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Tumors have a huge impact on human life and are now the main cause of disease-related deaths. The main means of treatment are surgery and radiotherapy, but they are more damaging to the organism and have a poor postoperative prognosis. Therefore, we urgently need safe and effective drugs to treat tumors. In recent years, Chinese herbal medicines have been widely used in tumor therapy as complementary and alternative therapies. Medicinal and edible herbs are popular and have become a hot topic of research, which not only have excellent pharmacological effects and activities, but also have almost no side effects. Therefore, as a typical medicine and food homology, some components of Paeoniae Radix Alba (PRA, called Baishao in China) have been shown to have good efficacy and safety against cancer. Numerous studies have also shown that Paeoniae Radix Alba and its active ingredients treat cancer through various pathways and are also one of the important components of many antitumor herbal compound formulas. In this paper, we reviewed the literature on the intervention of Paeoniae Radix Alba in tumors and its mechanism of action in recent years and found that there is a large amount of literature on its effect on total glucosides of paeony (TGP) and paeoniflorin (PF), as well as an in-depth discussion of the mechanism of action of Paeoniae Radix Alba and its main constituents, with a view to promote the clinical development and application of Paeoniae Radix Alba in the field of antitumor management.

Abstract Graphene quantum dots (GQDs) have garnered significant attention across numerous fields due to their ultrasmall size and exceptional properties. However, their extensive applications may lead to environmental exposure and subsequent uptake by humans. Yet, conflicting reports exist regarding the potential toxicity of GQDs based on experimental investigations. Therefore, a comprehensive understanding of GQD biosafety requires further microscopic and molecular-level investigations. In this study, we employed molecular dynamics (MD) simulations to explore the interactions between GQDs and graphene oxide quantum dots (GOQDs) with a protein model, the human intestinal fatty acid binding protein (HIFABP), that plays a crucial role in mediating the carrier of fatty acids in the intestine. Our MD simulation results reveal that GQDs can be adsorbed on the opening of HIFABP, which serves as an entrance for the fatty acid molecules into the protein’s interior cavity. This adsorption has the potential to obstruct the opening of HIFABP, leading to the loss of its normal biological function and ultimately resulting in toxicity. The adsorption of GQDs is driven by a combination of van der Waals (vdW), π-π stacking, cation-π, and hydrophobic interactions. Similarly, GOQDs also exhibit the ability to block the opening of HIFABP, thereby potentially causing toxicity. The blockage of GOQDs to HIFABP is guided by a combination of vdW, Coulomb, π-π stacking, and hydrophobic interactions. These findings not only highlight the potential harmful effects of GQDs on HIFABP but also elucidate the underlying molecular mechanism, which provides crucial insights into GQD toxicology.

Abstract The oxalate-carbonate pathway (OCP) involves degradation of soil oxalate to carbonate. To exploit and manage this natural mineralization of assimilated atmospheric CO2 into stable carbonates, improved understanding of this complex biotransformation process is needed. A strain of oxalate-degrading bacteria, Azospirillum sp. OX-1, was isolated from soil, and its secondary products of calcium oxalate degradation were analyzed and characterized using SEM, XRD, TG/DTG-DTA and FTIR-spectroscopy. The molecular mechanism of calcium oxalate degradation was also analyzed using proteomics. The results showed, for the first time, that OX-1 could not only degrade calcium oxalate to calcium carbonate, but also that the process was accompanied by synthesis of methane. Proteomic analysis demonstrated that OX-1 has a dual enzyme system for calcium oxalate degradation, using formyl-CoA transferase (FRC) and thiamine pyrophosphate (ThDP)-dependent oxalyl-CoA decarboxylase (OXC) to form calcium carbonate. Up-regulated expression of enzymes related to methane synthesis was also detected during calcium oxalate degradation. Since methane is also a potent greenhouse gas, these new results suggest that the utility of exploiting the OCP to reduce atmospheric CO2 must be re-evaluated and that further studies should be conducted to reveal how widespread the methane producing capacity of strain OX-1 is in other bacteria and soil environments.

Abstract The limited understanding of the molecular mechanism underlying MYCN-amplified (MNA) neuroblastoma (NB) has hindered the identification of effective therapeutic targets for MNA NB, contributing to its higher mortality rate compared to MYCN non-amplified (non-MNA) NB. Therefore, a comprehensive analysis integrating metabolomics and transcriptomics was conducted to systematically investigate the MNA NB. Metabolomics analysis utilized plasma samples from 28 MNA NB patients and 68 non-MNA NB patients, while transcriptomics analysis employed tissue samples from 15 MNA NB patients and 37 non-MNA NB patients. Notably, joint metabolomics and transcriptomics analysis was performed. A total of 46 metabolites exhibited alterations, with 21 displaying elevated levels and 25 demonstrating reduced levels in MNA NB. In addition, 884 mRNAs in MNA NB showed significant changes, among which 766 mRNAs were higher and 118 mRNAs were lower. Joint-pathway analysis revealed three aberrant pathways involving glycerolipid metabolism, purine metabolism, and lysine degradation. This study highlights the substantial differences in metabolomics and transcriptomics between MNA NB and non-MNA NB, identifying three abnormal metabolic pathways that may serve as potential targets for understanding the molecular mechanisms underlying MNA NB.

Adreno-cortical carcinoma (ACC) is an uncommon tumor, some of them may produce excessive steroid hormone. The prognosis of ACC is quite poor and current treatment options are relatively limited, especially for patients whose tumor is metastatic and difficult to remove by surgical operation. This makes the management of ACC challenging. Existing studies have shown that the mechanisms of ACC are complex. The molecular changes happen in adrenocortical development and homeostasis may explain the occurrence of ACC. This review focuses on recent studies and summarizes the genetic and molecular mechanism changes that potentially associated with ACC in the development process of the adrenal cortex and multi-omics studies, including genomic changes, epigenetic changes, differences in non-coding RNA, immune microenvironment and features found through multi-omics analysis. This information may support screening of therapeutic targets of ACC in future.

