Current Medicinal Chemistry - Volume 29, Issue 18, 2022

Background: The role of gut microbiota in human disease is fascinating for hundreds of researchers worldwide. Many works have highlighted that gut microbiota modulates the immune system and that its disruption can trigger autoimmune and inflammatory immune-mediated diseases. Probiotics are able to positively modify microbiota composition. Objective: The aim of this review is to report the most important findings regarding the effects of probiotics administration in the most common autoimmune disease and inflammatory immune-mediated diseases. Methods: Literature research was performed in PubMed, Google Scholar, and Medline, as well as in specific journal websites using the keywords: “autoimmunity”, “microbiota”, and “probiotics”. The article selection has been made independently by three authors, and controversies have been solved by a fourth researcher. Only English-language articles were included and preference was given to clinical trials, meta-analysis, and case series. After the review process, 68 articles have been considered. Results: Relying on this evidence, many studies have investigated the potential of probiotics in restoring gut eubiosis, thus affecting pathogenesis, clinical manifestations, and course of these pathologies. Even in the light of few and sometimes contradictory studies, physicians should start to consider these preliminary findings when approaching patients suffering from autoimmune disease. After an accurate case-by-case evaluation of potential candidates, probiotics might be introduced besides the standard therapeutic plan as supportive measures.

Phenolic compounds (PC) have many health benefits such as antioxidant, anticarcinogenic, neuroprotective, and anti-inflammatory activities. All of these activities depend on their chemical structures and their interaction with biological targets in the body. PC occur naturally in polymerized form, linked to glycosides and require metabolic transformation from their ingestion to their absorption. The gut microbiota can transform PC into more easily absorbed metabolites. PC, in turn, have prebiotic and antimicrobial actions on the microbiota. Despite this, their low oral bioavailability still compromises biological performance. Therefore, the use of nanocarriers has been demonstrated to be a useful strategy to improve PC absorption and, consequently, their health effects. Nanotechnology is an excellent alternative able to overcome the limits of oral bioavailability of PC, since it offers protection from degradation during their passage through the gastrointestinal tract. Moreover, nanotechnology is also capable of promoting controlled PC release and modulating the interaction between PC and the microbiota. However, little is known about the impact of nanotechnology on PC effects on the gut microbiota. This review highlights the use of nanotechnology for PC delivery on gut microbiota, focusing on the ability of such formulations to enhance oral bioavailability by applying nanocarriers (polymeric nanoparticles, nanostructured lipid carriers, solid lipid nanoparticles). In addition, the effects of free and nanocarried PC or nanocarriers per se on gut microbiota are also described.

