Epitranscriptomic orchestrations: Unveiling the regulatory paradigm of m6A, A-to-I editing, and m5C in breast cancer via long noncoding RNAs and microRNAs.

Breast cancer (BC) poses a persistent global health challenge, particularly in countries with elevated human development indices linked to factors such as increased life expectancy, education, and wealth. Despite therapeutic progress, challenges persist, and the role of epitranscriptomic RNA modifications in BC remains inadequately understood. The epitranscriptome, comprising diverse posttranscriptional modifications on RNA molecules, holds the potential to intricately modulate RNA function and regulation, implicating dysregulation in various diseases, including BC. Noncoding RNAs (ncRNAs), acting as posttranscriptional regulators, influence physiological and pathological processes, including cancer. RNA modifications in long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) add an extra layer to gene expression control. This review delves into recent insights into epitranscriptomic RNA modifications, such as N-6-methyladenosine (m6A), adenine-to-inosine (A-to-I) editing, and 5-methylcytosine (m5C), specifically in the context of lncRNA and miRNAs in BC, highlighting their potential implications in BC development and progression. Understanding this intricate regulatory landscape is vital for deciphering the molecular mechanisms underlying BC and identifying potential therapeutic targets.

Oxaliplatin-Loaded Mil-100(Fe) for Chemotherapy-Ferroptosis Combined Therapy for Gastric Cancer.

Oxaliplatin (Oxa) is a commonly used chemotherapy drug in the treatment of gastric cancer, but its toxic side effects and drug resistance after long-term use have seriously limited its efficacy. Loading chemotherapy drugs with nanomaterials and delivering them to the tumor site are common ways to overcome the above problems. However, nanomaterials as carriers do not have therapeutic functions on their own, and the effect of single chemotherapy is relatively limited, so there is still room for progress in related research. Herein, we construct Oxa@Mil-100(Fe) nanocomposites by loading Oxa with a metal-organic framework (MOF) Mil-100(Fe) with high biocompatibility and a large specific surface area. The pore structure of Mil-100(Fe) is conducive to a large amount of Oxa loading with a drug-loading rate of up to 27.2%. Oxa@Mil-100(Fe) is responsive to the tumor microenvironment (TME) and can release Oxa and Fe3+ under external stimulation. On the one hand, Oxa can inhibit the synthesis of DNA and induce the apoptosis of gastric cancer cells. On the other hand, Fe3+ can clear overexpressed glutathione (GSH) in TME and be reduced to Fe2+, inhibiting the activity of glutathione peroxidase 4 (GPX4), leading to the accumulation of intracellular lipid peroxides (LPO), and at the same time releasing a large number of reactive oxygen species (ROS) through the Fenton reaction, inducing ferroptosis in gastric cancer cells. With the combination of apoptosis and ferroptosis, Oxa@Mil-100(Fe) shows a good therapeutic effect, and the killing effect on gastric cancer cells is obvious. In a nude mouse model of subcutaneous tumor transplantation, Oxa@Mil-100(Fe) shows a significant inhibitory effect on tumor growth, with an inhibition rate of nearly 60%. In addition to its excellent antitumor activity, Oxa@Mil-100(Fe) has no obvious toxic or side effects. This study provides a new idea and method for the combined treatment of gastric cancer.

Oral and maxillofacial surgeons' views on the adoption of additive manufacturing: findings from a nationwide survey.

OBJECTIVES: Hospitals in many European countries have implemented Additive Manufacturing (AM) technology for multiple Oral and Maxillofacial Surgery (OMFS) applications. Although the technology is widely implemented, surgeons also play a crucial role in whether a hospital will adopt the technology for surgical procedures. The study has two objectives: (1) to investigate how hospital type (university or non-university hospital) influences surgeons' views on AM, and (2) to explore how previous experience with AM (AM experience or not) influences surgeons' views on AM. MATERIALS AND METHODS: An online questionnaire to capture surgeons' views was designed, consisting of 11 Likert scale questions formulated according to the Consolidated Framework for Implementation Research (CFIR). The questionnaire was sent to OMF surgeons through the channel provided by the Association of Oral and Maxillofacial Surgery in Sweden. Data were analyzed using the Mann-Whitney U test to identify significant differences among OMF surgeons in terms of organizational form (i.e., university hospital or non-university hospital) and experience of AM (i.e., AM experience or no-experience). RESULTS: In total, 31 OMF surgeons responded to the survey. Views of surgeons from universities and non-universities, as well as between surgeons with experience and no-experience, did not show significant differences in the 11 questions captured across five CFIR domains. However, the "individual characteristics" domain in CFIR, consisting of three questions, did show significant differences between surgeons' experience with AM and no-experience (P-values: P = 0.01, P = 0.01, and P = 0.04). CONCLUSIONS: Surgeons, whether affiliated with university hospitals or non-university hospitals and regardless of their prior experience with AM, generally exhibit a favorable attitude towards AM. However, there were significant differences in terms of individual characteristics between those who had prior experience with AM and those who did not. CLINICAL RELEVANCE: This investigation facilitates the implementation of AM in OMFS by reporting on the views of OMF surgeons on AM.

