Alzheimer's disease (AD) poses a major challenge due to its impact on the elderly population and the lack of effective early diagnosis and treatment options. In an effort to address this issue, a study focused on identifying potential biomarkers and therapeutic agents for AD was carried out. Using RNA-Seq data from AD patients and healthy individuals, 12 differentially expressed genes (DEGs) were identified, with 9 expressing upregulation (ISG15, HRNR, MTATP8P1, MTCO3P12, DTHD1, DCX, ST8SIA2, NNAT, and PCDH11Y) and 3 expressing downregulation (LTF, XIST, and TTR). Among them, TTR exhibited the lowest gene expression profile. Interestingly, functional analysis tied TTR to amyloid fiber formation and neutrophil degranulation through enrichment analysis. These findings suggested the potential of TTR as a diagnostic biomarker for AD. Additionally, druggability analysis revealed that the FDA-approved drug Levothyroxine might be effective against the Transthyretin protein encoded by the TTR gene. Molecular docking and dynamics simulation studies of Levothyroxine and Transthyretin suggested that this drug could be repurposed to treat AD. However, additional studies using in vitro and in vivo models are necessary before these findings can be applied in clinical applications.

Adenomyosis can reduce the chance of clinical pregnancy in women undergoing assisted conception. Treatment with prolonged gonadotrophin-releasing hormone analogue (GnRHa) downregulation prior to IVF/ICSI has been postulated to improve pregnancy outcomes.

Exposure to pesticides is a risk factor for various diseases, yet its association with biological aging remains unclear. We aimed to systematically investigate the relationship between pesticide exposure and biological aging.

Several studies show that the long non-coding RNA HOX transcript antisense RNA (HOTAIR) was upregulated in human cancer, which was associated with several clinical features and may have the potential to be prognostic markers. However, the significance of HOTAIR in hepatocellular carcinoma remains unclear. We performed a meta-analysis and bioanalysis to further investigate the association between HOTAIR and hepatocellular carcinoma.

Although toxicology uses animal models to represent real-world human health scenarios, a critical translational gap between laboratory-based studies and epidemiology remains. In this study, we aimed to understand the toxicoepigenetic effects on DNA methylation after developmental exposure to two common toxicants, the phthalate di(2-ethylhexyl) phthalate (DEHP) and the metal lead (Pb), using a translational paradigm that selected candidate genes from a mouse study and assessed them in four human birth cohorts. Data from mouse offspring developmentally exposed to DEHP, Pb, or control were used to identify genes with sex-specific sites with differential DNA methylation at postnatal day 21. Associations of human infant DNA methylation in homologous mouse genes with prenatal DEHP or Pb were examined with a meta-analysis. Differential methylation was observed on 6 cytosines (adjusted-p < 0.05) and 90 regions (adjusted-p < 0.001). This translational approach offers a unique method that can detect conserved epigenetic differences that are developmentally susceptible to environmental toxicants.

This meta-analysis examined the prognostic role of brain and acute leukemia, cytoplasmic (BAALC), Ecotropic virus integration site-1 (EVI1) and Wilms' tumor 1 (WT1) genes at different time-points during conventional chemotherapy.

Predicting cancer cells' response to a plant-derived agent is critical for the drug discovery process. Recently transcriptomes advancements have provided an opportunity to identify regulatory signatures to predict drug activity. Here in this study, a combination of meta-analysis and machine learning models have been used to determine regulatory signatures focusing on differentially expressed transcription factors (TFs) of herbal components on cancer cells. In order to increase the size of the dataset, six datasets were combined in a meta-analysis from studies that had evaluated the gene expression in cancer cell lines before and after herbal extract treatments. Then, categorical feature analysis based on the machine learning methods was applied to examine transcription factors in order to find the best signature/pattern capable of discriminating between control and treated groups. It was found that this integrative approach could recognize the combination of TFs as predictive biomarkers. It was observed that the random forest (RF) model produced the best combination rules, including AIP/TFE3/VGLL4/ID1 and AIP/ZNF7/DXO with the highest modulating capacity. As the RF algorithm combines the output of many trees to set up an ultimate model, its predictive rules are more accurate and reproducible than other trees. The discovered regulatory signature suggests an effective procedure to figure out the efficacy of investigational herbal compounds on particular cells in the drug discovery process.

Acute respiratory distress syndrome (ARDS) is defined as the acute onset of noncardiogenic edema and subsequent gas-exchange impairment due to a severe inflammatory process known as cytokine storm. Xuebijing injection (hereinafter referred to as Xuebijing) is a patent drug that was used to treat ARDS or severe pneumonia (SP) in China. However, its efficacy and mechanism of actions remain unclear. In this study, we used meta-analysis and network pharmacology to assess these traits of Xuebijing.

