Highlights • MicroRNAs have emerged as key regulators of cancer cell biology. • MicroRNA signatures can define tumor types, susceptibility, prognosis, and response. • Circulating microRNAs provide a potential source of biomarkers. • Modulation of specific microRNA activities is a potential therapeutic avenue.
Highlights • Microbiota is key to maintaining homeostasis including brain development. • Microbial colonization in the infant coincides with key neurodevelopment periods. • Disruptions of early life gut colonization may be linked to central nervous system dysfunction. • This provides opportunities for developing novel microbiota-modulating therapies.
Highlights • The infant microbiome educates the immune system and primes organ function. • Infant microbiome development is perturbed by C-section, perinatal antibiotics, and formula feeding. • Perturbed infant microbiomes have been linked to increased risk of metabolic and immune diseases. • Restoration of the microbiome in infants may decrease the risk of associated diseases.
Highlights • Nanomedicine brings new solutions for cancer therapy. • Nanomedicine has the potential to target specific cells for chemotherapy. • Stealth technology can enhance the circulation half-life and controlled release of therapeutic agents. • Drug/RNAi combinatorial strategies show promising synergistic effects.
Highlights • CD39 and CD73 are important for calibrating the duration, magnitude, and composition of the ‘purinergic halo’ surrounding immune cells. • CD39 and CD73 degrade ATP, ADP, and AMP to adenosine; they can be viewed as ‘immunological switches’ that shift ATP-driven proinflammatory immune cell activity toward an anti-inflammatory state mediated by adenosine. • CD39 and CD73 are highly expressed on the surface of Foxp3+ Tregs and have been increasingly used as markers of Tregs. • CD39 and CD73 are important for the immunosuppressive activity of Tregs. • CD39 and CD73 generate an immunosuppressed environment, characterized by increased adenosine levels, which promotes the development and progression of cancer.
Cell-penetrating peptides (CPPs) have been previously shown to be powerful transport vector tools for the intracellular delivery of a large variety of cargoes through the cell membrane. Intracellular delivery of plasmid DNA (pDNA), oligonucleotides, small interfering RNAs (siRNAs), proteins and peptides, contrast agents, drugs, as well as various nanoparticulate pharmaceutical carriers (e.g., liposomes, micelles) has been demonstrated both in vitro and in vivo . This review focuses on the peptide-based strategy for intracellular delivery of CPP-modified nanocarriers to deliver small molecule drugs or DNA. In addition, we discuss the rationales for the design of ‘smart’ pharmaceutical nanocarriers in which the cell-penetrating properties are hidden until triggered by exposure to appropriate environmental conditions (e.g., a particular pH, temperature, or enzyme level), applied local microwave, ultrasound, or radiofrequency radiation.
The current worldwide emergence of resistance to the powerful antibiotic carbapenem in Enterobacteriaceae constitutes an important growing public health threat. Sporadic outbreaks or endemic situations with enterobacterial isolates not susceptible to carbapenems are now reported not only in hospital settings but also in the community. Acquired class A (KPC), class B (IMP, VIM, NDM), or class D (OXA-48, OXA-181) carbapenemases, are the most important determinants sustaining resistance to carbapenems. The corresponding genes are mostly plasmid-located and associated with various mobile genetic structures (insertion sequences, integrons, transposons), further enhancing their spread. This review summarizes the current knowledge on carbapenem resistance in Enterobacteriaceae , including activity, distribution, clinical impact, and possible novel antibiotic pathways.
NRF2 has been traditionally considered as a tumor suppressor because its cytoprotective functions are deemed to be the main cellular defense mechanism against exogenous and endogenous insults, including xenobiotics and oxidative stress. However, several recent studies demonstrate that hyperactivation of the NRF2 pathway creates an environment that favors the survival of normal as well as malignant cells, protecting them against oxidative stress, chemotherapeutic agents, and radiotherapy. In a rapidly advancing field, this review summarizes some of the known mechanisms by which NRF2 can exert its oncogenic functions, and describes the current status of NRF2 inhibitors, providing a clear rationale for the consideration of NRF2 as a powerful putative therapeutic target in cancer treatment.
Highlights • The PD-1/PD-L1 pathway inhibits T cell functions. • The PD-1/PD-L1 pathway functions as immune evasion in some cancers. • Clinical trials targeting PD-1 and PD-L1 show impressive response rates.
The systemic inflammatory response is biologically complex, redundant, and activated by both infectious and noninfectious triggers. Its manipulation can cause both benefit and harm. More than 100 randomized clinical trials have tested the hypothesis that modulating the septic response to infection can improve survival. With one short-lived exception, none of these has resulted in new treatments. The current challenge for sepsis research lies in a failure of concept and reluctance to abandon a demonstrably ineffectual research model. Future success will necessitate large studies of clinical and biochemical epidemiology to understand the course of illness, better integration of basic and clinical science, and the creation of stratification systems to target treatment towards those who are most likely to benefit.
Highlights • MUC1 promotes growth, metastasis, and resistance to drugs in cancer. • In tumors, the cytoplasmic tail of MUC1 acts as an oncogenic signaling molecule. • MUC1 regulates gene expression at transcriptional and post-transcriptional levels. • MUC1 is critical for maintaining ‘stemness’ in embryonic and cancer stem cells.
