divided into three groups-the cognitively normal group, mild cognitive impairment group, and severe cognitive impairment group. We analyzed general demographic data, laboratory information, imaging data, the results of neuropsychological evaluation, and clinical features as well as influencing factors of PSCI in these patients and established a prediction model. Results: The three groups of patients were significantly different in terms of age, education level, course of diabetes mellitus (DM), recurrent cerebral infarction (RCI), and other factors. RCI, course of DM, and glycated hemoglobin (HbA1c) were independent risk factors of PSCI in patients with T2DM, with odds ratio (95% confidence interval): 7.17 (2.09, 30.37), 5.39 (2.40, 14.59), and 3.89 (1.66, 10.04), respectively, whereas female, senior high school, serum albumin were protective factors: 0.28 (0.07, 0.95), 0.05 (0.01, 0.21), 0.20 (0.08, 0.42), respectively. Furthermore, we constructed a prediction model using sex, age, education level, RCI, DM course, HbA1c and serum albumin and obtained a receiver operating characteristic (ROC) curve. The area under the ROC curve is 0.966, suggesting the significant association of these influencing factors with PSCI in patients with T2DM. Conclusion: In this study, the occurrence of PSCI in patients with T2DM was related to RCI, course of DM, and HbA1c, among other factors. Attention to influencing factors is needed in these patients for early diagnosis and timely intervention of cognitive impairment.

Unraveling the Design and Discovery of c-Jun N-Terminal Kinase Inhibitors and Their Therapeutic Potential in Human Diseases.

c-Jun N-terminal kinases (JNKs), members of the mitogen-activated protein kinase (MAPK) family, are encoded by three genes: jnk1, jnk2, and jnk3. JNKs are involved in the pathogenesis and development of many diseases, such as neurodegenerative diseases, inflammation, and cancers. Therefore, JNKs have become important therapeutic targets. Many JNK inhibitors have been discovered, and some have been introduced into clinical trials. However, the study of isoform-selective JNK inhibitors is still a challenging task. To further develop novel JNK inhibitors with clinical value, a comprehensive understanding of JNKs and their corresponding inhibitors is required. In this Perspective, we introduced the JNK signaling pathways and reviewed different chemical types of JNK inhibitors, focusing on their structure-activity relationships and biological activities. The challenges and strategies for the development of JNK inhibitors are also discussed. It is hoped that this Perspective will provide valuable references for the development of novel selective JNK inhibitors.

Study of the mechanism of mitochondrial division and mitochondrial autophagy in the male reproductive toxicity induced by nickel nanoparticles.

Male reproductive health is deteriorating, and fertility is largely affected by environmental factors. This study aims to investigate the potential mechanism underlying mitochondrial division and mitochondrial autophagy in the male reproductive toxicity of nickel nanoparticles (Ni NPs). An in vivo mouse (BALB/c) model was constructed to calculate testicular organ coefficients and sperm abnormality rates, and detect serum reproductive hormones, testicular pathological morphology, and the expression of Drp1, Pink1, and Parkin proteins. Furthermore, mouse spermatogonia (GC-1 cells) were used as an in vitro model to detect cell viability, apoptosis, intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), ATP and protein expression. After treatment with an additional inhibitor, Mdivi-1, such influences were further detected to explore the possible mechanism of male reproductive toxicity induced by Ni NPs. The in vivo studies showed that compared with the control group, exposure to Ni NPs reduced the serum levels of testosterone, follicle stimulating hormone and luteinizing hormone, increased the sperm abnormality rate, widened the gaps in the seminiferous tubules of the testes, decreased the sperm count, and increased the expression of Drp1, Pink1 and Parkin proteins (all P < 0.05). The in vitro studies further confirmed that compared with the control group, Ni NPs can lead to decreased cell viability, increased apoptosis, accumulation of ROS, decreased MMP and ATP, increased expression of Drp1, Pink1, Parkin, Bax, caspase-9 and caspase-3 proteins, and decreased expression of Bcl-2, resulting in an increased value of Bax/Bcl-2. It is worth noting that such influences induced by Ni NPs were significantly reversed by the additional Mdivi-1. In conclusion, Drp1-mediated mitochondrial division and Pink1/Parkin-mediated mitochondrial autophagy play an important role in the male reproductive toxicity of Ni NPs, during which both of them form an interaction cycle and accelerate the occurrence of cell apoptosis.

Intermittent exposure to airborne particulate matter induces subcellular dysfunction and aortic cell damage in BALB/c mice through multi-endpoint assessment at environmentally relevant concentrations.

Airborne particulate matter (PM) has been linked to cardiovascular diseases, but the underlying mechanisms remain unclear, especially at realistic exposure levels. In this study, both male and female BALB/c mice were employed to assess vascular homeostasis following a standard urban particulate matter, PM SRM1648a, via oropharyngeal aspiration at three environmentally relevant concentrations. The tested indicators included histopathological observation and lipid deposition, as well as redox biology and inflammatory responses. Furthermore, endothelial monolayer, vascular cell apoptosis and subcellular function were assessed to decipher whether episodic PM SRM1648a exposure leads to vascular damage after multiple periods of treatment, including subacute (4 weeks) and subchronic (8 weeks) durations. As a result, PM aspiration caused thickening of airways, leukocytes infiltration and adhesion to alveoli, with the spot of particles engulfed by pulmonary macrophages. Meanwhile, it induced local and systemic oxidative stress and inflammation, but limited pathological changes were captured throughout aortic tissues after either subacute or subchronic treatment. Furthermore, even in the absence of aortic impairment, vascular cell equilibrium has been disturbed by the characteristics of endothelial monolayer disintegration and cell apoptosis. Mechanistically, PM SRM1648a activated molecular markers of ER stress (BIP) and mitochondrial dynamics (DRP1) at both transcriptional and translational levels, which were strongly correlated to ox-inflammation and could serve as early checkpoints of hazardous events. In summary, our data basically indicate that episodic exposure of BALB/c mice to PM SRM1648a exerts limited effects on vascular histopathological alterations, but induces vascular cell apoptosis and subcellular dysfunction, to which local and systemic redox biology and inflammation are probably correlated.

