Pegylated nanoliposomal cisplatin ameliorates chemotherapy-induced peripheral neuropathy.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse effect of cisplatin. The current study aimed to determine whether PEGylated nanoliposomal cisplatin can limit CIPN in an animal model. METHODS: Cisplatin-loaded PEGylated liposome nanoparticles (Cis-PL) were produced as a combination of lecithin, cholesterol, and DSPE-mPEG2000 in a molar ratio of 50:45:5 and were characterized by polydispersity index (PDI), zeta potential, Field emission scanning electron microscopy (FESEM) analysis, as well as encapsulation efficiency (EE). Fifteen male rats were provided and randomly divided into 3 groups including Cis-PL group, cisplatin group, and control group. Behavioural tests (hot-plate test and acetone drop test) were used for evaluating CIPN. Moreover, oxidative stress markers and histopathological analysis were applied. Treatment-related toxicity was assessed by haematological analysis as well as liver and renal function tests. RESULTS: Cis-PL had an average particle size of 125.4, PDI of 0.127, and zeta potential of -40.9 mV. Moreover, the Cis-PL exhibited a high EE as well as low levels of leakage rate at 25 °C. In a hot-plate test, paw withdrawal latency was longer in Cis-PL group in comparison to rats treated with cisplatin. A lower number of withdrawal responses was detected during acetone drop test in Cis-PL group than in cisplatin-treated rats. Assessment of oxidative stress markers showed that Cis-PL could improve oxidative stress. Additionally, histopathological assessment demonstrated that the number of satellite cells was significantly reduced in the dorsal root ganglion (DRG) of Cis-PL-treated rats compared with those treated with cisplatin. The cisplatin group had elevated white blood cells counts, reduced platelet counts, and higher levels of bilirubin, ALT (alanine aminotransferase, and AST (aspartate aminotransferase), and creatinine compared with the control group, which was ameliorated in Cis-PL group. CONCLUSIONS: Data from the current study support the previous hypothesis that Cisplatin-loaded PEGylated liposome could be a promising solution for CIPN in the future by modulating oxidative stress and preventing glial cell activation in DRG, suggesting further clinical studies to investigate the efficacy of this agent and its potential application in clinical practice.

Growth-hormone-releasing Hormone as a Prognostic Biomarker and Therapeutic Target in Gastrointestinal Cancer.

Gastrointestinal cancers are prevalent cancers in the world with a poor prognosis, causing about one-half of all cancer deaths in the world. Unfortunately, there is no effective treatment for GI cancers. GHRH and GHRH receptors (GHRH-R) are expressed in various tumoral tissues and cell lines. The inhibition of GHRH-R is a new area of research because it provides a possible means of treating several types of cancer. Recent publications have reported GHRH and GHRH-R expressions in breast, pancreatic, prostate, colon, gastric, ovarian, and lung cancers, along with promising data about the use of GHRH antagonists in the treatment of different cancers. This review aims to summarize the recent studies on the relationship between GHRH and GI cancers and assess whether this hormone can be our target for therapy or used as a prognostic marker for GI cancers.

Remodeling of the Gut Microbiota in Colorectal Cancer and its Association with Obesity.

The considerable burden of colorectal cancer and the increasing prevalence in young adults emphasizes the necessity of understanding its underlying mechanisms and risk factors as well as providing more effective treatments. There is growing evidence of a positive relationship between obesity and colorectal cancer. Furthermore, the prominent role of gut microbiota dysbiosis in colorectal carcinogenesis is becoming more evident. Sequencing studies demonstrate an altered composition and ecology of intestinal microorganisms in both colorectal cancer and obese patients and have pinpointed some specific bacteria as the key role players. The purpose of this review is to provide a general outlook of how gut microbiota may impact the initiation and promotion of colorectal cancer and describes probable links between gut microbiota and obesity. We also provide evidence about targeting the microbiota as an intervention strategy for both ameliorating the risk of cancer and augmenting the therapy efficacy.

Therapeutic Potential of Targeting Transforming Growth Factor-beta (TGF-ß) and Programmed Death-ligand 1 (PD-L1) in Pancreatic Cancer.