Diabetic peripheral neuropathy (DPN) poses a significant threat, affecting half of the global diabetic population and leading to severe complications, including pain, impaired mobility, and potential amputation. The delayed manifestation of diabetic neuropathy (DN) makes early diagnosis challenging, contributing to its debilitating impact on individuals with diabetes mellitus (DM). This review examines the multifaceted nature of DPN, focusing on the intricate interplay between oxidative stress, metabolic pathways, and the resulting neuronal damage. It delves into the challenges of diagnosing DN, emphasizing the critical role played by hyperglycemia in triggering these cascading effects. Furthermore, the study explores the limitations of current neuropathic pain drugs, prompting an investigation into a myriad of pharmaceutical agents tested in both human and animal trials over the past decade. The methodology scrutinizes these agents for their potential to provide symptomatic relief for DPN. The investigation reveals promising results from various pharmaceutical agents tested for DPN relief, showcasing their efficacy in ameliorating symptoms. However, a notable gap persists in addressing the underlying problem of DPN. The results underscore the complexity of DPN and the challenges in developing therapies that go beyond symptomatic relief. Despite advancements in treating DPN symptoms, there remains a scarcity of options addressing the underlying problem. This review consolidates the state-of-the-art drugs designed to combat DPN, highlighting their efficacy in alleviating symptoms. Additionally, it emphasizes the need for a deeper understanding of the diverse processes and pathways involved in DPN pathogenesis.

Abstract The Mediterranean Diet (MD) has garnered increasing attention for its potential protective effects against gastric cancer (GC). The MD’s rich content of antioxidants, polyphenols, and other bioactive compounds contributes to its ability to modulate gene expression, inhibit tumor growth, and regulate apoptosis. Studies have shown significant reductions in inflammatory markers such as C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) among individuals adhering to the MD, suggesting its pivotal role in mitigating chronic inflammation-associated with cancer development. Furthermore, the MD’s anti-angiogenic properties, particularly in components like olive oil, red wine, fish, and tomatoes, offer promising avenues for reducing GC risk by inhibiting tumor angiogenesis. Additionally, the MD’s influence on intestinal microbiota composition underscores its potential in maintaining immune homeostasis and reducing systemic inflammation, factors crucial in GC prevention. Despite challenges such as variability in dietary adherence scoring systems and the need for further gender and geographical-specific studies, evidence supports the MD as a cost-effective and holistic approach to GC prevention. Emphasizing the role of nutrition in public health is a promising strategy with broad implications for global health and cancer prevention initiatives. Therefore, this review explores the multifaceted impacts of the MD on GC prevention, delving into its anti-inflammatory, anti-angiogenic, and molecular mechanisms.

Aging is an unavoidable process marked by numerous physiological and psychological changes that profoundly impact overall health and quality of life. As the global population ages, there is a growing interest in non-pharmacological therapies that can mitigate the adverse effects of aging and promote longevity. This narrative review explores the broad spectrum of non-pharmacological mechanisms offering anti-aging benefits, with a special emphasis on holistic practices such as yoga, meditation, and lifestyle interventions. These therapies influence critical biological processes, including reducing oxidative stress, modulating chronic inflammation, enhancing immune function, and preserving telomere length—key markers of cellular aging. Additionally, these practices contribute to improved cardiovascular health, musculoskeletal strength, and mental well-being, fostering a comprehensive approach to healthy aging. Yoga, for instance, combines physical postures, breath control, and meditation to enhance physical flexibility, mental clarity, and emotional balance. Meditation practices are shown to reduce stress and improve cognitive function, further supporting healthy aging. Lifestyle modifications, such as diet and regular physical activity, complement these therapies by promoting overall vitality and reducing the risk of age-related diseases. This review underscores the potential of integrating these non-pharmacological strategies into daily routines to enhance resilience against aging, improve quality of life, and extend healthspan. Furthermore, it highlights the need for continued research to fully elucidate the mechanisms by which these therapies exert their anti-aging effects and to develop evidence-based guidelines for their implementation.

Objective To study the relationship between ABO subtype, para-Bombay blood group and genotype, so as to explore the possible molecular mechanism of these two blood groups, and provide accurate genetic detection targets and theoretical basis for the accurate identification of ABO blood group. Methods First, the serology of 24 200 patients with blood type identification in the Ruijin Hospital from February to December in 2022 were analyzed, as well as 10 ambiguous ABO samples from other hospitals(3 were suspected ABO subtype and 7 were suspected para-Bombay blood group). Then ABO subtypes and para-Bombay blood groups were directly sequenced or post-clonal sequencing was performed to analyze ABO, FUT1 and FUT2 gene sequences. Results Among the 24 200 patients underwent blood type identification, 7 cases of ABO subtypes were detected. Among the 10 ambiguous samples sent by other hospitals, 2 of ABO subtypes, 1 of normal type A, and 7 of para-Bombay blood type were detected. In total, we identified blood types as follows: 1) 9 ABO subtypes: Ael(AEL.02/O.01.02), AelB(AEL.05/B.01), three of B3(2 of B3.03/O.01.01, 1 of B3.03/O.01.02), B(A)(BA.02/O.01.01), ABweak(A1.02/BW.07), Bweak(BW.31 /O.01.02), A2Bweak(A2.05 /BW.31); 2) 7 para-Bombay blood group: ABmh (FUT1*01N.13/FUT1*01N.13), 4 of Amh (3 of FUT1*01N.06/FUT1*01N.13, 1 of FUT1*01N.13/FUT1*01N.13); two of Bmh (FUT1*01N.06 /FUT1*01N.06, FUT1*01N.06/FUT1*01N.13), all of FUT2 of the 7 cases were FUT2*01/FUT2*01. Conclusion Clinical ABO blood group variant samples need to be identified in combination with serological and molecular biology to improve the accuracy of identification, thus providing a reference for safe blood transfusion, organ transplantation, and the prediction and prevention of fetal-maternal immune hemolytic disease.

Abstract Background This study aimed to explore the expression, molecular mechanism and its biological function of potassium two pore domain channel subfamily K member 1 (KCNK1) in bladder cancer (BC). Methods We integrated large numbers of external samples (n = 1486) to assess KCNK1 mRNA expression levels and collected in-house samples (n = 245) for immunohistochemistry (IHC) experiments to validate at the KCNK1 protein level. Single-cell RNA sequencing (scRNA-seq) analysis was performed to further assess KCNK1 expression and cellular communication. The transcriptional regulatory mechanisms of KCNK1 expression were explored by ChIP-seq, ATAC-seq and ChIA-PET data. Highly expressed co-expressed genes (HECEGs) of KCNK1 were used to explore potential signalling pathways. Furthermore, the immunoassay, clinical significance and molecular docking of KCNK1 were calculated. Results KCNK1 mRNA was significantly overexpressed in BC (SMD = 0.58, 95% CI [0.05; 1.11]), validated at the protein level (p

In this article, the epidemiology, molecular mechanism of occurrence and development, risk factors, and treatment of diabetic microvascular complications such as diabetic nephropathy, diabetic retinopathy, and diabetic peripheral neuropathy were discussed, providing the theoretical basis for more accurate elucidation of the pathogenesis and treatment of diabetic microvascular complications.