Chronic inflammation is associated with aging and plays a causative role in several age-related diseases such as cancer, atherosclerosis and osteoarthritis. The source of this chronic inflammation is often attributed to the progressive activation of immune cells over time. However, recent studies have shown that the process of cellular senescence, a tumor suppressive stress response that is also associated with aging, entails a striking increase in the secretion of proinflammatory proteins and might be an important additional contributor to chronic inflammation. Here, we list the secreted factors that make up the proinflammatory phenotype of senescent cells and describe the impact of these factors on tissue homeostasis. We also summarize the cellular pathways/processes that are known to regulate this phenotype – namely, the DNA damage response, microRNAs, key transcription factors and kinases and chromatin remodeling.
Highlights • The biology of sepsis is complex and not specific to infection. • Clinical criteria do not adequately delineate patients who will benefit from specific therapies. • Stratification systems are needed to guide optimal treatment decisions. • Success in developing new treatments will necessitate new collaborative research models.
The endoplasmic reticulum (ER) stress response, also commonly known as the unfolded protein response (UPR), is an adaptive response used to align ER functional capacity with demand. It is activated in various tissues under conditions related to obesity and type 2 diabetes. Hypothalamic ER stress contributes to inflammation and leptin/insulin resistance. Hepatic ER stress contributes to the development of steatosis and insulin resistance, and components of the UPR regulate liver lipid metabolism. ER stress in enlarged fat tissues induces inflammation and modifies adipokine secretion, and saturated fats cause ER stress in muscle. Finally, prolonged ER stress impairs insulin synthesis and causes pancreatic β cell apoptosis. In this review, we discuss ways in which ER stress operates as a common molecular pathway in the pathogenesis of obesity and diabetes.
Organoids are 3D in vitro culture systems derived from self-organizing stem cells. They can recapitulate the in vivo architecture, functionality, and genetic signature of original tissues. Thus, organoid technology has been rapidly applied to understanding stem cell biology, organogenesis, and various human pathologies. The recent development of human patient-derived organoids has enabled disease modeling with precision, highlighting their great potential in biomedical applications, translational medicine, and personalized therapy. In light of recent breakthroughs using organoids, it is only apt that we appreciate the advantages and shortcomings of this technology to exploit its full potential. We discuss recent advances in the application of organoids in studying cancer and hereditary diseases, as well as in the examination of host cell–microorganism interactions.
Highlights • Polymicrobial synergy and dysbiosis drive periodontitis in a susceptible host. • Dysbiosis involves specialized accessory and keystone pathogens and pathobionts. • Microbial immune subversion is central to the persistence of dysbiotic communities. • The dysbiotic microbiota sustains itself by feasting on the ‘inflammatory spoils’.
Glucosinolates and isothiocyanates have both been objects of research for more than half a century. Interest in these unique phytochemicals escalated following the discovery that sulforaphane, an isothiocyanate from broccoli, potently induces mammalian cytoprotective proteins through the Keap1–Nrf2–ARE pathway. In parallel with the advances in understanding the molecular regulation of this pathway and its critical role in protection against electrophiles and oxidants, there have been increased efforts toward translating this knowledge to improve human health and combat disease. This review focuses on the animal studies demonstrating the beneficial effects of glucosinolates and isothiocyanates in models of carcinogenesis, and cardiovascular and neurological diseases, as well as on the intervention studies of their safety, pharmacokinetics, and efficacy in humans.
Highlights • Extracellular vesicles are novel mediators of cell-to-cell communication. • Extracellular vesicles play important roles in regulating all facets of cancer development and spread. • Targeting aspects of extracellular vesicle biogenesis or function could prevent tumour progression.
The mechanistic target of rapamycin (mTOR) kinase controls growth and metabolism, and its deregulation underlies the pathogenesis of many diseases, including cancer, neurodegeneration, and diabetes. mTOR complex 1 (mTORC1) integrates signals arising from nutrients, energy, and growth factors, but how exactly these signals are propagated await to be fully understood. Recent findings have placed the lysosome, a key mediator of cellular catabolism, at the core of mTORC1 regulation by amino acids. A multiprotein complex that includes the Rag GTPases, Ragulator, and the v-ATPase forms an amino acid-sensing machinery on the lysosomal surface that affects the decision between cell growth and catabolism at multiple levels. The involvement of a catabolic organelle in growth signaling may have important implications for our understanding of mTORC1-related pathologies.
The gut microbiota is a key player in many physiological and pathological processes occurring in humans. Recent investigations suggest that the efficacy of some clinical approaches depends on the action of commensal bacteria. Antibiotics are invaluable weapons to fight infectious diseases. However, by altering the composition and functions of the microbiota, they can also produce long-lasting deleterious effects for the host. The emergence of multidrug-resistant pathogens raises concerns about the common, and at times inappropriate, use of antimicrobial agents. Here we review the most recently discovered connections between host pathophysiology, microbiota, and antibiotics highlighting technological platforms, mechanistic insights, and clinical strategies to enhance resistance to diseases by preserving the beneficial functions of the microbiota.