Cytokine storm is recognized as one of the factors contributing to organ failures and mortality in patients with COVID-19. Due to chronic inflammation, COVID-19 patients with diabetes mellitus (DM) or renal disease (RD) have more severe symptoms and higher mortality. However, the factors that contribute to severe outcomes of COVID-19 patients with DM and RD have received little attention. In an effort to investigate potential treatments for COVID-19, recent research has focused on the immunomodulation functions of mesenchymal stem cells (MSCs). In this study, the correlation between DM and RD and the severity of COVID-19 was examined by a combined approach with a meta-analysis and experimental research. The results of a systematic review and meta-analysis suggested that the odd of mortality in patients with both DM and RD was increased in comparison to those with a single comorbidity. In addition, in the experimental research, the data showed that high glucose and uremic toxins contributed to the induction of cytokine storm in human lung adenocarcinoma epithelial cells (Calu-3 cells) in response to SARS-CoV Peptide Pools. Of note, the incorporation of Wharton's jelly MSC-derived extracellular vesicles (WJ-EVs) into SARS-CoV peptide-induced Calu-3 resulted in a significant decrease in nuclear NF-κB p65 and the downregulation of the cytokine storm under high concentrations of glucose and uremic toxins. This clearly suggests the potential for WJ-EVs to reduce cytokine storm reactions in patients with both chronic inflammation diseases and viral infection.

Cervical cancer is the fourth most common cancer among women worldwide. Though several natural products have been reported regarding their efficacies against cervical cancer, there has been no review article that categorized them according to their anti-cancer mechanisms. In this study, anti-cancerous natural products against cervical cancer were collected using Pubmed (including Medline) and google scholar, published within three years. Their mechanisms were categorized as induction of apoptosis, inhibition of angiogenesis, inhibition of metastasis, reduction of resistance, and regulation of miRNAs. A total of 64 natural products suppressed cervical cancer. Among them, Penicillium sclerotiorum extracts from Cassia fistula L., ethanol extracts from Bauhinia variegate candida, thymoquinone obtained from Nigella sativa, lipid-soluble extracts of Pinellia pedatisecta Schott., and 1'S-1'-acetoxychavicol extracted from Alpinia conchigera have been shown to have multi-effects against cervical cancer. In conclusion, natural products could be attractive candidates for novel anti-cancer drugs.

Background: Bromodomain and extra-terminal domain (BET) inhibitors have shown profound efficacy against hematologic malignancies and solid tumors in preclinical studies. However, the underlying molecular mechanism in melanoma is not well understood. Here we identified secreted phosphoprotein 1 (SPP1) as a melanoma driver and a crucial target of BET inhibitors in melanoma. Methods: Bioinformatics analysis and meta-analysis were used to evaluate the SPP1 expression in normal tissues, primary melanoma, and metastatic melanoma. Real-time PCR (RT-PCR) and Western blotting were employed to quantify SPP1 expression in melanoma cells and tissues. Cell proliferation, wound healing, and Transwell assays were carried out to evaluate the effects of SPP1 and BET inhibitors in melanoma cells in vitro. A xenograft mouse model was used to investigate the effect of SPP1 and BET inhibitors on melanoma in vivo. Chromatin immunoprecipitation (ChIP) assay was performed to evaluate the regulatory mechanism of BET inhibitors on SPP1. Results: SPP1 was identified as a melanoma driver by bioinformatics analysis, and meta-analysis determined it to be a diagnostic and prognostic biomarker for melanoma. SPP1 overexpression was associated with poor melanoma prognosis, and silencing SPP1 suppressed melanoma cell proliferation, migration, and invasion. Through a pilot drug screen, we identified BET inhibitors as ideal therapeutic agents that suppressed SPP1 expression. Also, SPP1 overexpression could partially reverse the suppressive effect of BET inhibitors on melanoma. We further demonstrated that bromodomain-containing 4 (BRD4) regulated SPP1 expression. Notably, BRD4 did not bind directly to the SPP1 promoter but regulated SPP1 expression through NFKB2. Silencing of NFKB2 resembled the phenotype of BET inhibitors treatment and SPP1 silencing in melanoma. Conclusion: Our findings highlight SPP1 as an essential target of BET inhibitors and provide a novel mechanism by which BET inhibitors suppress melanoma progression via the noncanonical NF-κB/SPP1 pathway.