Pancreatic cancer (PC) is one the most lethal malignancies worldwide affecting around half a million individuals each year. The treatment of PC is relatively difficult due to the difficulty in making an early diagnosis. Transforming growth factor-beta (TGF-ß) is a multifunctional factor acting as both a tumor promoter in early cancer stages and a tumor suppressor in advanced disease. Programmed death-ligand 1 (PD-L1) is a ligand of programmed death-1 (PD-1), an immune checkpoint receptor, allowing tumor cells to avoid elimination by immune cells. Recently, targeting the TGF-ß signaling and PD-L1 pathways has emerged as a strategy for cancer therapy. In this review, we have summarized the current knowledge regarding these pathways and their contribution to tumor development with a focus on PC. Moreover, we have reviewed the role of TGF-ß and PD-L1 blockade in the treatment of various cancer types, including PC, and discussed the clinical trials evaluating TGF-ß and PD-L1 antagonists in PC patients.

Prognostic value of primary tumor location in colorectal cancer: an updated meta-analysis.

The clinical, histological, and molecular differences between right-sided colon cancer (RCC) and left-sided colon cancer (RCC) have received considerable attention. Over the past decade, many articles have been published concerning the association between primary tumor location (PTL) of colorectal cancer and survival outcomes. Therefore, there is a growing need for an updated meta-analysis integrating the outcomes of recent studies to determine the prognostic role of right vs left-sidedness of PTL in patients with colorectal cancer. We conducted a comprehensive database review using PubMed, SCOPUS, and Cochrane library databases from February 2016 to March 2023 for prospective or retrospective studies reporting data on overall survival (OS) and cancer-specific survival (CSS) of RCC compared with LCC. A total of 60 cohort studies comprising 1,494,445 patients were included in the meta-analysis. We demonstrated that RCC is associated with a significantly increased risk of death compared with LCC by 25% (hazard ratio (HR), 1.25; 95% confidence interval (CI), 1.19-1.31; I2 = 78.4%; Z = 43.68). Results showed that patients with RCC have a worse OS compared with LCC only in advanced stages (Stage III: HR, 1.275; 95% CI 1.16-1.4; P = 0.0002; I2 = 85.8%; Stage IV: HR, 1.34; 95% CI 1.25-1.44; P < 0.0001; I2 = 69.2%) but not in primary stages (Stage I/II: HR, 1.275; 95% CI 1.16-1.4; P = 0.0002; I2 = 85.8%). Moreover, a meta-analysis of 13 studies including 812,644 patients revealed that there is no significant difference in CSS between RCC and LCC (HR, 1.121; 95% CI 0.97-1.3; P = 0.112). Findings from the present meta-analysis highlight the importance of PTL in clinical decision-making for patients with CRC, especially in advanced stages. We provide further evidence supporting the hypothesis that RCC and LCC are distinct disease entities that should be managed differently.

Mechanism-based Pharmacological Management of Chemotherapy-induced Neuropathic Pain from Preclinical Studies to Clinical Prospective: Platinum-based Drugs, Taxanes, and Vinca Alkaloids.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a painful condition, experienced by patients undergoing chemotherapy with some specific drugs, such as platinum-based agents, taxanes, and vinca alkaloids. Painful CIPN may lead to dose interruptions and discontinuation of chemotherapy and can negatively impact on the quality of life and clinical outcome of these patients. Due to a lack of a practical medical therapy for CIPN, it is necessary to further explore and identify novel therapeutic options. METHODS: We have reviewed PubMed and EMBASE libraries to gather data on the mechanism-based pharmacological management of chemotherapy-induced neuropathic pain. RESULTS: This review has focused on the potential mechanisms by which these chemotherapeutic agents may be involved in the development of CIPN, and explains how this may be translated into clinical management. Additionally, we have presented an overview of emerging candidates for the prevention and treatment of CIPN in preclinical and clinical studies. CONCLUSION: Taken together, due to the debilitating consequences of CIPN for the quality of life and clinical outcome of cancer survivors, future studies should focus on identifying underlying mechanisms contributing to CIPN as well as developing effective pharmacological interventions based on these mechanistic insights.

Integrated analysis of multi-omics data for the discovery of biomarkers and therapeutic targets for colorectal cancer.