Background: The digestive tract represents an interface between the external environment and the body where the interaction of a complex polymicrobial ecology has an important influence on health and disease. The physiological mechanisms that are altered during hospitalization and in the intensive care unit (ICU) contribute to the pathobiota’s growth. Intestinal dysbiosis occurs within hours of being admitted to ICU. This may be due to different factors, such as alterations of normal intestinal transit, administration of various medications, or alterations in the intestinal wall, which causes a cascade of events that will lead to the increase of nitrates and decrease of oxygen concentration, and the liberation of free radicals. Objective: This work aims to report the latest updates on the microbiota’s contribution to developing sepsis in patients in the ICU department. In this short review, the latest scientific findings on the mechanisms of intestinal immune defenses performed both locally and systemically have been reviewed. Additionally, we considered it necessary to review the literature on the basis of the many studies carried out on the microbiota in the critically ill as a prevention to the spread of the infection in these patients. Materials and Methods: This review has been written to answer four main questions: 1- What are the main intestinal flora’s defense mechanisms that help us to prevent the risk of developing systemic diseases? 2- What are the main Systemic Abnormalities of Dysbiosis? 3- What are the Modern Strategies Used in ICU to Prevent the Infection Spreading? 4- What is the Relationship between COVID-19 and Microbiota? We reviewed 72 articles using the combination of following keywords: "microbiota" and "microbiota" and "intensive care", "intensive care" and "gut", "critical illness", "microbiota" and "critical care", "microbiota" and "sepsis", "microbiota" and "infection", and "gastrointestinal immunity" in: Cochrane Controlled Trials Register, Cochrane Library, Medline and Pubmed, Google Scholar, Ovid/Wiley. Moreover, we also consulted the site ClinicalTrials.com to find out studies that have been recently conducted or are currently ongoing. Results: The critical illness can alter intestinal bacterial flora leading to homeostasis disequilibrium. Despite numerous mechanisms, such as epithelial cells with calciform cells that together build a mechanical barrier for pathogenic bacteria, the presence of mucous associated lymphoid tissue (MALT) which stimulates an immune response through the production of interferon-gamma (IFN-y) and THN-a or or from the production of anti-inflammatory cytokines produced by lymphocytes Thelper 2. But these defenses can be altered following hospitalization in ICU and lead to serious complications, such as acute respiratory distress syndrome (ARDS), health care associated pneumonia (HAP) and ventilator associated pneumonia (VAP), systemic infection and multiple organ failure (MOF), but also to the development of coronary artery disease (CAD). In addition, the microbiota has a significant impact on the development of intestinal complications and the severity of the SARS-COVID-19 patients. Conclusion: The microbiota is recognized as one of the important factors that can worsen the clinical conditions of patients who are already very frail in the intensive care unit. At the same time, the microbiota also plays a crucial role in the prevention of ICU-associated complications. By using the resources that are available, such as probiotics, synbiotics or fecal microbiota transplantation (FMT), we can preserve the integrity of the microbiota and the GUT, which will later help maintain homeostasis in ICU patients.

Gut microbiota (GM) comprises more than one thousand microorganisms between bacterial species, viruses, fungi, and protozoa and represents the main actor of a wide net of molecular interactions, involving, among others, the endocrine system, immune responses, and metabolism. GM influences many endocrine functions, such as adrenal steroidogenesis, thyroid function, sexual hormones, IGF-1 pathway and peptides, produced in the gastrointestinal system. It is fundamental in glycaemic control and obesity, while also exerting an important function in modulating the immune system and associated inflammatory disease. The result of this crosstalk in gut mucosa is the formation of the intestinal immunological niche. Visceral adipose tissue (VAT) produces about 600 different peptides and it is involved in lipid and glucose metabolism, and some immune reactions, through several adipokines. GM and VAT interact in a bidirectional fashion: while gut dysbiosis can modify VAT adipokines and hormone secretion, VAT hyperplasia modifies GM composition. Acquired or genetic factors leading to gut dysbiosis or increasing VAT (i.e., Western diet) induce a pro-inflammatory condition, which plays a pivotal role in the development of dysmetabolic and immunologic conditions, such as diabetes mellitus. Diabetes is associated with specific patterns of GM alterations, an abundance or reduction of GM species involved in controlling mucosal barrier status, glycaemic levels and exerting a pro- or anti-inflammatory activity. All these factors could explain the higher incidence of several inflammatory conditions in Western countries; furthermore, besides the specific alterations observed in diabetes, this paradigm could represent a common pathway acting in many metabolic conditions and could pave the way to new, interesting therapeutic approaches.

The human gut microbiome has received a crescendo of attention in recent years due to the countless influences on human pathophysiology, including cancer. Research on cancer and anticancer therapy is constantly looking for new hints to improve the response to therapy while reducing the risk of relapse. In this scenario, the gut microbiome and the plethora of microbial-derived metabolites are considered a new opening in the development of innovative anticancer treatments for a better prognosis. This narrative review summarizes the current knowledge on the role of the gut microbiome in the onset and progression of cancer, as well as in response to chemo-immunotherapy. Recent findings regarding the tumor microbiome and its implications for clinical practice are also commented on. Current microbiome-based intervention strategies (i.e., prebiotics, probiotics, live biotherapeutics and fecal microbiota transplantation) are then discussed, along with key shortcomings, including a lack of long-term safety information in patients who are already severely compromised by standard treatments. The implementation of bioinformatic tools applied to microbiomics and other omics data, such as machine learning, has an enormous potential to push research in the field, enabling the prediction of health risk and therapeutic outcomes, for a truly personalized precision medicine.

