Broad-spectrum mono- and combinational drug therapies for global viral pandemic preparedness

Broadly effective antiviral therapies must be developed to be ready for clinical trials, which should begin soon after the emergence of new life-threatening viruses. Here, we pave the way towards this goal by analyzing conserved druggable virus-host interactions, mechanisms of action and immunomodulatory properties of broad-spectrum antivirals (BSAs), routes of BSA delivery, and BSA interactions with other antivirals. Based on the analysis we developed scoring systems, which allowed us to predict novel BSAs and BSA-containing drug combinations (BCCs). Thus, we have developed a new strategy to broaden the spectrum of BSA indications and predict novel mono- and combinational therapies that can help better prepare for imminent future viral outbreaks.

A Review of Antimicrobial Activity of Dental Mesenchymal Stromal Cells: Is There Any Potential?

Antimicrobial defense is an essential component of host-microbial homeostasis and contributes substantially to oral health maintenance. Dental mesenchymal stromal cells (MSCs) possess multilineage differentiation potential, immunomodulatory properties and play an important role in various processes like regeneration and disease progression. Recent studies show that dental MSCs might also be involved in antibacterial defense. This occurs by producing antimicrobial peptides or attracting professional phagocytic immune cells and modulating their activity. The production of antimicrobial peptides and immunomodulatory abilities of dental MSCs are enhanced by an inflammatory environment and influenced by vitamin D3. Antimicrobial peptides also have anti-inflammatory effects in dental MSCs and improve their differentiation potential. Augmentation of antibacterial efficiency of dental MSCs could broaden their clinical application in dentistry.

Tuberculosis, BCG Vaccination and COVID-19: Are They Connected?

Evidence from multiple scientific studies suggests that the Bacillus Calmette–Guérin (BCG) vaccine, widely used worldwide as a preventive measure against tuberculosis, also offers cross-protection against other pathogens. This review aimed to gather data from research that studied the mechanisms involved in the immunological protection induced by the BCG vaccine, which may be important in the control of viral infections, such as COVID-19. Through a literature review, we compiled information about the different BCG strains used worldwide, as well as the responses and protection elicited by them. We commented on the mechanisms of immune response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and we discussed the possibility of cross-protection of different BCG strains on the control of COVID-19. Due to the immunomodulatory properties of BCG, some BCG strains were able to induce an effective cellular immune response and, through epigenetic modifications, activate cells of the innate immune system, such as monocytes, macrophages and natural killer cells, which are crucial for the control of viral infections. Although several vaccines have already been developed and used in an attempt to control the COVID-19 pandemic, some BCG vaccine strains may help stimulate the basal defences against these pathogens and can be used as additional defences in this and future pandemics.

Immunomodulatory Properties of Polysaccharides from the Coral Pseudopterogorgia americana in Macrophages

Polysaccharides from marine organisms produce an important regulatory effect on the mammalian immune system. In this study, the immunomodulatory properties of a polysaccharide that was isolated from the coral Pseudopterogorgia americana (PPA) were investigated. PPA increased the expression levels of tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2), but not inducible nitric oxide synthase and nitric oxide, in macrophages. A mechanistic study revealed that PPA activated macrophages through the toll-like receptor-4 and induced the generation of reactive oxygen species (ROS), increased the phosphorylation levels of protein kinase C (PKC)-α, PKC-δ and mitogen-activated protein kinases (MAPK), and activated NF-κB. The inhibition of ROS and knockdown of PKC-α reduced PPA-mediated TNF-α and IL-6 expression; however, the knockdown of PKC-δ significantly increased PPA-mediated TNF-α expression. In addition, the inhibition of c-Jun N-terminal kinase-1/2 and NF-κB reduced PPA-mediated TNF-α, IL-6 and COX-2 expression. Furthermore, the inhibition of ROS, MAPK and PKC-α/δ reduced PPA-mediated NF-κB activation, indicating that ROS, MAPK and PKC-α/δ function as upstream signals of NF-κB. Finally, PPA treatment decreased the phagocytosis activity of macrophages and reduced cytokine expression in bacteria-infected macrophages. Taken together, our current findings suggest that PPA can potentially play a role in the development of immune modulators in the future.

RESEARCH DEVELOPMENTS IN IMMUNOMODULATORY AND ANTIOXIDANT ACTIVITIES OF SHILAJATU

Ayurveda focuses upon preventing and promoting health along with curing of diseases in a systematic way. Ayurvedic literature has numerous single and compound plant-based, herbo-mineral, herbo-metallic formulations for general well being and in disease-specifi c conditions relating to geriatrics. Rasayana is a specialized branch that deals with the problems related to ageing and methods to counter the same. Shilajatu is one such compound, which has been used in Ayurveda for centuries as Rasayana and as a treatment for all the ailments of body. It is composed of mainly humic acid (60-80 %), and fulvic acid, oxygenated dibenzo- -pyrones and minerals in ionic form (20-40 %). This article is aimed at analyzing and disseminating the classical concepts and available published researches inferring antioxidant and immunomodulatory properties of Shilajatu. The review reveals that Shilajatu exhibits signifi cant antioxidant, immunomodulatory, chelating, cognitive and memory enhancing activities, thus it could prove to be a panacea for mankind.

Role of PD-L1 in licensing immunoregulatory function of dental pulp mesenchymal stem cells

Background Dental pulp stem cells (DPSCs) are low immunogenic and hold immunomodulatory properties that, along with their well-established multi-potency, might enhance their potential application in autoimmune and inflammatory diseases. The present study focused on the ability of DPSCs to modulate the inflammatory microenvironment through PD1/PD-L1 pathway. Methods Inflammatory microenvironment was created in vitro by the activation of T cells isolated from healthy donors and rheumatoid arthritis (RA) patients with anti-CD3 and anti-CD28 antibodies. Direct and indirect co-cultures between DPSCs and PBMCs were carried out to evaluate the activation of immunomodulatory checkpoints in DPSCs and the inflammatory pattern in PBMCs. Results Our data suggest that the inflammatory stimuli trigger DPSCs immunoregulatory functions that can be exerted by both direct and indirect contact. As demonstrated by using a selective PD-L1 inhibitor, DPSCs were able to activate compensatory pathways targeting to orchestrate the inflammatory process by modulating pro-inflammatory cytokines in pre-activated T lymphocytes. The involvement of PD-L1 mechanism was also observed in autologous inflammatory status (pulpitis) and after direct exposure to pre-activated T cells from RA patients suggesting that immunomodulatory/anti-inflammatory properties are strictly related to their stemness status. Conclusions Our findings point out that the communication with the inflammatory microenvironment is essential in licensing their immunomodulatory properties.