The considerable burden of colorectal cancer and the rising trend in young adults emphasize the necessity of understanding its underlying mechanisms, providing new diagnostic and prognostic markers, and improving therapeutic approaches. Precision medicine is a new trend all over the world and identification of novel biomarkers and therapeutic targets is a step forward towards this trend. In this context, multi-omics data and integrated analysis are being investigated to develop personalized medicine in the management of colorectal cancer. Given the large amount of data from multi-omics approach, data integration and analysis is a great challenge. In this Review, we summarize how statistical and machine learning techniques are applied to analyze multi-omics data and how it contributes to the discovery of useful diagnostic and prognostic biomarkers and therapeutic targets. Moreover, we discuss the importance of these biomarkers and therapeutic targets in the clinical management of colorectal cancer in the future. Taken together, integrated analysis of multi-omics data has great potential for finding novel diagnostic and prognostic biomarkers and therapeutic targets, however, there are still challenges to overcome in future studies.

Natriuretic Peptides in Gastrointestinal Cancer: Biomarkers and Potential Therapeutic Targets.

Gastrointestinal (GI) cancers are an important health problem globally. Natriuretic peptides are hormones that have a crucial role in human physiology. There are a variety of treatments for GI cancer, but conventional therapies have side effects and low efficacy. Studies have demonstrated that natriuretic peptides are therapeutic in different cancer types. Natriuretic peptides are best known for their involvement in regulating blood pressure and blood volume. The anti-tumor effect exerted by natriuretic peptides is via their inhibitory effects on DNA synthesis and by their effects on apoptosis. The anti-proliferative role of natriuretic peptides has been shown in human breast cancer, prostate, colon, pancreatic, lung, ovarian, and other tumors. The roles of natriuretic peptides in these cancers are diverse and not well understood. Therefore, we have reviewed the recent literature on natriuretic peptides in GI cancers as a common malignancy in adults to assess the pathways that NPs are involved in the progression of GI cancers and its effect on the prevention or treatment of GI cancers.

Extracellular vesicles: Emerging mediators of cell communication in gastrointestinal cancers exhibiting metabolic abnormalities.

There is a complex interaction between pro-tumoural and anti-tumoural networks in the tumour microenvironment (TME). Throughout tumourigenesis, communication between malignant cells and various cells of the TME contributes to metabolic reprogramming. Tumour Dysregulation of metabolic pathways offer an evolutional advantage in the TME and enhance the tumour progression, invasiveness, and metastasis. Therefore, understanding these interactions within the TME is crucial for the development of innovative cancer treatments. Extracellular vesicles (EVs) serve as carriers of various materials that include microRNAs, proteins, and lipids that play a vital role in the communication between tumour cells and non-tumour cells. EVs are actively involved in the metabolic reprogramming process. This review summarized recent findings regarding the involvement of EVs in the metabolic reprogramming of various cells in the TME of gastrointestinal cancers. Additionally, we highlight identified microRNAs involved in the reprogramming process in this group of cancers and explained the abnormal tumour metabolism targeted by exosomal cargos as well as the novel potential therapeutic approaches.

The Prognostic Value of ASPHD1 and ZBTB12 in Colorectal Cancer: A Machine Learning-Based Integrated Bioinformatics Approach.

Introduction: Colorectal cancer (CRC) is a common cancer associated with poor outcomes, underscoring a need for the identification of novel prognostic and therapeutic targets to improve outcomes. This study aimed to identify genetic variants and differentially expressed genes (DEGs) using genome-wide DNA and RNA sequencing followed by validation in a large cohort of patients with CRC. Methods: Whole genome and gene expression profiling were used to identify DEGs and genetic alterations in 146 patients with CRC. Gene Ontology, Reactom, GSEA, and Human Disease Ontology were employed to study the biological process and pathways involved in CRC. Survival analysis on dysregulated genes in patients with CRC was conducted using Cox regression and Kaplan-Meier analysis. The STRING database was used to construct a protein-protein interaction (PPI) network. Moreover, candidate genes were subjected to ML-based analysis and the Receiver operating characteristic (ROC) curve. Subsequently, the expression of the identified genes was evaluated by Real-time PCR (RT-PCR) in another cohort of 64 patients with CRC. Gene variants affecting the regulation of candidate gene expressions were further validated followed by Whole Exome Sequencing (WES) in 15 patients with CRC. Results: A total of 3576 DEGs in the early stages of CRC and 2985 DEGs in the advanced stages of CRC were identified. ASPHD1 and ZBTB12 genes were identified as potential prognostic markers. Moreover, the combination of ASPHD and ZBTB12 genes was sensitive, and the two were considered specific markers, with an area under the curve (AUC) of 0.934, 1.00, and 0.986, respectively. The expression levels of these two genes were higher in patients with CRC. Moreover, our data identified two novel genetic variants-the rs925939730 variant in ASPHD1 and the rs1428982750 variant in ZBTB1-as being potentially involved in the regulation of gene expression. Conclusions: Our findings provide a proof of concept for the prognostic values of two novel genes-ASPHD1 and ZBTB12-and their associated variants (rs925939730 and rs1428982750) in CRC, supporting further functional analyses to evaluate the value of emerging biomarkers in colorectal cancer.