PLAU and GREM1 are prognostic biomarkers for predicting immune response in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a common malignant tumor. Identification of biomarkers and understanding their potential functions will facilitate the treatment and diagnosis in LUAD patients. The yellow module (cor = 0.31, P = 2e-6) was selected as the core module based on weighted gene co-expression network analysis (WGCNA) by integrating RNA-seq data and tumor stage. Two upregulated genes (PLAU and GREM1) in yellow module were identified to be biomarkers. Kaplan-Meier curve analysis displayed that high expression levels of them had a poor overall survival (OS). And, their high expression levels revealed higher tumor stage and relapse possibility in LUAD patients, and could be a prognostic parameter. Both biomarkers showed similar immune cell expression profiles in low- and high-expression groups. Strongly positive correlation between both biomarkers and biomarkers of tumor-infiltrating lymphocytes were also clarified in TCGA-LUAD cohort. Importantly, single gene GSEA showed that transcriptional mis-regulation in cancer and microRNAs in cancer were enriched in LUAD patients. Therefore, a miRNA-mRNA-transcription factors (TFs) co-expression regulatory networks was constructed for each biomarker, various miRNAs and TFs were related to PLAU and GREM1. Among which, 6 downstream TFs were overlapped genes for both biomarkers. Notably, 2 of these TFs (FOXF1 and TFAP2A) exhibited significantly abnormal expression levels. Among which, FOXF1 was downregulated and TFAP2A was upregulated in TCGA-LUAD cohort. Both TFs showed a significantly positive correlation with the expression level of PLAU. In conclusion, we identified 2 biomarkers related to immune response and achieved a good accuracy in predicting OS in patients with LUAD.

The integration of multidisciplinary approaches revealed PTGES3 as a novel drug target for breast cancer treatment.

BACKGROUND: The main challenge in personalized treatment of breast cancer (BC) is how to integrate massive amounts of computing resources and data. This study aimed to identify a novel molecular target that might be effective for BC prognosis and for targeted therapy by using network-based multidisciplinary approaches. METHODS: Differentially expressed genes (DEGs) were first identified based on ESTIMATE analysis. A risk model in the TCGA-BRCA cohort was constructed using the risk score of six DEGs and validated in external and clinical in-house cohorts. Subsequently, independent prognostic factors in the internal and external cohorts were evaluated. Cell viability CCK-8 and wound healing assays were performed after PTGES3 siRNA was transiently transfected into the BC cell lines. Drug prediction and molecular docking between PTGES3 and drugs were further analyzed. Cell viability and PTGES3 expression in two BC cell lines after drug treatment were also investigated. RESULTS: A novel six-gene signature (including APOOL, BNIP3, F2RL2, HINT3, PTGES3 and RTN3) was used to establish a prognostic risk stratification model. The risk score was an independent prognostic factor that was more accurate than clinicopathological risk factors alone in predicting overall survival (OS) in BC patients. A high risk score favored tumor stage/grade but not OS. PTGES3 had the highest hazard ratio among the six genes in the signature, and its mRNA and protein levels significantly increased in BC cell lines. PTGES3 knockdown significantly inhibited BC cell proliferation and migration. Three drugs (gedunin, genistein and diethylstilbestrol) were confirmed to target PTGES3, and genistein and diethylstilbestrol demonstrated stronger binding affinities than did gedunin. Genistein and diethylstilbestrol significantly inhibited BC cell proliferation and reduced the protein and mRNA levels of PTGES3. CONCLUSIONS: PTGES3 was found to be a novel drug target in a robust six-gene prognostic signature that may serve as a potential therapeutic strategy for BC.