Toad venom is an active extract of toad, which is processed by distilling or drying at high temperature the venom secreted from the skin glands and ear-side glands of Toad Chinensis. As a natural product that has been used to treat diseases in China for thousands of years, toad venom has many pharmacological effects such as heart strengthening, analgesia, anti-myocardial ischemia, anti-endotoxin shock, and anti-cancer. Arenobufagin (ARE) is one of the main chemical components of toad venom, and its anti-cancer mechanism has been increasingly clarified in the past decade. ARE can play an anti-cancer role through a variety of ways, such as inducing apoptosis and/or autophagy of cancer cells, necrosis, and cell cycle arrest, inhibiting cancer cell migration and invasion, and inhibiting angiogenesis. The current research on ARE mainly focuses on the selective toxicity of cancer cells and the molecular mechanism of anti-cancer, mostly at the cellular and animal levels. Due to the large toxic and side effects of ARE, unclear targets and unclear pharmacokinetic characteristics, ARE has not yet entered the clinical application in Western medicine. This article summarizes relevant research results on the anti-cancer activity and molecular mechanism of ARE, and its combination with other anti-cancer drugs in order to provide a new direction for improving the anti-cancer mechanism of ARE.

Abstract Heterotopic ossification (HO) is a pathological process in which ectopic bone develops in soft tissues within the skeletal system. Endochondral ossification can be divided into the following types of acquired and inherited ossification: traumatic HO (tHO) and fibrodysplasia ossificans progressiva (FOP). Nuclear transcription factor kappa B (NF-κB) signalling is essential during HO. NF-κB signalling can drive initial inflammation through interactions with the NOD‐like receptor protein 3 (NLRP3) inflammasome, Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK). In the chondrogenesis stage, NF-κB signalling can promote chondrogenesis through interactions with mechanistic target of rapamycin (mTOR), phosphatidylinositol-3-kinase (PI3K)/AKT (protein kinase B, PKB) and other molecules, including R-spondin 2 (Rspo2) and SRY-box 9 (Sox9). NF-κB expression can modulate osteoblast differentiation by upregulating secreted protein acidic and rich in cysteine (SPARC) and interacting with mTOR signalling, bone morphogenetic protein (BMP) signalling or integrin-mediated signalling under stretch stimulation in the final osteogenic stage. In FOP, mutated ACVR1-induced NF-κB signalling exacerbates inflammation in macrophages and can promote chondrogenesis and osteogenesis in mesenchymal stem cells (MSCs) through interactions with smad signalling and mTOR signalling. This review summarizes the molecular mechanism of NF-κB signalling during HO and highlights potential therapeutics for treating HO.

Background: NTRK1, NTRK2, and NTRK3 are members of the neurotrophic receptor tyrosine kinases (NTRK) family, which encode TrkA, TrkB, and TrkC receptors, respectively. Hematologic cancers are also linked to point mutations in the NTRK gene's kinase domain. Trk fusions are the most common genetic change associated with oncogenic activity in Trk-driven liquid tumors. Thus, point mutations in NTRK genes may also play a role in tumorigenesis. The structural and functional effect of mutations in Trk-B & Trk-C proteins remains unclear. Methods: In this research, Homology (threading-based approach) modeling and the all-atom molecular dynamics simulations approaches are applied to examine the structural and functional behavior of native and mutant Trk-B and Trk-C proteins at the molecular level. Results: The result of this study reveals how the mutations in Trk-B (A203T & R458G) and Trk-C (E176D & L449F) proteins lost their stability and native conformations. The Trk-B mutant A203T became more flexible than the native protein, whereas the R458G mutation became more rigid than the native conformation of the Trk-B protein. Also, the Trk-C mutations (E176D & L449F) become more rigid compared to the native structure. Conclusions: This structural transition may interrupt the function of Trk-B and Trk-C proteins. Observing the impact of NTRK-2/3 gene alterations at the atomic level could aid in discovering a viable treatment for Trk-related leukemias.

Abstract Background Allergic diseases (ADs) such as asthma are presumed risk factors for COVID-19 infection. However, recent observational studies suggest that the assumed correlation contradicts each other. We therefore systematically investigated the genetic causal correlations between various ADs and COVID-19 infection/severity. Methods We performed a two-sample, bidirectional Mendelian randomization (MR) study for five types of ADs and the latest round of COVID-19 GWAS meta-analysis datasets (critically ill, hospitalized, and infection cases). We also further validated the significant causal correlations and elucidated the potential underlying molecular mechanisms. Results With the most suitable MR method, asthma consistently demonstrated causal protective effects on critically ill and hospitalized COVID-19 cases (OR

Abstract Background Cadmium (Cd) exposure has been found to have detrimental effects on the development of the central nervous system and cognitive ability in children. However, there is ongoing debate regarding the impact of maternal Cd exposure on the cognitive ability of offspring. In this study, we aimed to investigate the mechanisms underlying the influence of maternal Cd exposure on the cognitive ability of offspring rats. Methods Here, we constructed a model of cadmium poisoning in first-generation rats through gavage. The cognitive and memory abilities of its offspring were evaluated by water maze experiment. Then, we used the gene chip to find out the key genes, and we performed qRT-PCR detection of these genes. Subsequently, enrichment analysis was employed to identify pathways. Finally, we constructed a co-expression network consisting of LncRNAs and mRNAs to elucidate the biological functions and regulatory mechanisms of LncRNAs. Results The results of the water maze trial demonstrated that the offspring of rats exposed to cadmium in the first generation had reduced cognitive and memory abilities. Through an analysis of gene expression in the hippocampus of the cadmium-treated rats' offspring and the control group, we identified a correlation between the islet secretion pathway and the cognitive impairment observed in the offspring. Utilizing various algorithms, we identified Cpa1 and Prss1 as potential key genes associated with the cognitive impairment caused by cadmium. The results of qRT-PCR demonstrated a decrease in the expression levels of these genes in the hippocampus of the cadmium-treated rats’ offspring. In addition, in the co-expression network, we observed that Cpa1 was co-expressed with 11 LncRNAs, while Prss1 was associated with 4 unexplored LncRNAs. Furthermore, we conducted an analysis to examine the relationship between Cpa1, Prss1-related transcription factors, and LncRNAs. Conclusion Overall, this study provides novel insights into the molecular effects of first generation Cd exposure on the cognitive ability of offspring. The target genes and signaling pathways investigated in this study could serve as potential targets for improving neurodevelopment and cognitive ability in children.