Pharmacological Targeting of Epithelial-to-Mesenchymal Transition in Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most common cause of cancer deaths, and metastasis is a major cause of mortalities. The survival rate of patients diagnosed with metastasis remains disappointing. Therefore, the prevention of tumor dissemination as well as treatment of existing metastatic lesions is an important focus of new cancer therapies. Epithelial-to-mesenchymal transition (EMT) is defined as a cellular transition from an epithelial to a mesenchymal state and determines lethal cancer characteristics consisting of invasiveness, metastasis formation, and drug resistance. METHODS: We reviewed PubMed and EMBASE libraries to collect data about pharmacological targeting of Epithelial- to-Mesenchymal Transition in colorectal cancer to prevent metastatic tumor distribution and improve the survival of patients with CRC. RESULTS: We provided an overview of the available EMT-based therapies in CRC, summarized FDA-approved and under-clinical trial drugs with EMT-inhibiting properties in metastatic CRC, and described several agents preventing EMT-associated progression and metastasis in preclinical studies. Although various preclinical and clinical findings have proven that inhibiting EMT via different pharmacological approaches can reduce aggressive features of many cancers, not all agents possessing EMT-inhibiting function in preclinical research exhibit improvement in clinical studies. CONCLUSION: Combating EMT as a therapeutic intervention with the aim of preventing tumor dissemination, eliminating exiting metastasis, and promoting resistance to therapy may be a novel and effective strategy in the treatment of CRC. We hope that further exploration of EMT-related mechanisms and EMT-inhibiting drugs will provide more opportunities to treat CRC efficiently.

Metabolic Pathways Regulating Colorectal Cancer: A Potential Therapeutic Approach.

Colorectal cancer (CRC) is one of the most prevalent cancers globally. Despite recent progress in identifying etiologies and molecular genetics as well as new therapeutic approaches, the clinical outcome of current CRC therapies remains poor. This fact highlights the importance of further understanding underlying mechanisms involved in colorectal tumor initiation and progression. Abnormal metabolic alterations offer an evolutional advantage for CRC tumor cells and enhance their aggressive phenotype. Therefore, dysregulation of cellular metabolism is intricately associated with colorectal tumorigenesis. This review summarizes recent findings regarding the CRC-related changes in cellular metabolic pathways such as glycolysis, tricarboxylic acid cycle, fatty acid oxidation, and mitochondrial metabolism. We describe the oncogenic signaling pathways associated with metabolic dysregulation during malignant transformation and tumor progression. Given the crucial role of metabolic pathway alterations in the pathogenesis of CRC, we provide an overview of novel pharmacological strategies for the treatment of CRC by targeting metabolic and signaling pathways.

Role of gut bacterial and non-bacterial microbiota in alcohol-associated liver disease: Molecular mechanisms, biomarkers, and therapeutic prospective.

Alcohol-associated liver disease (ALD) comprises a spectrum of liver diseases that include: steatosis to alcohol-associated hepatitis, cirrhosis, and ultimately hepatocellular carcinoma. The pathophysiology and potential underlying mechanisms for alcohol-associated liver disease are unclear. Moreover, the treatment of ALD remains a challenge. Intestinal microbiota include bacteria, fungi, and viruses, that are now known to be important in the development of ALD. Alcohol consumption can change the gut microbiota and function leading to liver disease. Given the importance of interactions between intestinal microbiota, alcohol, and liver injury, the gut microbiota has emerged as a potential biomarker and therapeutic target. This review focuses on the potential mechanisms by which the gut microbiota may be involved in the pathogenesis of ALD and explains how this can be translated into clinical management. We discuss the potential of utilizing the gut microbiota signature as a biomarker in ALD patients. Additionally, we present an overview of the prospect of modulating the intestinal microbiota for the management of ALD.