Secreted Non-Coding RNAs: Functional Impact on the Tumor Microenvironment and Clinical Relevance in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma characterized by poor prognosis and high rate of metastasis. Current treatment is based on chemo- and/or radiotherapy and surgery. TNBC is devoid of estrogen, progesterone and HER2 receptors. Although precision medicine has come a long way to ameliorate breast cancer disease management, targeted therapies for the treatment of TNBC patients are still limited. Mounting evidence has shown that non-coding RNAs (ncRNAs) drive many oncogenic processes at the basis of increased proliferation, invasion and angiogenesis in TNBC, strongly contributing to tumor progression and resistance to treatments. Many of these ncRNAs are secreted in the tumor microenvironment (TME) and impinge on the activity of the diverse immune and stromal cell types infiltrating the TME. Importantly, secreted ncRNAs may be detected as circulating molecules in serum/plasma from cancer patients and are emerging a promising diagnostic/therapeutic tools in TNBC. This review aims to discuss novel insights about the role of secreted circulating ncRNAs in the intercellular communication in the tumor microenvironment and their potential clinical use as diagnostic and prognostic non-invasive biomarkers in TNBC.

Molecules Containing Cyclobutyl Fragments as Therapeutic Tools: A Review on Cyclobutyl Drugs

In recent years, cyclobutyl has become ever more influential in the field of drug design. Its unique four-membered ring structure is not only a useful intermediate for the synthesis of biomedical candidate materials, but also an indispensable framework for drug design and application. According to the therapeutic field, cyclobutyl drugs are roughly divided into tumor and cancer drugs, nervous system drugs, analgesics, antiviral drugs, and gastrointestinal drugs. Among them, platinum-based anticancer drugs containing cyclobutyl fragments have achieved remarkable success in the treatment of cancer, bringing new hope for the development of more cyclobutyl drugs. This article provides details of the research progress of the structure types, structure-activity relationships, targets, and mechanisms of cyclobutyl drugs that have been on the market or are in the clinical stage, and provides ideas for the discovery and synthesis of novel cyclobutyl-containing drugs.

Shedding Light on Autophagy During Human Tuberculosis. A Long Way to Go

Immunity against Mycobacterium tuberculosis (Mtb) is highly complex, and the outcome of the infection depends on the role of several immune mediators with particular temporal dynamics on the host microenvironment. Autophagy is a central homeostatic mechanism that plays a role on immunity against intracellular pathogens, including Mtb. Enhanced autophagy in macrophages mediates elimination of intracellular Mtb through lytic and antimicrobial properties only found in autolysosomes. Additionally, it has been demonstrated that standard anti-tuberculosis chemotherapy depends on host autophagy to coordinate successful antimicrobial responses to mycobacteria. Notably, autophagy constitutes an anti-inflammatory mechanism that protects against endomembrane damage triggered by several endogenous components or infectious agents and precludes excessive inflammation. It has also been reported that autophagy can be modulated by cytokines and other immunological signals. Most of the studies on autophagy as a defense mechanism against Mycobacterium have been performed using murine models or human cell lines. However, very limited information exists about the autophagic response in cells from tuberculosis patients. Herein, we review studies that face the autophagy process in tuberculosis patients as a component of the immune response of the human host against an intracellular microorganism such as Mtb. Interestingly, these findings might contribute to recognize new targets for the development of novel therapeutic tools to combat Mtb. Actually, either as a potential successful vaccine or a complementary immunotherapy, efforts are needed to further elucidate the role of autophagy during the immune response of the human host, which will allow to achieve protective and therapeutic benefits in human tuberculosis.