Adoption of additive manufacturing in oral and maxillofacial surgery among university and non-university hospitals in Sweden: findings from a nationwide survey.

PURPOSE: Additive manufacturing (AM) is an innovative printing technology that can manufacture 3-dimensional solid objects by adding layers of material from model data. AM in oral and maxillofacial surgery (OMFS) provides several clinical applications such as surgical guides and implants. However, the adoption of AM in OMFS is not well covered. The purpose was to study the adoption of AM in OMFS in university and non-university hospitals in Sweden. Three research questions were addressed: What is the degree of using AM solutions in university and non-university hospitals?; What are AM solutions used?; How are the AM solutions accessed (production mode) in university hospitals and non-university hospitals? METHODS: A survey was distributed to OMF surgeons in Sweden. The questionnaire consisted of 16 questions. Data were analyzed through descriptive and content analysis. RESULTS: A total of 14 university and non-university hospitals were captured. All 14 hospitals have adopted AM technology and 11 of the hospitals adopted AM in OMFS. Orthognathic and trauma surgery are two major types of surgery that involve AM technology where material extrusion and vat polymerization are the two most used AM technologies in OMFS. The primary application of AM was in medical models and guides. CONCLUSION: Majority of Swedish university hospitals and non-university hospitals have adopted AM in OMFS. The type of hospital (university or non-university hospital) has no impact on AM adoption. AM in OMFS in Sweden can be perceived to be a mature clinical application.

Construction and Application of a Nomogram for Predicting Benign and Malignant Parotid Tumors.

OBJECTIVE: A prediction model of benign and malignant differentiation was established by magnetic resonance signs of parotid gland tumors to provide an important basis for the preoperative diagnosis and treatment of parotid gland tumor patients. METHODS: The data from 138 patients (modeling group) who were diagnosed based on a pathologic evaluation in the Department of Stomatology of Jilin University from June 2019 to August 2021 were retrospectively analyzed. The independent factors influencing benign and malignant differentiation of parotid tumors were selected by logistic regression analysis, and a mathematical prediction model for benign and malignant tumors was established. The data from 35 patients (validation group) who were diagnosed based on pathologic evaluation from September 2021 to February 2022 were collected for verification. RESULTS: Univariate and multivariate logistic regression analysis showed that tumor morphology, tumor boundary, tumor signal, and tumor apparent diffusion coefficient (ADC) were independent risk factors for predicting benign and malignant parotid gland tumors ( P < 0.05). Based on multivariate logistic regression analysis of the modeling group, a mathematical prediction model was established as follows: Y = the ex/(1 + ex) and X = 0.385 + (1.416 × tumor morphology) + (1.473 × tumor border) + (1.306 × tumor signal) + (2.312 × tumor ADC value). The results showed that the area under the receiver operating characteristic curve of the model was 0.832 (95% confidence interval, 0.75-0.91), the sensitivity was 82.6%, and the specificity was 70.65%. The validity of the model was verified using validation group data, for which the sensitivity was 85.71%, the specificity was 96.4%, and the correct rate was 94.3%. The results showed that the area under receiver operating characteristic curve was 0.936 (95% confidence interval, 0.83-0.98). CONCLUSIONS: Combined with tumor morphology, tumor ADC, tumor boundary, and tumor signal, the established prediction model provides an important reference for preoperative diagnosis of benign and malignant parotid gland tumors.

Comparative proteomics analysis of kidney in chicken infected by infectious bronchitis virus.

The gamma coronavirus infectious bronchitis virus (IBV) is known to cause an acute and highly contagious infectious disease in poultry. Here, this study aimed to investigate the impact of virulent or avirulent IBV infection on the avian host by conducting proteomics with data-independent acquisition mass spectrometry (DIA-MS) in the kidneys of IBV-infected chickens. The results revealed 267, 489, and 510 differentially expressed proteins (DEPs) in the chicken kidneys at 3, 5, and 7 days postinfection (dpi), respectively, when infected with the GD17/04 strain, which is a highly nephrogenic strain and belongs to the 4/91 genotype. In contrast, the attenuated 4/91 vaccine resulted in the identification of 144, 175, and 258 DEPs at 3, 5, and 7 dpi, respectively. Functional enrichment analyses indicated distinct expression profiles between the 2 IBV strains. Upon GD17/04 infection, metabolic pathways respond initially in the early stage (3 dpi) and immune-related signaling pathways respond in the middle and late stages (5 and 7 dpi). The 4/91 vaccine elicited a completely opposite response compared to the GD17/04 infection. Among all DEPs, 62 immune-related DEPs were focused on and found to be mainly enriched in the type I interferon (IFN-I) signaling pathway and involved in humoral and cellular immunity. Notably, key molecules in the IFN-I signaling pathway including MDA5, LGP2, and TBK1 may serve as regulatory targets of IBV. Overall, this study highlights similarities and discrepancies in the patterns of protein expression at different stages of infection with virulent and avirulent IBV strains, with the IFN-I signaling pathway emerging as a critical response to IBV infection.

