Molecular functions of microRNAs in colorectal cancer: recent roles in proliferation, angiogenesis, apoptosis, and chemoresistance.

MiRNAs (microRNAs) constitute a group of diminutive molecules of non-coding RNA intricately involved in regulating gene expression. This regulation is primarily accomplished through the binding of miRNAs to complementary sequences situated in the 3'-UTR of the messenger RNA (mRNA) target; as a result, they are degraded or repressed. The multifaceted biogenesis of miRNAs is characterized by a meticulously orchestrated sequence of events encompassing transcription, processing, transportation, and decay. Colorectal cancer stands as a pervasive and formidable ailment, afflicting millions across the globe. Colorectal cancer is not well diagnosed early, and metastasis rates are high, which results in low survival rates in advanced stages. The genesis and progression of colorectal cancer are subject to the influence of genetic and epigenetic factors, among which miRNAs play a pivotal role. When it comes to colorectal cancer, miRNAs have a dual character, depending on the genes they target, functioning as either tumor suppressors or oncogenes and the prevailing cellular milieu. Their impact extends to modulating critical facets of colorectal cancer pathogenesis, including proliferation, angiogenesis, apoptosis, chemoresistance, and radiotherapy response. The discernible potential of miRNAs which are used as biomarkers to diagnose colorectal cancer, prognosis, and treatment response has come to the forefront. Notably, miRNAs are easily found and detected readily in a variety of biological fluids, including saliva, blood, urine, and feces. This prominence is attributed to the inherent advantages of miRNAs over conventional biomarkers, including heightened stability, specificity, sensitivity, and accessibility. Various investigations have pinpointed miRNA signatures or panels capable of differentiating colorectal cancer patients from their healthy counterparts, predicting colorectal cancer stage and survival, and monitoring colorectal cancer recurrence and therapy response. Although there has been research on miRNAs in various diseases, there has been less research on miRNAs in cancer. Moreover, updated results of preclinical and clinical studies on miRNA biomarkers and drugs are required. Nevertheless, the integration of miRNAs as biomarkers for colorectal cancer is not devoid of challenges and limitations. These encompass the heterogeneity prevalent among colorectal cancer subtypes and stages, the variability in miRNA expression across different tissues and individuals, the absence of standardized methodologies for miRNA detection and quantification, and the imperative for validation through extensive clinical trials. Consequently, further research is imperative to conclusively establish the clinical utility and reliability of miRNAs as colorectal cancer biomarkers. MiR-21 demonstrates carcinogenic characteristics by targeting several tumor suppressor genes, which encourages cell division, invasion, and metastasis. On the other hand, by controlling the Wnt/ß-catenin pathway, the tumor suppressor miRNA miR-34a prevents CRC cell proliferation, migration, and invasion. Furthermore, in colorectal cancer, the miR-200 family increases chemotherapy sensitivity while suppressing epithelial-mesenchymal transition (EMT). As an oncogene, the miR-17-92 cluster targets elements of the TGF-ß signaling pathway to encourage the growth of CRC cells. Finally, miR-143/145, which is downregulated in CRC, influences apoptosis and the progression of the cell cycle. These miRNAs affect pathways like Wnt, TGF-ß, PI3K-AKT, MAPK, and EMT, making them potential clinical biomarkers and therapeutic targets. This review summarizes recent research related to miRNAs, their role in tumor progression and metastasis, and their potential as biomarkers and therapeutic targets in colorectal cancer. In addition, we combined miRNAs' roles in tumorigenesis and development with the therapy of CRC patients, leading to novel perspectives on colorectal cancer diagnosis and treatment.

Neoadjuvant botensilimab plus balstilimab response pattern in locally advanced mismatch repair proficient colorectal cancer.