ObjectiveThis study aimed at conducting retrospective analysis of the clinical symptoms and genetic mutations in 20 children with Gitelman syndrome treated at the Affiliated Children′s Hospital of Nanjing Medical University from August 2015 to November 2022 and also explored the molecular mechanism of the pathogenic high-frequency mutation D486N in the Chinese population.MethodsWe collected the clinical manifestations, growth and development status, laboratory examination results, and SLC12A3 gene variations of the patients. We distinguished the wild-type and mutant SLC12A3 genes overexpressed in human embryonic kidney 293T cells (HEK293T). We used protein immunoblotting to detect the expression level of NCC, and used immunofluorescence techniques to examine the subcellular localization of NCC. In addition, we investigated the impact of the high-frequency SLC12A3 gene mutation D486N on NCC protein expression and localization.ResultsIn the 20 patients with Gitelman syndrome, all of them had hypokalemia. We indemnified twenty-six SLC12A3 gene mutations, 13 of which are missense mutation, 1 of which synonymous mutation, 1 nonsense mutation, 4 frameshift mutation, and 7 splicing site mutation. Among them, four mutations (p.T235K, c.1096-1G > A, p.A464A, and c.2660+1_2660+2insT) were novel mutations.ConclusionsWe found the preliminary evidence that the high-frequency mutation D486N in the Chinese population affected the expression of total and membrane-bound NCC protein and influenced the membrane localization of NCC protein. The findings of this study provides experimental evidence for genetic counseling, diagnosis, and treatment of Gitelman syndrome.

The aberrant activation of yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), downstream effectors of the Hippo signaling pathway, has been implicated in hepatocellular carcinoma(HCC). The microRNAs (miRNAs) works as a tumor suppressors that influence the proliferation, migration and apoptosis of tumor cells by modulating Hippo-YAP/TAZ signaling during hepatic tumorigenesis. Exploring the role of miRNAs in regulating Hippo YAP/TAZ pathway in HCC can provide new ideas for the diagnosis and treatment of HCC.

Abstract Wound healing is a tandem process involving inflammation, proliferation, and remodeling, through which damage is repaired and ultimately scar tissue is formed. This process mainly relies on the complex and extensive interaction of growth factors and cytokines, which coordinate the synthesis of various cell types. The loss of normal regulation in any part of this process can lead to excessive scarring or unhealed wounds. Recent studies have shown that it is possible to improve wound healing and even achieve scar-free wound healing through proper regulation of cytokines and molecules in this process. In recent years, many studies have focused on accelerating wound healing and reducing scar size by regulating the molecular mechanisms related to wound healing and scar formation. We summarized the role of these factors in wound healing and scar formation, to provide a new idea for clinical scar-free healing treatment of uterine incisions.

Hepatocellular carcinoma （HCC） has emerged as a significant public health concern， posing a serious threat to the lives and health of residents in China. Furthermore， the incidence and mortality rates of HCC are notably higher in males than in females. Androgen receptors （AR） can contribute to the occurrence of male-specific cancers such as prostate cancer， suggesting a potential link to the increased susceptibility of males to HCC. Elucidating the cancer-promoting mechanism of AR and developing specific targeted interventions are effective ways to advance tertiary prevention of HCC and improve patient prognosis. This paper reviews the relevant evidence of AR’s role in promoting the occurrence and development of HCC， summarizes relevant mechanisms discovered to date， including promoting the stemness of HCC cells， altering the immune microenvironment， regulating key signaling pathways， inducing glycolysis in hepatocellular carcinoma， and synergizing with hepatitis B virus to promote HCC. Additionally， research directions for targeted interventions in HCC through AR-related signaling pathways are discussed.

The severe acute respiratory syndrome coronavirus 2 （SARS-CoV-2） and its variants are still globally spreading. Vaccines can reduce the mortality， but cannot eliminate the risk of infection. The identification and protection of the high-risk susceptible population remains of great importance for the prevention and control of SARS-CoV2 and other coronavirus infections. Smoking is an important risk factor for many respiratory diseases， and therefore may also influence the risk of SARS-CoV2 infection and the disease progression after infection. This study reviewed the epidemiological and mechanistic evidence supporting the relationship between tobacco exposure and SARS-CoV2 infection， summarized the contributing effects of tobacco exposure to the infection risk， disease severity， and mortality of COVID-19， and analyzed the molecular mechanisms by which cigarette smoking affects COVID-19 through regulating inflammatory microenvironment and gene expression.

Abstract Colorectal cancer (CRC) has become a global health problem which has almost highest morbidity and mortality in all types of cancers. This study aimed to uncover the biological functions and underlying mechanism of MCM8 in the development and progression of CRC. The expression level of MCM8 was found to be upregulated in CRC tissues and significantly associated with tumor grade and patients’ survival. Knocking down MCM8 expression in CRC cells could restrain cell growth and cell motility while promoting cell apoptosis in vitro, as well as inhibit tumor growth in xenograft mice model. Based on the RNA screening performing on CRC cells with or without MCM8 knockdown and the following IPA analysis, CHSY1 was identified as a potential target of MCM8 in CRC, whose expression was also found to be higher in tumor tissues than in normal tissues. Moreover, it was demonstrated that MCM8 may regulate the expression of CHSY1 through affecting its NEDD4-mediated ubiquitination, both of which synergistically execute tumor promotion effects on CRC. In conclusion, the outcomes of our study showed the first evidence that MCM8 act as a tumor promotor in CRC, and may be a promising therapeutic target of CRC treatment.

Pathogenic Bacillus and clostridial (i.e., Clostridium and Clostridioides) bacteria express a diverse repertoire of effector proteins to promote disease. This includes production of binary toxins, which enter host epithelial cells and seriously damage the intestinal tracts of insects, animals, and humans. In particular, binary toxins form an AB-type complex composed of a catalytic subunit that is toxic (A) and an oligomeric cell-binding and delivery subunit (B), where upon delivery of A into the cytoplasm of the host cell it catalytically ADP-ribosylates actin and rapidly induces host cell death. In this review, binary toxins expressed by Bacillus thuringiensis, Clostridioides difficile, and Clostridium perfringens will be discussed, with particular focus placed upon the structural elucidations of their respective B subunits and how these findings help to deconvolute how toxic enzyme delivery into target host cells is achieved by these deadly bacteria.