Aggressive fibromatosis near the incision after cervical spinal cord ependymoma: A case report.

Aggressive fibromatosis (AF), also known as ligamentoid fibromatosis and desmoid tumor, is a fibroblast clonoproliferative lesion located in the deep soft tissue. The present study reports the case of a 36-year-old female with AF who underwent cervical spinal cord ependymoma surgery. AF developed in the soft tissue of the neck adjacent to the incision site. The size of the neck AF increased rapidly over 2 years, and due to discomfort, the patient underwent initial surgical resection without any other combined treatment methods. When the patient was routinely reviewed at 6 months post-surgery, a recurrence of AF of the neck was found. The patient was recommended surgical resection and radiotherapy. This case report should improve the understanding of clinicians with regard to AF, and help the diagnostic process and treatment plan.

Differentiation of neurogenic tumours and pleomorphic adenomas in the parapharyngeal space based on texture analysis of T2WI.

BACKGROUND: The purpose of this study was to identify neurogenic tumours and pleomorphic adenomas of the parapharyngeal space based on the texture characteristics of MRI-T2WI. METHODS: MR findings and pathological reports of 25 patients with benign tumours in the parapharyngeal space were reviewed retrospectively (13 cases with pleomorphic adenomas and 12 cases with neurogenic tumours). Using PyRadiomics, the texture of the region of interest in T2WI sketched by radiologists was analysed. By using independent sample t-tests and Mann‒Whitney U tests, the selected texture features of 36 Gray Level Co-Occurrence Matrix (GLCM) and Gray Level Dependence Matrix (GLDM) were tested. A set of parameters of texture features showed statistically significant differences between the two groups, which were selected, and the diagnostic efficiency was evaluated via the operating characteristic curve of the subjects. RESULTS: The differences in the three parameters - small dependence low level emphasis (SDLGLE), low level emphasis (LGLE) and difference variance (DV) of characteristics - between the two groups were statistically significant (P < 0.05). No significant difference was found in the other indices. ROC curves were drawn for the three parameters, with AUCs of 0.833, 0.795, and 0.744, respectively. CONCLUSIONS: There is a difference in the texture characteristic parameters based on magnetic resonance T2WI images between neurogenic tumours and pleomorphic adenomas in the parapharyngeal space. For the differential diagnosis of these two kinds of tumours, texture analysis of significant importance is an objective and quantitative analytical tool.

Infectious bronchitis virus nucleocapsid protein suppressed type I interferon production by interfering with the binding of MDA5-dsRNA and interacting with LGP2.

The type I interferon (IFN-I) is a critical component of the innate immune responses, and Coronaviruses (CoVs) from both the Alphacoronavirus and Betacoronavirus genera interfere with the IFN-I signaling pathway in various ways. Of the gammacoronaviruses that mainly infect birds, little is known about how infectious bronchitis virus (IBV), evades or interferes with the innate immune responses in avian hosts since few IBV strains have been adapted to grow in avian passage cells. Previously, we reported that a highly pathogenic IBV strain GD17/04 has adaptability in an avian cell line, providing a material basis for further study on the interaction mechanism. In the present work, we describe the suppression of IBV to IFN-I and the potential role of IBV-encoded nucleocapsid (N) protein. We show that IBV significantly inhibits the poly I: C-induced IFN-I production, accordingly the nuclear translocation of STAT1, and the expression of IFN-stimulated genes (ISGs). A detailed analysis revealed that N protein, acting as an IFN-I antagonist, significantly impedes the activation of the IFN-ß promoter stimulated by MDA5 and LGP2 but does not counteract its activation by MAVS, TBK1, and IRF7. Further results showed that IBV N protein, verified to be an RNA-binding protein, interferes with MDA5 recognizing double-stranded RNA (dsRNA). Moreover, we found that the N protein targets LGP2, which is required in the chicken IFN-I signaling pathway. Taken together, this study provides a comprehensive analysis of the mechanism by which IBV evades avian innate immune responses.