Rationale: MicroRNAs are known to influence the development of a variety of cancers. Previous studies revealed that miR-1291 has antiproliferative functions in cancer cells. Carnitine palmitoyltransferase 1C (CPT1C) has a vital role in mitochondrial energy metabolism and modulation of cancer cell proliferation. Since both miR-1291 and CPT1C regulate tumor cell metabolism and cancer progression, we hypothesized that they might be regulated synergistically. Methods: A series of cell phenotype indicators, such as BrdU, colony formation, cell cycle, ATP production, ROS accumulation and cell ability to resist metabolic stress, were performed to clarify the effects of miR-1291 and ERRα expression on tumor cell proliferation and metabolism. A xenograft tumor model was used to evaluate cell tumorigenesis. Meta-analysis and bioinformatic prediction were applied in the search for the bridge-link between miR-1291 and CPT1C. RT-qPCR, western-blot and IHC analysis were used for the detection of mRNA and protein expression. Luciferase assays and ChIP assays were conducted for in-depth mechanism studies. Results: The expression of miR-1291 inhibited growth and tumorigenesis as a result of modulation of metabolism. CPT1C expression was indirectly and negatively correlated with miR-1291 levels. ESRRA was identified as a prominent differentially expressed gene in both breast and pancreatic cancer samples, and estrogen-related receptor α (ERRα) was found to link miR-1291 and CPT1C. MiR-1291 targeted ERRα and CPT1C was identified as a newly described ERRα target gene. Moreover, ERRα was found to influence cancer cell metabolism and proliferation, consistent with the cellular changes caused by miR-1291. Conclusion: This study demonstrated the existence and mechanism of action of a novel miR-1291-ERRα-CPT1C cancer metabolism axis that may provide new insights and strategies for the development of miRNA-based therapies for malignant cancers.

Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -β, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC.

Schizophrenia (SCZ) is a psychiatric disorder characterized by both positive and negative symptoms, including cognitive dysfunction, decline in motivation, delusion and hallucinations. Antipsychotic agents are currently the standard of care treatment for SCZ. However, only about one-third of SCZ patients respond to antipsychotic medications. In the current study, we have performed a meta-analysis of publicly available whole-genome expression datasets on Brodmann area 46 of the brain dorsolateral prefrontal cortex in order to prioritize potential pathways underlying SCZ pathology. Moreover, we have evaluated whether the differentially expressed genes in SCZ belong to specific subsets of cell types. Finally, a cross-tissue comparison at both the gene and functional level was performed by analyzing the transcriptomic pattern of peripheral blood mononuclear cells of SCZ patients. Our study identified a robust disease-specific set of dysfunctional biological pathways characterizing SCZ patients that could in the future be exploited as potential therapeutic targets.

Shenxian-Shengmai (SXSM) Oral Liquid is a CFDA-approved patent Chinese Herbal medicine, which has been clinically used for the treatment of bradycardia. However, its active components and action mechanism remain to be established. The present study aimed to evaluate the efficacy of SXSM on bradycardia and to identify the possible active components and their pharmacological targets for this action.

Defence priming by organismal and non-organismal stimulants can reduce effects of biotic stress in plants. Thus, it could help efforts to enhance the sustainability of agricultural production by reducing use of agrochemicals in protection of crops from pests and diseases. We have explored effects of applying this approach to both Arabidopsis plants and seeds of various crops in meta-analyses. The results show that its effects on Arabidopsis plants depend on both the priming agent and antagonist. Fungi and vitamins can have strong priming effects, and priming is usually more effective against bacterial pathogens than against herbivores. Moreover, application of bio-stimulants (particularly vitamins and plant defence elicitors) to seeds can have promising defence priming effects. However, the published evidence is scattered, does not include Arabidopsis, and additional studies are required before we can draw general conclusions and understand the molecular mechanisms involved in priming of seeds' defences. In conclusion, defence priming of plants has clear potential and application of bio-stimulants to seeds may protect plants from an early age, promises to be both labour- and resource-efficient, poses very little environmental risk, and is thus both economically and ecologically promising.