Abstract Glioma is a common primary tumor of the central nervous system (CNS), with glioblastoma multiforme (GBM) being the most malignant, aggressive, and drug resistant. Most drugs are designed to induce cancer cell death, either directly or indirectly, but malignant tumor cells can always evade death and continue to proliferate, resulting in a poor prognosis for patients. This reflects our limited understanding of the complex regulatory network that cancer cells utilize to avoid death. In addition to classical apoptosis, pyroptosis, ferroptosis, and autophagy are recognized as key cell death modalities that play significant roles in tumor progression. Various inducers or inhibitors have been discovered to target the related molecules in these pathways, and some of them have already been translated into clinical treatment. In this review, we summarized recent advances in the molecular mechanisms of inducing or inhibiting pyroptosis, ferroptosis, or autophagy in GBM, which are important for treatment or drug tolerance. We also discussed their links with apoptosis to better understand the mutual regulatory network among different cell death processes. Video Abstract

Polymethoxylated flavonoids (PMFs) are a subclass of flavonoids found in citrus fruits that have shown multifunctional biological activities and potential anticancer effects against breast cancer. We studied the absorption, metabolism, species source, toxicity, anti-cancer mechanisms, and molecular targets of PMFs to better utilize their anticancer activity against breast cancer. We discuss the absorption and metabolism of PMFs in the body, including the methylation, demethylation, and hydroxylation processes. The anticancer mechanisms of PMFs against breast cancer were also reviewed, including the estrogen activity, cytochrome P-450 enzyme system, and arylhydrocarbon receptor (AhR) inhibition, along with various molecular targets and potential anticancer effects. Although PMFs may be advantageous in the prevention and treatment for breast cancer, there is a lack of clinical evidence and data to support their efficacy. Despite their promise, there is still a long way to go before PMFs can be applied clinically.

Abstract Sepsis is defined as “a life‐threatening organ dysfunction caused by dysregulated host systemic inflammatory and immune response to infection.” At present, sepsis continues to pose a grave healthcare concern worldwide. Despite the use of supportive measures in treating traditional sepsis, such as intravenous fluids, vasoactive substances, and oxygen plus antibiotics to eradicate harmful pathogens, there is an ongoing increase in both the morbidity and mortality associated with sepsis during clinical interventions. Therefore, it is urgent to design specific pharmacologic agents for the treatment of sepsis and convert them into a novel targeted treatment strategy. Herein, we provide an overview of the molecular mechanisms that may be involved in sepsis, such as the inflammatory response, immune dysfunction, complement deactivation, mitochondrial damage, and endoplasmic reticulum stress. Additionally, we highlight important targets involved in sepsis‐related regulatory mechanisms, including GSDMD, HMGB1, STING, and SQSTM1, among others. We summarize the latest advancements in potential therapeutic drugs that specifically target these signaling pathways and paramount targets, covering both preclinical studies and clinical trials. In addition, this review provides a detailed description of the crosstalk and function between signaling pathways and vital targets, which provides more opportunities for the clinical development of new treatments for sepsis.

Intrauterine adhesions (IUA) is a refractory disease affecting female reproductive health. With the development of medicine, the etiology of IUA has been further studied. At present, the high risk factors that can lead to IUA include: curettage after pregnancy, post-caesarean section, trophoblastocyte disease curettage, postpartum hemorrhage curettage, diagnostic curettage, hysteroscopic surgery, intrauterine device placement, reproductive tract tuberculosis infection, Müllerian duct malformation, etc. Endometrial fibrosis is a main pathological feature. After various signals stimulate different molecular signaling pathways, various growth factors and cytokines interact with each other in vivo to promote the development of fibrosis, which ultimately lead to the occurrence of IUA. At present the current clinical treatment and prevention of IUA is not ideal, especially for moderate and severe IUA. Therefore, the research of the pathogenesis may support the targeted therapy for IUA. This paper aims to review the recent progress in the etiology and molecular mechanism of IUA.

Immune diseases are caused by the imbalance of immune regulation. This imbalance is regulated by many factors, both negative and positive. Leukocyte immunoglobulin-like receptor B4 (LILRB4) is a member of leukocyte immunoglobulin-like receptors (LILRs). LILRs are expressed constitutively on the surface of multiple immune cells which associate with membrane adaptors to signal through multi- ple cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) or immunoreceptor tyro-sine-based activation motifs (ITAMs). Through ITIM, LILRB4 could recruit the src homology domain type-2-containing tyrosine phosphatase 1 or 2 (SHP-1 or SHP-2) into the cell membrane. In addition, many factors can induce the expression of LILRB4, such as vitamin D, interferon and so on. Studies have demonstrated that LILRB4 had a negative regulatory role in various of immune diseases. The present review intends to expound the structure and function of LILRB4, as well as its regulators and receptors in the immune cells, so as to provide a theoretical basis for immune disease therapy.

Microcystin-LR (MC-LR) is a cyanobacterial metabolite produced during cyanobacterial blooms and is toxic to aquatic animals, and the liver is the main targeted organ of MC-LR. To comprehensively understand the toxicity mechanism of chronic exposure to environmental levels of MC-LR on the liver of fish, juvenile Nile tilapia were exposed to 0 μg/L (control), 1 μg/L (M1), 3 μg/L (M3), 10 μg/L (M10), and 30 μg/L (M30) MC-LR for 60 days. Then, the liver hepatotoxicity induced by MC-LR exposure was systematically evaluated via histological and biochemical determinations, and the underlying mechanisms were explored through combining analysis of biochemical parameters, multi-omics (transcriptome and metabolome), and gene expression. The results exhibited that chronic MC-LR exposure caused slight liver minor structural damage and lipid accumulation in the M10 group, while resulting in serious histological damage and lipid accumulation in the M30 group, indicating obvious hepatotoxicity, which was confirmed by increased toxicity indexes (i.e., AST, ALT, and AKP). Transcriptomic and metabolomic analysis revealed that chronic MC-LR exposure induced extensive changes in gene expression and metabolites in six typical pathways, including oxidative stress, apoptosis, autophagy, amino acid metabolism, primary bile acid biosynthesis, and lipid metabolism. Taken together, chronic MC-LR exposure induced oxidative stress, apoptosis, and autophagy, inhibited primary bile acid biosynthesis, and caused fatty deposition in the liver of Nile tilapia.