Background: The scientific interest regarding the involvement of peptides in cancer has increased in the last few years. In tumor cells, the overexpression of peptides and their receptors is known, and new therapeutic targets for the treatment of cancer have been suggested. The overexpression of the neurotensinergic system has been associated with poor prognosis, tumor size, higher tumor aggressiveness, increased relapse risk, and worse sensitivity to chemotherapy agents. Objective: The aim of this review is to update the findings regarding the involvement of the neurotensinergic system in cancer to suggest anticancer therapeutic strategies targeting this system. The neurotensin (NT) precursor, NT and its receptors (NTR), and the involvement of the neurotensinergic system in lung, breast, prostate, gastric, colon, liver, and pancreatic cancers, glioblastoma, neuroendocrine tumors, and B-cell leukemia will be mentioned and discussed as well as the signaling pathways mediated by NT. Some research lines to be developed in the future will be suggested, such as molecules regulating the expression of the NT precursor, the influence of the diet in the development of tumors, molecules and signaling pathways activated by NT, and antitumor therapeutic strategies targeting the neurotensinergic system. Conclusion: NT, via the NTR, exerts oncogenic (tumor cell proliferation, invasion, migration, angiogenesis) and antiapoptotic effects, whereas NTR antagonists inhibit these effects. NTR expression can be used as a diagnostic tool/therapeutic target, and the administration of NTR antagonists as antitumor drugs could be a therapeutic strategy to treat tumors overexpressing NTR.

Background: Photodynamic therapy (PDT), in comparison to other skin cancers, is still far less effective for melanoma, due to the strong absorbance and the role of melanin in cytoprotection. The tumour microenvironment (TME) has a significant role in tumour progression, and the hypoxic TME is one of the main reasons for melanoma progression to metastasis and its resistance to PDT. Hypoxia is also a feature of solid tumours in the head and neck region that indicates negative prognosis. Objective: The aim of this study was to individuate and describe systematically the main strategies in targeting the TME, especially hypoxia, in PDT against melanoma and head and neck cancers (HNC), and assess the current success in their application. Methods: PubMed was used for searching, in MEDLINE and other databases, for the most recent publications on PDT against melanoma and HNC in combination with the TME targeting and hypoxia. Results: In PDT for melanoma and HNC, it is very important to control hypoxia levels, and amongst the different approaches, oxygen self-supply systems are often applied. Vascular targeting is promising, but to improve it, optimal drug-light interval, and formulation to increase the accumulation of the photosensitiser in the tumour vasculature, have to be established. On the other side, the use of angiogenesis inhibitors, such as those interfering with VEGF signalling, is somewhat less successful than expected and needs to be further investigated. Conclusion: The combination of PDT with immunotherapy by using multifunctional nanoparticles continues to develop and seems to be the most promising for achieving a complete and lasting antitumour effect.

In this review, we discussed the biological targets of carnitine, its effects on immune function, and how L-carnitine supplementation may help critically ill patients. L-carnitine is a potent antioxidant. L-carnitine depletion has been observed in prolonged intensive care unit (ICU) stays, while L-carnitine supplementation has beneficial effects in health promotion and regulation of immunity. It is essential for the uptake of fatty acids into mitochondria. By inhibiting the ubiquitin-proteasome system, down-regulating the apelin receptor in cardiac tissue, and reducing β-oxidation of fatty acid, carnitine may decrease vasopressor requirement in septic shock and improve clinical outcomes of this group of patients. We also reviewed animal and clinical studies that have been recruited for evaluating the beneficial effects of L-carnitine in the management of sepsis/ septic shock. Additional clinical data are required to evaluate the optimal daily dose and duration of L-carnitine supplementation.