Several studies have demonstrated that metformin (MTF) acts with variable efficiency as an anticancer agent. The pleiotropic anticancer effects of MTF on cancer cells have not been fully explored yet. By interrogating the Gene Expression Omnibus (GEO) for microarray expression data, we identified eight eligible submissions, representing five different studies, that employed various conditions including different cell lines, MTF concentrations, treatment durations, and cellular components. A compilation of the data sets of 13 different conditions contained 443 repeatedly up- and 387 repeatedly down-regulated genes; the majority of these 830 differentially expressed genes (DEGs) were associated with higher MTF concentrations and longer MTF treatment. The most frequently upregulated genes include DNA damage inducible transcript 4 (DDIT4), chromodomain helicase DNA binding protein 2 (CHD2), endoplasmic reticulum to nucleus signaling 1 (ERN1), and growth differentiation factor 15 (GDF15). The most commonly downregulated genes include arrestin domain containing 4 (ARRDC4), and thioredoxin interacting protein (TXNIP). The most significantly (p-value < 0.05, Fisher's exact test) overrepresented protein class was entitled, nucleic acid binding. Cholesterol biosynthesis and other metabolic pathways were specifically affected by downregulated pathway molecules. In addition, cell cycle pathways were significantly related to the data set. Generated networks were significantly related to, e.g., carbohydrate and lipid metabolism, cancer, cell cycle, and DNA replication, recombination, and repair. A second compilation comprised genes that were at least under one condition up- and in at least another condition down-regulated. Herein, the most frequently deregulated genes include nuclear paraspeckle assembly transcript 1 (NEAT1) and insulin induced gene 1 (INSIG1). The most significantly overrepresented protein classes in this compilation were entitled, nucleic acid binding, ubiquitin-protein ligase, and mRNA processing factor. In conclusion, this study provides a comprehensive list of deregulated genes and biofunctions related to in vitro MTF application and individual responses to different conditions. Biofunctions affected by MTF include, e.g., cholesterol synthesis and other metabolic pathways, cell cycle, and DNA replication, recombination, and repair. These findings can assist in defining the conditions in which MTF exerts additive or synergistic effects in cancer treatment.

Background: Approximately, one-third of adult patients with acute myeloid leukemia (AML) are refractory to initial induction chemotherapy and relapse occurs in most patients who achieve remission. This study evaluates the efficacy of decitabine in the management of refractory or relapsed AML. Methods: After literature search in electronic databases (Google Scholar, Embase, Ovid, and PubMed) studies were selected by following pre-determined eligibility criteria. Random-effects meta-analyses were performed to achieve effect sizes of complete remission (CR) rate, response rate (RR), and median survival after therapy. Subgroup analyses were performed with regards to use of decitabine with either epigenetics-based therapy, molecular therapy or chemotherapy. Results: Twenty studies were included (310 patients; age 55.1 years [95% confidence interval (CI): 43.8, 66.4]; 57% [52%, 63%] males). Overall RR was 46.1% [95% CI: 36.1%, 56.1%]. Overall CR rate was 23.5% [95% CI: 22.1%, 24.9%] but was 14.85% [95% CI: 3.8%, 25.9%] for decitabine with epigenetics-based therapies, 15.4% [95% CI: 6.7%, 24.0%] for decitabine with immunotherapy or molecular therapy, 34.8% [95% CI: 18.7%, 50.9%] for decitabine with chemotherapy, and 37.5% [36.4%, 38.7%] for decitabine with chemotherapy and molecular therapy. Median survival was 7.2 months [95% CI: 5.17, 9.3]. Major adverse events were neutropenia, nausea/vomiting, infections, fatigue, febrile neutropenia, diarrhea, thrombocytopenia, anemia, anorexia, leukopenia, hemorrhage, and hyperglycemia. Conclusion: Decitabine in combination with chemotherapy or molecular therapy has shown efficacious properties in refractory or relapsed AML patients.

Schizophrenia (SZ) is a debilitating mental illness with a multigenic aetiology and significant heritability. Despite extensive genetic studies, the molecular aetiology has remained enigmatic. A recent systems biology study suggested a protein-protein interaction network for SZ with 504 novel interactions. The onset of psychiatric disorders is predominant during adolescence, often accompanied by subtle structural abnormalities in multiple regions of the brain. The availability of BrainSpan Atlas data allowed us to re-examine the genes present in the SZ interactome as a function of space and time. The availability of genomes of healthy centenarians and nonpsychiatric Exome Aggregation Consortium database allowed us to identify the variants of criticality. The expression of the SZ candidate genes responsible for cognition and disease onset was studied in different brain regions during particular developmental stages. A subset of novel interactors detected in the network was further validated using gene expression data of post-mortem brains of patients with psychiatric illness. We have narrowed down the list of drug targets proposed by theprevious interactome study to 10 proteins. These proteins belonging to 81 biological pathways are targeted by 34 known Food and Drug Administration-approved drugs that have distinct potential for the treatment of neuropsychiatric disorders. We also report the possibility of targeting key genes belonging to celecoxib pharmacodynamics, Gα signalling and cGMP-PKG signalling pathwaysthat are not known to be specific to SZ aetiology.

The standard treatment of rectal cancer is surgery along with preoperative radiotherapy, administered alone or in combination with chemotherapy. Preoperative chemoradiotherapy (preCRT) is widely used as it allows better local control and the use of sphincter-saving surgery. Pathological response after preCRT has been shown to be a significant prognostic factor of rectal cancer recurrence and survival. In this review we will assess the value of Hypoxia Induced Factor 1α (HIF-1α), Carbonic Anhydrase IX (CA-9) and Glucose Transporter 1 (GLUT-1) genes as predictive markers of the course of local advanced rectal cancer in patients who underwent pre-CRT.