NOG-Derived Peptides Can Restore Neuritogenesis on a CRASH Syndrome Cell Model

Homo- and heterophilic binding mediated by the immunoglobulin (Ig)-like repeats of cell adhesion molecules play a pivotal role in cell-cell and cell-extracellular matrix interactions. L1CAM is crucial to neuronal differentiation, in both mature and developing nervous systems, and several studies suggest that its functional interactions are mainly mediated by Ig2–Ig2 binding. X-linked mutations in the human L1CAM gene are summarized as L1 diseases, including the most diagnosed CRASH neurodevelopmental syndrome. In silico simulations provided a molecular rationale for CRASH phenotypes resulting from mutations I179S and R184Q in the homophilic binding region of Ig2. A synthetic peptide reproducing such region could both mimic the neuritogenic capacity of L1CAM and rescue neuritogenesis in a cellular model of the CRASH syndrome, where the full L1CAM ectodomain proved ineffective. Presented functional evidence opens the route to the use of L1CAM-derived peptides as biotechnological and therapeutic tools.

Natural AMPK Activators in Cardiovascular Disease Prevention

Cardiovascular diseases (CVD), as a life-threatening global disease, is receiving worldwide attention. Seeking novel therapeutic strategies and agents is of utmost importance to curb CVD. AMP-activated protein kinase (AMPK) activators derived from natural products are promising agents for cardiovascular drug development owning to regulatory effects on physiological processes and diverse cardiometabolic disorders. In the past decade, different therapeutic agents from natural products and herbal medicines have been explored as good templates of AMPK activators. Hereby, we overviewed the role of AMPK signaling in the cardiovascular system, as well as evidence implicating AMPK activators as potential therapeutic tools. In the present review, efforts have been made to compile and update relevant information from both preclinical and clinical studies, which investigated the role of natural products as AMPK activators in cardiovascular therapeutics.

Immune Maturation Effects on Viral Neutralization and Avidity of Hyperimmunized Equine Anti-SARS-CoV-2 Sera

Mass-vaccination against COVID-19 is still a distant goal for most low-to-middle income countries. The experience gained through decades producing polyclonal immunotherapeutics (such as antivenoms) in many of those countries is being redirected to develop similar products able to neutralize SARS-CoV-2 infection. In this study we analyzed the biological activity (viral neutralization or NtAb) and immunochemical properties of hyperimmune horses’ sera (HHS) obtained during initial immunization (I) and posterior re-immunization (R) cycles using the RBD domain of the SARS-CoV-2 spike protein as antigen. HHS at the end of the R cycle showed higher NtAb titers when compared to those after the I cycle (35,585 vs. 7000 mean NtAb, respectively). Moreover, this increase paralleled an increase in avidity (95.2% to 65.2% mean avidity units, respectively). The results presented herein are relevant for manufacturers of these therapeutic tools against COVID-19.

Treatment of Sialolithiasis: What Has Changed? An Update of the Treatment Algorithms and a Review of the Literature

Treatment for sialolithiasis has undergone significant changes since the 1990s. Following the development of new minimally invasive and gland-preserving treatment modalities, a 40–50% rate of gland resection was reduced to less than 5%. Extracorporeal shock-wave lithotripsy (ESWL), refinement and extension of methods of transoral duct surgery (TDS), and in particular diagnostic and interventional sialendoscopy (intSE) are substantial parts of the new treatment regimen. It has also become evident that combining the different treatment modalities further increases the effectiveness of therapy, as has been especially evident with the combined endoscopic–transcutaneous approach. In the wake of these remarkable developments, a treatment algorithm was published in 2009 including all the known relevant therapeutic tools. However, new developments have also taken place during the last 10 years. Intraductal shock-wave lithotripsy (ISWL) has led to remarkable improvements thanks to the introduction of new devices, instruments, materials, and techniques, after earlier applications had not been sufficiently effective. Techniques involving combined approaches have been refined and modified. TDS methods have been modified through the introduction of sialendoscopy-assisted TDS in submandibular stones and a retropapillary approach for distal parotid sialolithiasis. Recent trends have revealed a potential for significant changes in therapeutic strategies for both major salivary glands. For the submandibular gland, ISWL has replaced ESWL and TDS to some extent. For parotid stones, ISWL and modifications of TDS have led to reduced use of ESWL and the combined transcutaneous–sialendoscopic approach. To illustrate these changes, we are here providing an updated treatment algorithm, including tried and tested techniques as well as promising new treatment modalities. Prognostic factors (e.g., the size or location of the stones), which are well recognized as having a strong impact on the prognosis, are taken into account and supplemented by additional factors associated with the new applications (e.g., the visibility or accessibility of the stones relative to the anatomy of the duct system).