Abstract Tumor suppressor p53 can transcriptionally activate downstream genes in response to stress, and then regulate the cell cycle, DNA repair, metabolism, angiogenesis, apoptosis, and other biological responses. p53 has seven functional domains and 12 splice isoforms, and different domains and subtypes play different roles. The activation and inactivation of p53 are finely regulated and are associated with phosphorylation/acetylation modification and ubiquitination modification, respectively. Abnormal activation of p53 is closely related to the occurrence and development of cancer. While targeted therapy of the p53 signaling pathway is still in its early stages and only a few drugs or treatments have entered clinical trials, the development of new drugs and ongoing clinical trials are expected to lead to the widespread use of p53 signaling‐targeted therapy in cancer treatment in the future. TRIAP1 is a novel p53 downstream inhibitor of apoptosis. TRIAP1 is the homolog of yeast mitochondrial intermembrane protein MDM35, which can play a tumor‐promoting role by blocking the mitochondria‐dependent apoptosis pathway. This work provides a systematic overview of recent basic research and clinical progress in the p53 signaling pathway and proposes that TRIAP1 is an important therapeutic target downstream of p53 signaling.

Cancer stem cells (CSCs) are involved in tumor formation, drug and radiation resistance, invasive growth, metastasis, and tumor progression and are major causes of cancer-related mortality. Gastrointestinal cancers are one of the most common malignancies and causes of cancer death worldwide. Because gastrointestinal cancer stem cells are thought to be resistant to common treatments, new and effective treatments are needed. Cancer stem cells have been reported in colorectal, esophageal, gastric, liver and pancreatic cancers. Given that, understanding the formation of cancer stem cells and identifying control pathways and investigating the molecular mechanism of signaling involved in these cells and their role in cancer treatment leads to the development of diagnostic and therapeutic methods in basic and clinical cancer research. In this study, the functional role and molecular mechanisms of cancer stem cells in the treatment of gastrointestinal cancers are investigated.

Neural networks are groups of interconnected neurons, which collectively give rise to emergent neural activities and functions that cannot be explained by the activity of single neurons. How neural networks are assembled is poorly understood. While all aspects of neuronal development are essential for the assembly of a functional neural network, we know little about high-level principles that govern neural network assembly beyond the basic steps of neuronal development. In this review, I use vertebrate spinal motor columns, Drosophila larval motor circuit, and the lamination in the vertebrate inner retina to highlight the spatial codes, temporal codes, and cell adhesion codes for neural network assembly. Nevertheless, these examples only show preliminary connections between neural network development and their functions. Much needs to be done to understand the molecular mechanisms that underlie the assembly of functional neural networks.

Small nuclear RNAs (snRNAs) are rarely reported in cancer. This study is based on The Cancer Genome Atlas genome-wide data set to explore the prognostic value and molecular mechanism of snRNAs in gastric cancer (GC). Gene ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analysis were used to explore the molecular mechanism of snRNAs. A total of 351 patients were included in the survival analysis, and 14 prognostic snRNAs were identified using multivariate survival analysis. We constructed a prognostic signature containing nine snRNAs, which can signally classify patients into high- and low-risk phenotypes (adjusted P < 0.0001, hazard ratio = 2.671, 95% confidence interval = 1.850–3.858). Combining the molecular mechanisms obtained by the three functional enrichment approaches, we concluded that this prognostic signature snRNAs participated in classical tumor-related signaling pathways, including Notch, PI3K, toll-like receptor, etc.; cell adhesion; cell cycle; cell proliferation; and other biological processes that affect the biological phenotype of cancer cells. We also found significant downregulation of the abundance of immune cell infiltrates and immune microenvironment scores for high-risk phenotypes of GC patients. In conclusion, this study has identified 14 prognostic snRNAs signally associated with GC overall survival and also constructed a novel prognostic signature containing nine prognostic snRNAs.

Background: NTRK1, NTRK2, and NTRK3 are members of the neurotrophic receptor tyrosine kinases (NTRK) family, which encode TrkA, TrkB, and TrkC receptors, respectively. Hematologic cancers are also linked to point mutations in the NTRK gene's kinase domain. Trk fusions are the most common genetic change associated with oncogenic activity in Trk-driven liquid tumors. Thus, point mutations in NTRK genes may also play a role in tumorigenesis. The structural and functional effect of mutations in Trk-B & Trk-C proteins remains unclear. Methods: In this research, Homology (threading-based approach) modeling and the all-atom molecular dynamics simulations approaches are applied to examine the structural and functional behavior of native and mutant Trk-B and Trk-C proteins at the molecular level. Results: The result of this study reveals how the mutations in Trk-B (A203T & R458G) and Trk-C (E176D & L449F) proteins lost their stability and native conformations. The Trk-B mutant A203T became more flexible than the native protein, whereas the R458G mutation became more rigid than the native conformation of the Trk-B protein. Also, the Trk-C mutations (E176D & L449F) become more rigid compared to the native structure. Conclusions: This structural transition may interrupt the function of Trk-B and Trk-C proteins. Observing the impact of NTRK-2/3 gene alterations at the atomic level could aid in discovering a viable treatment for Trk-related leukemias.

Abstract Vascular calcification (VC) is recognized as a pathological vascular disorder associated with various diseases, such as atherosclerosis, hypertension, aortic valve stenosis, coronary artery disease, diabetes mellitus, as well as chronic kidney disease. Therefore, it is a life‐threatening state for human health. There were several studies targeting mechanisms of VC that revealed the importance of vascular smooth muscle cells transdifferentiating, phosphorous and calcium milieu, as well as matrix vesicles on the progress of VC. However, the underlying molecular mechanisms of VC need to be elucidated. Though there is no acknowledged effective therapeutic strategy to reverse or cure VC clinically, recent evidence has proved that VC is not a passive irreversible comorbidity but an active process regulated by many factors. Some available approaches targeting the underlying molecular mechanism provide promising prospects for the therapy of VC. This review aims to summarize the novel findings on molecular mechanisms and therapeutic interventions of VC, including the role of inflammatory responses, endoplasmic reticulum stress, mitochondrial dysfunction, iron homeostasis, metabolic imbalance, and some related signaling pathways on VC progression. We also conclude some recent studies on controversial interventions in the clinical practice of VC, such as calcium channel blockers, renin–angiotensin system inhibitions, statins, bisphosphonates, denosumab, vitamins, and ion conditioning agents.

Head and neck paragangliomas(HNPGL) are rare neurogenic tumors, in which genetic factors play a certain role. So far, 10 genes related to HNPGL(SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, HIF2A, RET, NF1 and TMEM127) have been found. The clinical phenotypes of different gene mutations are different. SDHD, SDHC and SDHAF2 gene mutations are almost 100% related to HNPGL. SDHD and SDHAF2 gene mutations tend to form multiple paragangliomas, and its genetic pattern has obviously maternal imprinting. SDHB mutations have sympathetic paraganglioma and malignant tendency. Understanding the molecular mechanism and genotype-phenotypic relationship of paraganglioma can provide significant help for genetic counseling, diagnosis and treatment, and development of follow-up strategies in patients with HNPGL.