Immune-related biomarkers predict the prognosis and immune response of breast cancer based on bioinformatic analysis and machine learning.

Breast cancer (BC) is the malignancy with the highest mortality rate among women, identification of immune-related biomarkers facilitates precise diagnosis and improvement of the survival rate in early-stage BC patients. 38 hub genes significantly positively correlated with tumor grade were identified based on weighted gene coexpression network analysis (WGCNA) by integrating the clinical traits and transcriptome analysis. Six candidate genes were screened from 38 hub genes basing on least absolute shrinkage and selection operator (LASSO)-Cox and random forest. Four upregulated genes (CDC20, CDCA5, TTK and UBE2C) were identified as biomarkers with the log-rank p < 0.05, in which high expression levels of them showed a poor overall survival (OS) and recurrence-free survival (RFS). A risk model was finally constructed using LASSO-Cox regression coefficients and it possessed superior capability to identify high risk patients and predict OS (p < 0.0001, AUC at 1-, 3- and 5-years are 0.81, 0.73 and 0.79, respectively). Decision curve analysis demonstrated risk score was the best prognostic predictor, and low risk represented a longer survival time and lower tumor grade. Importantly, multiple immune cell types and immunotherapy targets were observed increase in expression levels in high-risk group, most of which were significantly correlated with four genes. In summary, the immune-related biomarkers could accurately predict the prognosis and character the immune responses in BC patients. In addition, the risk model is conducive to the tiered diagnosis and treatment of BC patients.

Long Non-Coding RNAs, Cell Cycle, and Human Breast Cancer.

The long non-coding RNAs (lncRNAs) constitute an important class of the human transcriptome. The discovery of lncRNAs provided one of many unexpected results of the post-genomic era and uncovered a huge number of previously ignored transcriptional events. In recent years, lncRNAs are known to be linked with human diseases, with particular focus on cancer. Growing evidence has indicated that dysregulation of lncRNAs in breast cancer (BC) is strongly associated with the occurrence, development, and progress. Increasing numbers of lncRNAs have been found to interact with cell cycle progression and tumorigenesis in BC. The lncRNAs can exert their effect as a tumor suppressor or oncogene and regulate tumor development through direct or indirect regulation of cancer-related modulators and signaling pathways. What is more, lncRNAs are excellent candidates for promising therapeutic targets in BC due to the features of high tissue and cell-type specific expression. However, the underlying mechanisms of lncRNAs in BC still remain largely undefined. Here, we concisely summarize and sort out the current understanding of research progress in relationships of the roles for lncRNA in regulating the cell cycle. We also summarize the evidence for aberrant lncRNA expression in BC, and the potential for lncRNA to improve BC therapy is also discussed. Together, lncRNAs can be considered as exciting therapeutic candidates whose expression can be altered to impede BC progression.

ABO Blood Group and the Risk and Prognosis of Lymphoma.

ABO blood group antigens exhibit alternative phenotypes and genetically derived structures that are located on the red cell surface. The role of ABO blood group in cancer biology has been intensely reported by several studies, and it is now widely recognized that ABO antigens are associated with the risk and prognosis of several types of tumors, namely gastric cancer and pancreatic cancer. However, there have been contentious limited issues with the association between the ABO blood group and lymphoma. In this narrative review, based on literature data, we discuss the role of ABO blood group in the risk and prognosis of lymphoma and summarize the current knowledge of the underlying pathogenic mechanisms of the association. The possible association of ABO blood group with racial disparities and pathological classification in lymphoma patients is also discussed.

Colorimetric Sensor Array for Identification of Proteins and Classification of Metabolic Profiles under Various Osmolyte Conditions.