Active Targeted Nanoformulations via Folate Receptors: State of the Art and Future Perspectives

In normal tissues, the expression of folate receptors is low and limited to cells that are important for embryonic development or for folate reabsorption. However, in several pathological conditions some cells, such as cancer cells and activated macrophages, overexpress folate receptors (FRs). This overexpression makes them a potential therapeutic target in the treatment of cancer and inflammatory diseases to obtain a selective delivery of drugs at altered cells level, and thus to improve the therapeutic efficacy and decrease the systemic toxicity of the pharmacological treatments. Two strategies have been used to achieve this folate receptor targeting: (i) the use of ligands with high affinity to FRs (e.g., folic acid or anti-FRs monoclonal antibodies) linked to the therapeutic agents or (ii) the use of nanocarriers whose surface is decorated with these ligands and in which the drug is encapsulated. This manuscript analyzes the use of FRs as a target to develop new therapeutic tools in the treatment of cancer and inflammatory diseases with an emphasis on the nanoformulations that have been developed for both therapeutic and imaging purposes.

Amyloid Beta Dynamics in Biological Fluids—Therapeutic Impact

Despite the significant impact of Alzheimer’s disease (AD) at individual and socioeconomic levels and the numerous research studies carried out on this topic over the last decades, the treatments available in daily clinical practice remain less than satisfactory. Among the accepted etiopathogenic hypotheses, the amyloidogenic pathway theory, although intensively studied and even sometimes controversial, is still providing relevant theoretical elements for understanding the etiology of AD and for the further development of possible therapeutic tools. In this sense, this review aims to offer new insights related to beta amyloid (Aβ), an essential biomarker in AD. First the structure and function of Aβ in normal and pathological conditions are presented in detail, followed by a discussion on the dynamics of Aβ at the level of different biological compartments. There is focus on Aβ elimination modalities at central nervous system (CNS) level, and clearance via the blood–brain barrier seems to play a crucial/dominant role. Finally, different theoretical and already-applied therapeutic approaches for CNS Aβ elimination are presented, including the recent “peripheral sink therapeutic strategy” and “cerebrospinal fluid sinks therapeutic strategy”. These data outline the need for a multidisciplinary approach designed to deliver a solution to stimulate Aβ clearance in more direct ways, including from the cerebrospinal fluid level.

Advances in the Field of Micro- and Nanotechnologies Applied to Extracellular Vesicle Research: Take-Home Message from ISEV2021

Extracellular Vesicles (EVs) are naturally secreted nanoparticles with a plethora of functions in the human body and remarkable potential as diagnostic and therapeutic tools. Starting from their discovery, EV nanoscale dimensions have hampered and slowed new discoveries in the field, sometimes generating confusion and controversies among experts. Microtechnological and especially nanotechnological advances have sped up biomedical research dealing with EVs, but efforts are needed to further clarify doubts and knowledge gaps. In the present review, we summarize some of the most interesting data presented in the Annual Meeting of the International Society for Extracellular Vesicles (ISEV), ISEV2021, to stimulate discussion and to share knowledge with experts from all fields of research. Indeed, EV research requires a multidisciplinary knowledge exchange and effort. EVs have demonstrated their importance and significant biological role; still, further technological achievements are crucial to avoid artifacts and misleading conclusions in order to enable outstanding discoveries.