We develop integrated co-evolution and dynamic coupling (ICDC) approach to identify, mutate, and assess distal sites to modulate function. We validate the approach first by analyzing the existing mutational fitness data of TEM-1 β-lactamase and show that allosteric positions co-evolved and dynamically coupled with the active site significantly modulate function. We further apply ICDC approach to identify positions and their mutations that can modulate binding affinity in a lectin, cyanovirin-N (CV-N), that selectively binds to dimannose, and predict binding energies of its variants through Adaptive BP-Dock. Computational and experimental analyses reveal that binding enhancing mutants identified by ICDC impact the dynamics of the binding pocket, and show that rigidification of the binding residues compensates for the entropic cost of binding. This work suggests a mechanism by which distal mutations modulate function through dynamic allostery and provides a blueprint to identify candidates for mutagenesis in order to optimize protein function.

Autophagy and apoptosis are two different physiological phenomena, however they are closely related in function. This paper introduces the classification and process of autophagy and apoptosis, and discusses the effects of some key regulatory proteins in the formation of autophagosome and the dual role of apoptosis and anti-apoptosis proteins on autophagy and apoptosis, so as to explore the relationship between autophagy and apoptosis, and to provide theoretical basis for further study of autophagy and apoptosis related diseases.

At present, the drug treatment for invasive fungal infection is challenged by serious adverse effects and drug resistance. Therefore, the research and development of safe and effective new antifungal drugs is a great importance to support the clinical treatment of invasive fungal diseases. This article reviewed new targets of invasive fungi, and explores the underlying mechanisms of fungal biofilm formation, cell wall,key metabolic enzymes, mitochondria in the aspects of small molecule inhibitors and secondary metabolites, which may provide reference for the research and development of new drugs.

Lung cancer, featured with strong heterogeneity and plasticity, is the most devastating diseaseworldwide. Based on histological classification, lung cancer can be categorized as small cell lung cancer(SCLC) and non-small cell lung cancer (NSCLC), among which the latter could be further classified into lungadenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Mixed pathologies ofADC and SCC (Adenosquamous Cell Carcinoma, Ad-SCC) or mixed SCLC with ADC and/or SCC pathology(mixed SCLC) have been consistently observed in clinic. Lung Ad-SCC is about 4%~10% of NSCLC. Recentclinical studies have shown that epidermal growth factor receptor (EGFR) mutant lung ADC could transition to SCC in relapsed patients failed from chemotherapy, targeted therapy or immunotherapy. Studies of liver kinaseB1 (Lkb1)-defi cient mouse model have provided convincing evidence in supporting that lung ADC derived fromclub cells or AT2 cells (Alveolar Epithelial Type 2 Cells) is prone to squamous transition, and the mixed AdSCC is identified as the intermediate stage. Mechanistic studies demonstrate that uncontrolled accumulation ofexcessive oxidative stress resulted from extracellular matrix depletion and metabolic reprogramming somehowtriggers the up-regulation of SCC-lineage specific transcription factor, p63, which eventually promotes thesquamous transition. Such transition confers lung tumors with drug resistance in mouse models. This review willsummarize current research progress of the transition from lung ADC to SCC as well as its correlation with drugresistance acquisition, which hopefully provides novel insights into lung cancer plasticity and drug resistance.

Abstract Background Orthodox dentistry has undergone significant changes in recent times with the introduction of various omics and molecular targeted therapies both at the experimental/trial and clinical implementation level. Although, significant milestones have been achieved in the molecular dentistry field in the past decade, there remains a dearth of application of phytopharmacological innovation in personalized and targeted therapies for dental diseases. Main body From time immemorial, plant products have long been an integral aspect of dental practice ranging from chewing sticks/herbal kinds of toothpaste to dental/impression materials. The current era of precision medicine seeks to apply a multipronged molecular and bio-computational approaches to solve fundamental medical problems that have hitherto remained difficult. Remarkable changes in the molecular/omics era, have transformed empirical therapies into personalized/individualized ones. Furthermore, the combinatorial application and the widespread introduction of high-throughput molecular tools such as pharmacogenomics, phytopharmacology, metabolomics, mathematical modelling, and genetic engineering inter alia, has tremendously improved the diagnostic and therapeutic landscape of medicine. Additionally, the variable molecular epidemiology of diseases among different population and emerging molecular evidence warrants the use of customized novel theranostic techniques. Unfortunately, the footprint of such emerging application is sparse in dental diseases such as maxillofacial cancers. Conclusion Hence, this review seeks to evaluate the potential application of phytopharmacological approaches to head and neck cancers in a resource-limited environment, such as Africa.

Cannabidiol (CBD), one of the most promising constituents isolated from Cannabis sativa, exhibits diverse pharmacological actions. However, the applications of CBD are restricted mainly due to its poor oral bioavailability. Therefore, researchers are focusing on the development of novel strategies for the effective delivery of CBD with improved oral bioavailability. In this context, researchers have designed nanocarriers to overcome limitations associated with CBD. The CBD-loaded nanocarriers assist in improving the therapeutic efficacy, targetability, and controlled biodistribution of CBD with negligible toxicity for treating various disease conditions. In this review, we have summarized and discussed various molecular targets, targeting mechanisms and types of nanocarrier-based delivery systems associated with CBD for the effective management of various disease conditions. This strategic information will help researchers in the establishment of novel nanotechnology interventions for targeting CBD.

As an important part of traditional Chinese medicine (TCM) nursing technology, moxibustion plays a unique role in improving the symptoms of ankylosing spondylitis (AS). The research on the mechanism of moxibustion intervention in AS mainly focuses on anti-inflammatory effects, immune regulation, bone metabolism regulation, intestinal flora regulation, and so on. Molecular medicine is of great significance to further clarify the mechanism of moxibustion intervention in AS. However, there are still some problems in the research on the molecular mechanism of moxibustion intervention in AS: the existing biomedical research methods only explore from a specific field and lack the exploration of moxibustion-targeted molecules based on biomedical network. In the future, the molecular network effect of moxibustion on AS can be discussed comprehensively and systematically with the help of omics technology and the construction of biological information interaction network between omics. The effect of moxibustion on upstream osteogenic transcription factors and related signaling pathways such as WNT, β-catenin, and BMP/Smads is not yet clear. Future research can focus on the relevant signal targets of bone reconstruction and clarify the mechanism of moxibustion against the new bone formation. In addition, there is a lack of research on the molecular mechanism of moxibustion in the treatment of AS from the perspective of metabolites. It is necessary to further explore the mechanism of moxibustion in the treatment of AS with the help of metabonomics technology.

