Study of ischemia-reperfusion induced metabolite changes in porcine kidney model and their potential role in acute kidney injury

Acute kidney injury (AKI) is a common and serious complication in patients undergoing surgery, chronic treatment or kidney transplantation. In AKI patients, the normal functioning of kidneys are suddenly compromised leading to morbidity and mortality. It is reported that annually more than 40,000 inpatient deaths and expenditure of one billion pounds by National Health Service (NHS) in England are associated with AKI. There is a critical need to understand the pathophysiology of ischemia-reperfusion induced acute kidney injury and develop biomarkers useful for clinical management of AKI. In the present study, mass spectrometry based metabolomics approach was employed to investigate the metabolite changes in the kidney tissues of porcine AKI model. To ischemia or reperfusion induced porcine kidneys, two step solvent extraction followed by chromatography separation of metabolites was done prior to mass spectrometric analysis. The mass spectrometric data was generated and processed using IDEOM or Progenesis CoMet software algorithms. Further multivariate and univariate statistical analysis was done using SIMCA or Metaboanalyst software to identify key metabolites associated with Ischemia or reperfusion. Comparative analysis between control, ischemia and reperfusion kidneys revealed altered levels of several metabolites and majority of them belongs to amino acid, lipid and carbohydrate metabolisms. Degradation of several glucogenic and ketogenic amino acids was observed implicating their potential role in ischemia-reperfusion induced acute kidney injury. The combination of high throughput mass spectrometry, bioinformatics and statistical tools resulted in high confidence identification of metabolites and pathways associated with AKI and provide an opportunity for clinical intervention that may help prevent acute kidney injury

Investigating Flavonoid Extracts from Medicinal Plants: Evaluating their Anti-Cancer Potential, Mechanisms, and Synergistic Impact on Colon Cancer

Colon cancer, the leading cause of global cancer-related mortality, demands innovative therapeutic approaches to combat its formidable impact. This empirical study embarks on a quest to unlock novel avenues for colon cancer treatment by investigating the anti-cancer potential of flavonoid extracts sourced from medicinal plants. Our research journey commences with an in-depth examination of the staggering global burden imposed by colon cancer and the inherent limitations of current therapeutic regimens. In response to this pressing challenge, we spotlight the emerging enthusiasm for natural compounds, specifically flavonoids, as transformative agents within the realm of cancer research and therapy. In our pursuit of innovative solutions, we meticulously select medicinal plants celebrated for their flavonoid-rich content and extract these bioactive compounds with precision. Rigorous phytochemical analyses unveil the specific flavonoids at play. In a series of in vitro experiments employing colon cancer cell lines, we uncover a compelling narrative of concentration-dependent cytotoxicity, underscoring the remarkable anti-proliferative attributes of these extracts. Moreover, our investigations reveal that flavonoid extracts possess the remarkable capability to induce apoptosis, substantiated through Annexin V/PI staining and caspase activation assays. As we delve deeper into mechanistic insights, a rich tapestry unfolds, elucidating the intricate modulation of pivotal apoptosis-related pathways by these natural compounds. This study not only furnishes compelling evidence of flavonoid extracts' anti-cancer potential against colon cancer but also underscores the pivotal role of natural compounds in the ever-evolving landscape of cancer research, offering a beacon of hope for pioneering therapeutic strategies. The journey has only begun, and further investigations, alongside rigorous clinical trials, are warranted to harness the full therapeutic potential of flavonoid-based interventions in colon cancer management, potentially redefining the paradigm of cancer treatment

The ANZUS Treaty during the Cold War: a reinterpretation of U.S. diplomacy in the Southwest Pacific

This article explains the origins of the Australia–New Zealand–United States (ANZUS) Treaty by highlighting U.S. ambitions in the Pacific region after World War II. Three clarifications to the historiography merit attention. First, an alliance with Australia and New Zealand reflected the pursuit of U.S. interests rather than the skill of antipodean diplomacy. Despite initial reservations in Washington, geostrategic anxiety and economic ambition ultimately spurred cooperation. The U.S. government's eventual recourse to coercive diplomacy against the other ANZUS members, and the exclusion of Britain from the alliance, substantiate claims of self-interest. Second, the historiography neglects the economic rationale underlying the U.S. commitment to Pacific security. Regional cooperation ensured the revival of Japan, the avoidance of discriminatory trade policies, and the stability of the Bretton Woods monetary system. Third, scholars have unduly played down and misunderstood the concept of race. U.S. foreign policy elites invoked ideas about a “White Man's Club” in Asia to obscure the pursuit of U.S. interests in the region and to ensure British exclusion from the treaty

Quantitative tissue proteome profile reveals neutrophil degranulation and remodeling of extracellular matrix proteins in early stage gallbladder cancer

Gallbladder cancer (GBC) is an aggressive malignancy of the gastrointestinal tract with a poor prognosis. It is important to understand the molecular processes associated with the pathogenesis of early stage GBC and identify proteins useful for diagnostic and therapeutic strategies. Here, we have carried out an iTRAQ-based quantitative proteomic analysis of tumor tissues from early stage GBC cases (stage I, n=7 and stage II, n=5) and non-tumor controls (n=6) from gallstone disease (GSD). We identified 357 differentially expressed proteins (DEPs) based on ≥ 2 unique peptides and ≥ 2 fold change with p value < 0.05. Pathway analysis using the STRING database showed, ‘neutrophil degranulation’ to be the major upregulated pathway that includes proteins such as MPO, PRTN3, S100A8, MMP9, DEFA1, AZU, and ‘ECM organization’ to be the major downregulated pathway that includes proteins such as COL14A1, COL1A2, COL6A1, COL6A2, COL6A3, BGN, DCN. Western blot and/or IHC analysis confirmed the elevated expression of MPO, PRTN3 and S100A8 in early stage of the disease. Based on the above results, we hypothesize that there is an increased neutrophil infiltration in tumor tissue and neutrophil degranulation leading to degradation of extracellular matrix (ECM) proteins promoting cancer cell invasion in the early stage GBC. Some of the proteins (MPO, MMP9, DEFA1) associated with ‘neutrophil degranulation’ showed the presence of ‘signal sequence’ suggesting their potential as circulatory markers for early detection of GBC. Overall, the study presents a protein dataset associated with early stage GBC