Mechanisms underlying reproductive toxicity induced by nickel nanoparticles identified by comprehensive gene expression analysis in GC-1 spg cells.

The public around the world is increasingly concerned about male reproductive health. The impact of nickel nanoparticles (Ni NPs) on male reproductive toxicity including sperm production, motility and fertilizing capacity has been confirmed by our previous researches. In the current study of Ni NPs-inducing toxicity, the expression profiles of piRNAs and their predicted target genes associated with male infertility, were obtained. The results showed that piR-mmu-32362259 was the highest differential expression multiples in both the testis tissues of male mice and GC-1 cells similarly. Notably, piR-mmu-32362259 target gene was significantly enriched in the PI3K-AKT signaling pathway. All these results suggest that piR-mmu-32362259 may affect the occurrence and development of injury in the mouse spermatogenesis process by regulating the PI3K-AKT signaling pathway. In order to verify the result, piR-mmu-32362259 low-expression lentivirus was used to transfect GC-1 cells to establish a stable transfected cell model. The effects of piR-mmu-32362259 on the viability, cycle and apoptosis as well as related protein expression levels of GC-1 cells induced by Ni NPs were detected using CCK8, flow cytometry and western blot assay, respectively. The results showed that low expression of piR-mmu-32362259 could not only alleviate the decrease of GC-1 cell viability, affect the cell cycle and reduce the apoptosis rate, but also significantly affect the expression levels of key proteins and their downstream molecules of PI3K/AKT/mTOR signaling pathway. Collectively, our current results provide a theoretical basis for further exploring the molecular regulatory mechanism of male reproductive toxicity induced by Ni NPs.

Exposure effects of inhaled nickel nanoparticles on the male reproductive system via mitochondria damage.

Nickel nanoparticles (Ni NPs) have a wide range of application prospects, however there is still a lack of their safety evaluation for the reproductive system. Nowadays, male reproductive health has been widely concerned for the increasing incidence of male infertility. To investigate the male reproductive toxicity induced by Ni NPs and its relation with the mitochondrial fission and mitophagy, male mice were administered with or without 5, 15, and 45 mg/kg of Ni NPs by intratracheal instillation. At the end of intervention, sex hormone level, sperm abnormality rate, pathological morphology of testis, cell apoptosis and the expression levels of Drp1, Pink1 and Parkin proteins in testis tissues were detected. The results indicated that the rate of sperm deformity and serum levels of reproductive hormones increased obviously with the increasing concentrations of Ni NPs. Testicular spermatogenic cells were damaged and the number of apoptotic cells increased significantly. Furthermore, the expressions of key proteins (Drp1, Pink1 and Parkin) related to mitochondrial fission/autophagy in testis tissues also increased after exposure to Ni NPs. Collectively, mitochondria damage may play an important role in male mice reproductive toxicity induced by the intratracheal instillation of Ni NPs.

Effect and mechanism of PI3K/AKT/mTOR signaling pathway in the apoptosis of GC-1 cells induced by nickel nanoparticles.

Nickel nanoparticles (Ni NPs) have a wide range of application prospects, but there is still a lack of their safety evaluation for the reproductive system. Nowadays, male reproductive health has been widely concerned because of the increasing incidence of male infertility. Studies have shown that Ni NPs can cause male reproductive toxicity. The purpose of this study was to investigate the toxicity of Ni NPs on GC-1 cells, a mouse spermatogonia cell line, and to explore the possible mechanism underlying the induction of apoptosis via PI3K/AKT/mTOR signaling pathway. The cell ultrastructure was firstly observed under a transmission electron microscope. Then, cell proliferation, cycle and apoptosis were detected by CCK-8 and flow cytometry, respectively. Furthermore, the expression levels of related proteins and genes were determined by Western blot and Reverse transcription-polymerase chain reaction, respectively. The results showed that Ni NPs could not only cause changes in cell ultrastructure, decreased survival rate and arrested G1 phase cell cycle, but also activated apoptosis pathway by inhibiting the PI3K/AKT/mTOR signaling pathway. The results of this study provide novel insights to explore the mechanisms of reproductive toxicity of Ni NPs and are of great significance to develop safety evaluation criteria for Ni NPs.

Advance on toxicity of metal nickel nanoparticles.

As a kind of conventional metal nanomaterial, nickel nanoparticles (Ni NPs) have broad application prospects in the fields of magnetism, energy technology and biomedicine and have quickly attracted great interest. The potential negative effects of Ni NPs have also attracted wide attention from some researchers. Studies have shown that Ni NPs cause a variety of toxic effects on cells, animals and humans and have toxic effects of multiple systems such as respiratory system, cardiovascular system and reproductive system. Ni NPs can lead to oxidative stress, apoptosis, DNA damage and inflammation and induce the increase of intracellular reactive oxygen species. The toxicity of Ni NPs is also found to be related to the mitogen-activated protein kinase pathway and the hypoxia inducible factor-1α pathway. Therefore, the toxicity and mechanism of Ni NPs are reviewed in this paper, and the future researches in this field are also proposed.