In patients with locally advanced cancer without distant metastases, the neoadjuvant setting presents a platform to evaluate new drugs. For mismatch repair proficient/microsatellite stable (pMMR/MSS) colon and rectal cancer, immunotherapy has shown limited efficacy. Herein, we report exceptional responses observed with neoadjuvant botensilimab (BOT), an Fc-enhanced next-generation anti-CTLA-4 antibody, alongside balstilimab (BAL; an anti-PD-1 antibody) in two patients with pMMR/MSS colon and rectal cancer. The histological pattern of rapid immune response observed ("inside-out" (serosa-to-mucosa) tumor regression) has not been described previously in this setting. Spatial biology analyses (RareCyte Inc.) reveal mechanisms of actions of BOT, a novel innate-adaptive immune activator. These observations have downstream implications for clinical trial designs using neoadjuvant immunotherapy and potentially sparing patients chemotherapy.

Recent advancement, immune responses, and mechanism of action of various vaccines against intracellular bacterial infections.

Emerging and re-emerging bacterial infections are a serious threat to human and animal health. Extracellular bacteria are free-living, while facultative intracellular bacteria replicate inside eukaryotic host cells. Many serious human illnesses are now known to be caused by intracellular bacteria such as Salmonella enterica, Escherichia coli, Staphylococcus aureus, Rickettsia massiliae, Chlamydia species, Brucella abortus, Mycobacterium tuberculosis and Listeria monocytogenes, which result in substantial morbidity and mortality. Pathogens like Mycobacterium, Brucella, MRSA, Shigella, Listeria, and Salmonella can infiltrate and persist in mammalian host cells, particularly macrophages, where they proliferate and establish a repository, resulting in chronic and recurrent infections. The current treatment for these bacteria involves the application of narrow-spectrum antibiotics. FDA-approved vaccines against obligate intracellular bacterial infections are lacking. The development of vaccines against intracellular pathogenic bacteria are more difficult because host defense against these bacteria requires the activation of the cell-mediated pathway of the immune system, such as CD8+ T and CD4+ T. However, different types of vaccines, including live, attenuated, subunit, killed whole cell, nano-based and DNA vaccines are currently in clinical trials. Substantial development has been made in various vaccine strategies against intracellular pathogenic bacteria. This review focuses on the mechanism of intracellular bacterial infection, host immune response, and recent advancements in vaccine development strategies against various obligate intracellular bacterial infections.

Therapeutic potential and bioactive phenolics of locally grown Pakistani and Chinese varieties of ginger in relation to extraction solvents

Abstract Current study compares the Therapeutic/nutra-pharmaceuticals potential and phenolics profile of Pakistani grown Pakistani and Chinese varieties of ginger. Crude yield of bioactive components from the varieties tested, using different extraction solvents including chloroform, ethyl acetate, ether, methanol, ethanol and distilled water. The crude bioactives varied from 14.1-82.5%. The highest extraction yield was noted for Pakistani species. The HPLC analysis revalued significant amounts of phenolics including vanillin, protocatechuic, vanillic, ferulic, sinapinic and cinnamic acids. The highest anti-inflammatory activity was shown by ethanolic extract of Pakistani variety (IC50: 26.5±1.8) whereas Chinese variety exhibited potent anticancer potential against MCF-7 cell line (Inhibition: 91.38 %). The Chinese variety in general showed higher phenolics and anticancer, while the Pakistani exhibited higher anti-inflammatory activity. Pakistani grown ginger and ethanolic extract of Chinese ginger showed highest antimicrobial activity against Pseudomonas aeruginosa 18.0±0.02 & 15.00±0.02 mm respectively. Minimum results obtained with water for both varieties of ginger with range of 7.2±0.22 and 6±0.07 respectively. Moreover, the phenolics composition, anti-inflammatory, antibacterial and anticancer activities of both tested varieties of ginger were notably affected as a function of extraction solvents. Our findings advocate selection of appropriate solvent for recovery of effective phenolic bioactive compounds from ginger verities to support the Nutra-pharmaceutical formulation.