Rapid and efficient detection and identification of proteins hold great promise in medical diagnostics, treatment of different diseases, and proteomics. Here, we present a simple colorimetric sensor array for the differentiation of proteins in various osmolyte solutions. Osmolytes have different influences on the conformation of proteins, which have differential binding to silver nanoparticles, resulting in color changes. The sensor array shows unique color change patterns for each of the 19 proteins, allowing unambiguous identification. Very interestingly, the differentiation of 19 proteins is related to their molecular weight. Moreover, the sensor array can be used to identify protein mixtures, thermal denaturized proteins, and unknown protein samples. Finally, the sensor array can also analyze the plasma or liver samples of the four groups of salt-sensitive rats fed with different diets, indicating that it has the potential for the classification of metabolic profiles.

Benincasa hispida extracts positively regulated high salt-induced hypertension in Dahl salt-sensitive rats: Impact on biochemical profile and metabolic patterns.

Salt-induced hypertension is one of the major issues worldwide and one of the main factors involved in heart and kidney failure. The objective of this study was to investigate the potential role of Benincasa hispida extracts on high salt-induced hypertension in Dahl-salt sensitive (D-SS) rats and to find out the metabolic and biochemical pattern involved in the reduction of hypertension. Twenty-six Dahl salt-sensitive (D-SS) rats were selected and divided into four groups. The metabolic strategy was applied to test the extracts on salt-sensitive hypertension in kidney. Gas Chromatography-Mass spectrometry (GC-MS) was used to identify the potent biochemical profile in renal medulla and cortex of rat kidneys. The differential metabolites of cortex and medulla, enrichment analysis and pathway analysis were performed using metabolomics data. The GC-MS data revealed that 24 different antihypertensive metabolites was detected in renal cortex, while 16 were detected in renal medulla between different groups. The significantly metabolic pathways namely citrate cycle, glutathione metabolism, glycine, serine, and threonine metabolism, glyoxylate and dicarboxylate metabolism, glycerolipid metabolism, alanine, aspartate and glutamate metabolism in renal cortex and glycerolipid metabolism, pentose phosphate pathway, citrate cycle, glycolysis, glycerophospholipid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis in renal medulla were involved in the process of Hypertension. The results suggest that the extract mainly alter the metabolic pathways of amino acid in Dahl salt-sensitive rats and its antioxidant potential reduced the hypertension patterns of Salt-sensitive rat. The antihypertensive components malic acid, aspartic acid, and glycine of extract can be used as therapeutic drugs to protect kidneys from salt-induced hypertension. PRACTICAL APPLICATIONS: Hypertension is a multifactorial disease and one of the risk factors for heart and kidney failure. Benincasa hispida is a widely used vegetable in China, which belongs to the Cucurbitaceae family. Benincasa hispida (wax gourd) has been used in traditional Chinese medicine for the treatment of inflammation and hypertension. The Benincasa hispida contains many compounds such as amino acids, carbohydrates, volatile compounds, vitamins, and minerals. The amino acid present in the pulp of Benincasa hispida are ornithine, threonine, aspartate, glutamate, serine, glycine, proline, alanine, valine, cysteine, isoleucine, tyrosine, leucine, lysine, phenylalanine, histidine, arginine, and γ-aminobutyric acid. Our results showed that Benincasa hispida is one of the potent natural antioxidants and can maintain normal blood pressure in Dahl salt-sensitive rats (D-SS). In conclusion, the current results provide good theoretical basis for the development and research using Benincasa hispida as an effective natural antioxidant for hypertension.

Energy metabolism pathways in breast cancer progression: The reprogramming, crosstalk, and potential therapeutic targets.

Breast cancer (BC) is a malignant tumor that seriously endangers health in women. BC, like other cancers, is accompanied by metabolic reprogramming. Among energy metabolism-related pathways, BC exhibits enhanced glycolysis, tricarboxylic acid (TCA) cycle, pentose phosphate pathway (PPP), glutamate metabolism, and fatty acid metabolism activities. These pathways facilitate the proliferation, growth and migration of BC cells. The progression of BC is closely related to the alterations in the activity or expression level of several metabolic enzymes, which are regulated by the intrinsic factors such as the key signaling and transcription factors. The metabolic reprogramming in the progression of BC is attributed to the aberrant expression of the signaling and transcription factors associated with the energy metabolism pathways. Understanding the metabolic mechanisms underlying the development of BC will provide a druggable potential for BC treatment and drug discovery.

Momordica charantia Extract Confers Protection Against Hypertension in Dahl Salt-Sensitive Rats.