Objective The objective of this study was to clarify the potential mechanism of quercetin against knee osteoarthritis (KOA) based on network pharmacology and molecular docking.

Nuclear-cytoplasmic translocation is an important cause of abnormal gene localization, which occurs at various stages of tumor development and is closely related to tumor treatment and drug resistance. In this paper, the basic structure, biological function and regulatory mechanism of nuclear translocation are described, and the role of nuclear-cytoplasmic translocation in the genesis and development of tumors, as well as the progress in tumor therapy and drug resistance are further reviewed, in order to provide theoretical basis for exploring novel anti-tumor strategies.

Introduction: Human papillomavirus (HPV) and human immunodeficiency virus (HIV) are the most common sexually transmitted infections (STI) globally. According to the World Health Organisation (WHO) there are around 17.4 million women living with HIV and over 290 million HPV infected women worldwide.Purpose: This review is to summarize available data concerning the relationship between HIV and HPV infection among women. The analysis comprises molecular mechanisms of HPV infection among HIV(+) women as well as HIV infection among HPV(+) women, prevalence of HPV and cervical lesions among women living with HIV and screening of HPV and cervical cancer (CC) among HIV infected women.Material and methods: The review includes publications from 2011 to 2020. The data has been collected by the use of the PubMed, Ovid, Up-To-Date and WHO website. Key words used to search for references include: HPV, HIV, prevalence, molecular mechanism, screening.Results: HIV infection is a risk factor for HPV acquisition. On the one hand, prevalence of HPV, multiple HPV, high risk HPV (hrHPV) infections and cervical intraepithelial neoplasia (CIN) is higher among HIV(+) women. On the other hand, HPV infection can also predispose to HIV acquisition. Evidence on how these viruses influence each other can be a breakthrough in the range of prevention, detection and treatment of both HIV and HPV infection.Conclusions: Relationship between HPV and HIV is an interest of nowadays medicine. Possibly, these viruses may cooperate and enable infection of each other. It has been showed that the prevalence of HPV, multiple HPV, hrHPV infections and cervical lesions is higher among HIV(+) in comparison to HIV(-) women. Further studies should be performed providing an insight into a molecular mechanism responsible for this cooperation.

The secondary contamination of microcystin disinfection by-products (MC-DBPs) is of concern due to the residual structure similar to their original toxin. Based on identification and preparation, the potential inhibition effect of typical MCLR-DBPs (associated with the oxidation of Adda5) on PP2A was confirmed in the sequence of MCLR > P1 > P4 > P3 ≈ P2 > P7 ≈ P6 ≈ P5 > P8. To elucidate the molecular mechanism underlying the inhibition effect, the interaction models for typical MCLR-DBPs and PP2A were constructed using a modeling-based-on-ligand-similarity approach, and the candidate interaction parameters between typical MCLR-DBPs and PP2A were obtained by molecular docking. By analyzing the correlation between inhibition data and candidate interaction parameters, the key interaction parameters were filtered as hydrogen bonds “Adda5”←Asn117, “Adda5”←His118, MeAsp3←Arg89, Arg4←Arg214, Arg4→Pro213; ionic bonds Glu6-Arg89, Asp85-Mn12+, Asp57-Mn22+; and metal bonds Glu6-Mn12+, Glu6-Mn22+. With the gradual intensification of chlorination, Adda5 was destroyed to varying degrees. The key interactions changed correspondingly, resulting in the discrepant inhibition effects of typical MCLR-DBPs on PP2A.

A type of evolutionarily conserved, noncoding, small, endogenous, single-stranded RNA, miRNAs are widely distributed in eukaryotes, where they participate in various biological processes as critical regulatory molecules. miR-1299 has mainly been investigated in cancers. miR-1299 is a tumor suppressor that regulates the expression of its target genes, activating or inhibiting the transcription of genes regulating biological activities including cell proliferation, migration, survival and programmed cell death. miR-1299 has become a hotspot in research of disease mechanisms and biomarkers; elucidation of the regulatory roles of miR-1299 in tumorigenesis, proliferation, apoptosis, invasion, migration and angiogenesis may provide a new perspective for understanding its biological functions as a tumor suppressor.

Objectives: Histone acetylation is determined by a balance between the activities of the enzymes that are involved in the histone modifications, including histone deacetylases (HDACs) and histone acetyltransferases which affect gene expression and play a significant role in carcinogens. Valproic acid (VPA) belongs to the HDAC inhibitor family which inhibits HDAC activity and regulate biological events such as apoptosis in various cancers. The current review summarized various pathways by which VPA affects different types of cancers. Methods: For this review, an online search of different sources such as ISI, PubMed, and Scopus resulted in finding the articles correlated with mechanisms and pathways of VPA in different cancers. Results: Based on these results, VPA may be a suitable agent and a good candidate for cancer treatment with multiple mechanisms of apoptosis induction. Conclusions: Overall, VPA can protect against cancer by regulating histone modification and tumor suppressor gene reactivation.

Abstract Background Pituitary adenoma and meningioma are the most common benign tumors in the central nervous system. Pituitary adenoma associated with meningioma (PAM) is a rare disease and the clinical features and mechanisms of PAM are unclear. Methods We summarized the clinical data of 57 PAM patients and compared with sporadic pituitary adenoma (SPA) and sporadic meningioma (SM). 5 pituitary adenomas of PAM and 5 SPAs were performed ceRNA microarray. qRT-PCR, Western Blot, siMEN1 and rapamycin inhibition experiment were validated for ceRNA microarray. Results Clinical variable analyses revealed that significant correlations between PAM and female sex as well as older age when compared with SPA and significant correlations between PAM and transitional meningioma as well as older age when compared with SM. Additionally, the characteristics of PAM were significantly different for MEN1 patients. Functional experiments showed lower expression of MEN1 can upregulate mTOR signaling, in accordance with the result of ceRNA microarray. Rapamycin treatment promotes apoptosis in primary pituitary adenoma and meningioma cells of PAM. Conclusions MEN1 plays an important role in PAM by upregulating mTOR signaling pathway. Rapamycin represents a potential therapeutic strategy for PAM in the future.