Study of ischemia-reperfusion induced metabolite changes in porcine kidney model and their potential role in acute kidney injury

Acute kidney injury (AKI) is a common and serious complication in patients undergoing surgery, chronic treatment or kidney transplantation. In AKI patients, the normal functioning of kidneys are suddenly compromised leading to morbidity and mortality. It is reported that annually more than 40,000 inpatient deaths and expenditure of one billion pounds by National Health Service (NHS) in England are associated with AKI. There is a critical need to understand the pathophysiology of ischemia-reperfusion induced acute kidney injury and develop biomarkers useful for clinical management of AKI. In the present study, mass spectrometry based metabolomics approach was employed to investigate the metabolite changes in the kidney tissues of porcine AKI model. To ischemia or reperfusion induced porcine kidneys, two step solvent extraction followed by chromatography separation of metabolites was done prior to mass spectrometric analysis. The mass spectrometric data was generated and processed using IDEOM or Progenesis CoMet software algorithms. Further multivariate and univariate statistical analysis was done using SIMCA or Metaboanalyst software to identify key metabolites associated with Ischemia or reperfusion. Comparative analysis between control, ischemia and reperfusion kidneys revealed altered levels of several metabolites and majority of them belongs to amino acid, lipid and carbohydrate metabolisms. Degradation of several glucogenic and ketogenic amino acids was observed implicating their potential role in ischemia-reperfusion induced acute kidney injury. The combination of high throughput mass spectrometry, bioinformatics and statistical tools resulted in high confidence identification of metabolites and pathways associated with AKI and provide an opportunity for clinical intervention that may help prevent acute kidney injury

Serum Total Sialic Acid and Highly Sensitive C-reactive Protein: Prognostic Markers for the Diabetic Nephropathy

Background: This study was undertaken to evaluate and establish the role of total sialic acid (TSA) and highly sensitive C-reactive protein (hs-CRP) in type 2 diabetes mellitus (T2DM) and its correlation with complications such as diabetic nephropathy. Materials and Methods: One hundred fifty-seven patients with T2DM with nephropathy (DN) and 162 patients of T2DM without nephropathy (DM) along with 165 unrelated age and sex-matched healthy controls were included in the study. Serum glucose (fasting and postprandial) levels, renal profile, and lipid profile were done as per standard protocol. Serum TSA test levels and hs-CRP level were evaluated using thiobarbituric acid assay and immunoturbidimetric method respectively. Results: We observed a higher concentration of serum TSA (82.67 ± 6.63 mg/dl) and hs-CRP (3.2 ± 1.44 mg/L) in diabetic nephropathy than the diabetes mellitus group (73.83 ± 6.90 mg/dl and 2.07 ± 1.32 mg/L, respectively). Both TSA and hs-CRP levels were found significantly correlated with fasting and postprandial blood sugar, hemoglobin A1c, and urine microalbumin levels in both DM and DN groups. Multinomial logistic regression analysis showed that both TSA and hs-CRP was independently associated with diabetic nephropathy. Conclusion: High serum TSA and hs-CRP levels may increase the microangiopathic (diabetic nephropathy) complications of T2DM

Platelet count to spleen diameter ratio for the diagnosis of esophageal varices: Is it feasible?

AIM: To study the value of platelet count to spleen diameter ratio as a noninvasive parameter for diagnosing esophageal varices (EVs) in liver cirrhosis

Transcriptomic and Proteomic Data Integration and Two-Dimensional Molecular Maps with Regulatory and Functional Linkages: Application to Cell Proliferation and Invasion Networks in Glioblastoma

Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, is characterized by high rates of cell proliferation, migration, and invasion. New therapeutic strategies and targets are being continuously explored with the hope for better outcome. By overlaying transcriptomic and proteomic data from GBM clinical tissues, we identified 317 differentially expressed proteins to be concordant with the messenger RNAs (mRNAs). We used these entities to generate integrated regulatory information at the level of microRNAs (miRNAs) and their mRNA and protein targets using prediction programs or experimentally verified miRNA target mode in the miRWalk database. We observed 60% or even more of the miRNA–target pairs to be consistent with experimentally observed inverse expression of these molecules in GBM. The integrated view of these regulatory cascades in the contexts of cell proliferation and invasion networks revealed two-dimensional molecular interactions with regulatory and functional linkages (miRNAs and their mRNA–protein targets in one dimension; multiple miRNAs associated in a functional network in the second dimension). A total of 28 of the 35 differentially expressed concordant mRNA–protein entities represented in the proliferation network, and 51 of the 59 such entities represented in the invasion network, mapped to altered miRNAs from GBM and conformed to an inverse relationship in their expression. We believe the two-dimensional maps of gene expression changes enhance the strength of the discovery datasets derived from omics-based studies for their applications in GBM as well as tumors in general