Hypertension is one of the main factors of cardiovascular disease worldwide and is strongly related to the overall mortality. High salt intake is a major risk factors for hypertension. Identifying functional foods that can help prevent mechanistic abnormalities mediating salt-induced hypertension is an issue of considerable nutraceutical and scientific interest. Dietary Momordica charantia may be an alternative approach to avoid salt-induced hypertension. Dahl salt-sensitive (DSS) rats were used to determine whether Momordica charantia water extracts (ME) exerts anti-hypertensive effects in the present study. ME gavage could significantly prevented the increase of blood pressure, blood urea nitrogen, creatinine, and urine protein-to-creatinine ratio of DSS rats. Metabolomics analysis indicated that high-salt diet induced abnormal amino acid metabolism was related to nitric oxide (NO) deficiency, but ME gavage could upregulate the activities of nitric oxide synthase, aspartate aminotransferase, argininosuccinate lyase, argininosuccinate synthase and restore endogenous synthesis of arginine and NO. Meanwhile, renal function was improved after ME gavage. Citrulline, as one of the important component in ME, could attenuate salt-induced hypertension by increasing endogenous synthesis of arginine and NO. Antioxidants in ME, such as phenolic compound, may avoid high-salt induced oxidative stress in DSS rats, which may be another mechanism by which ME prevented blood pressure increase. Thus, the present study indicated that feeding Momordica charantia could avoid high-salt-induced hypertension in DSS rats.

Supplementation of amino acids and organic acids prevents the increase in blood pressure induced by high salt in Dahl salt-sensitive rats.

A high-salt (HS) diet leads to metabolic disorders in Dahl salt-sensitive (SS) rats, and promotes the development of hypertension. According to the changes in the metabolites of SS rats, a set of combined dietary supplements containing amino acids and organic acids (AO) were designed. The purpose of the present study was to evaluate the effect of AO supplementation on the blood pressure of SS rats after the HS diet and clarify the mechanism of AO by metabolomics and biochemical analyses. The results showed that AO supplementation avoided the elevation of blood pressure induced by the HS diet in SS rats, increased the renal antioxidant enzyme activities (catalase, superoxide dismutase, glutathione reductase, and glutathione S-transferase), reduced the H2O2 and MDA levels, and restored the normal antioxidant status of the serum and kidneys. AO also reversed the decrease in the nitric oxide (NO) levels and NO synthase activity induced by the HS feed, which involved the L-arginine/NO pathway. Metabolomics analysis showed that AO administration increased the levels of amino acids such as cysteine, glycine, hypotaurine, and lysine in the renal medulla and the levels of leucine, isoleucine, and serine in the renal cortex. Of note, lysine, hypotaurine and glycine had higher metabolic centrality in the metabolic correlation network of the renal medulla after AO administration. In conclusion, AO intervention could prevent HS diet-induced hypertension in SS rats by restoring the metabolic homeostasis of the kidneys. Hence, AO has the potential to become a functional food additive to improve salt-sensitive hypertension.

ß-Aminoisobutyric acid supplementation attenuated salt-sensitive hypertension in Dahl salt-sensitive rats through prevention of insufficient fumarase.

The human Dietary Approaches to Stop Hypertension-Sodium Trial has shown that ß-aminoisobutyric acid (BAIBA) may prevent the development of salt-sensitive hypertension (SSHT). However, the specific antihypertensive mechanism remains unclear in the renal tissues of salt-sensitive (SS) rats. In this study, BAIBA (100 mg/kg/day) significantly attenuated SSHT via increased nitric oxide (NO) content in the renal medulla, and it induced a significant increase in NO synthesis substrates (L-arginine and malic acid) in the renal medulla. BAIBA enhanced the activity levels of total NO synthase (NOS), inducible NOS, and constitutive NOS. BAIBA resulted in increased fumarase activity and decreased fumaric acid content in the renal medulla. The high-salt diet (HSD) decreased fumarase expression in the renal cortex, and BAIBA increased fumarase expression in the renal medulla and renal cortex. Furthermore, in the renal medulla, BAIBA increased the levels of ATP, ADP, AMP, and ADP/ATP ratio, thus further activating AMPK phosphorylation. BAIBA prevented the decrease in renal medullary antioxidative defenses induced by the HSD. In conclusion, BAIBA's antihypertensive effect was underlined by the phosphorylation of AMPK, the prevention of fumarase's activity reduction caused by the HSD, and the enhancement of NO content, which in concert attenuated SSHT in SS rats.