Herpesviruses and SARS-CoV-2: Viral Association with Oral Inflammatory Diseases.

The oral cavity is a niche for diverse microbes, including viruses. Members of the Herpesviridae family, comprised of dsDNA viruses, as well as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an ssRNA virus, are among the most prevalent viruses infecting the oral cavity, and they exhibit clinical manifestations unique to oral tissues. Viral infection of oral mucosal epithelia triggers an immune response that results in prolonged inflammation. The clinical and systemic disease manifestations of HHV have been researched extensively, and several recent studies have illuminated the relationship between HHV and oral inflammatory diseases. Burgeoning evidence suggests the oral manifestation of SARS-CoV-2 infection includes xerostomia, dysgeusia, periodontal disease, mucositis, and opportunistic viral and bacterial infections, collectively described as oral post-acute sequelae of COVID-19 (PASC). These diverse sequelae could be a result of intensified immune responses initially due to the copious production of proinflammatory cytokines: the so-called "cytokine storm syndrome", facilitating widespread oral and non-oral tissue damage. This review explores the interplay between HHV, SARS-CoV-2, and oral inflammatory diseases such as periodontitis, endodontic disease, and peri-implantitis. Additionally, the review discusses proper diagnostic techniques for identifying viral infection and how viral diagnostics can lead to improved overall patient health.

In-vitro and ex-vivo antidiabetic, and antioxidant activities of Box-Behnken design optimized Solanum xanthocarpum extract loaded niosomes.

One of the most prevalent lifestyle diseases, diabetes mellitus (DM) is brought on by an endocrine issue. DM is frequently accompanied by hyperglycemia, a disease that typically results in an excess of free radicals that stress tissues. The medical community is currently concentrating on creating therapeutic medications with roots in nature to lessen the damage associated with hyperglycemia. Solanum xanthocarpum has a number of medicinal benefits. The investigation aimed to produce and analyze niosomal formulations containing S. xanthocarpum extract (SXE). Niosomes were made by implementing the solvent evaporation process, which was further optimized using Box-Behnken design. Drug release, DPPH assessments, α-amylase inhibition assay, α-glucosidase inhibition assay, and confocal laser scanning microscopy (CLSM) investigation were all performed on the developed formulation (SXE-Ns-Opt). SXE-Ns-Opt displayed a 253.6 nm vesicle size, a PDI of 0.108, 62.4% entrapment efficiency, and 84.01% drug release in 24 h. The rat's intestinal CLSM image indicated that the rhodamine red B-loaded SXE-Ns-Opts had more intestinal penetration than the control. Additionally, the antioxidant effect of the obtained formulation was demonstrated as 89.46% as compared to SXE (78.10%). Additionally, acarbose, SXE, and SXE-Ns-Opt each inhibited the activity of α-amylase by 95.11%, 85.88%, and 89.87%, and also suppressed the enzyme of α-glucosidase by 88.47%, 81.07%, and 85.78%, respectively. To summarise, the establishment of the SXE-Ns-Opt formulation and its characterization demonstrated the legitimacy of the foundation. A promising candidate for the treatment of diabetes mellitus has been shown as in vitro studies, antioxidant against oxidative stress, CLSM of rat's intestine and a high degree of penetration of formulation.

Inhibition of IRAK4 dysregulates SARS-CoV-2 spike protein-induced macrophage inflammatory and glycolytic reprogramming.

Escalated innate immunity plays a critical role in SARS-CoV-2 pathology; however, the molecular mechanism is incompletely understood. Thus, we aim to characterize the molecular mechanism by which SARS-CoV-2 Spike protein advances human macrophage (MÏ´) inflammatory and glycolytic phenotypes and uncover novel therapeutic strategies. We found that human MÏ´s exposed to Spike protein activate IRAK4 phosphorylation. Blockade of IRAK4 in Spike protein-stimulated MÏ´s nullifies signaling of IRAK4, AKT, and baseline p38 without affecting ERK and NF-κB activation. Intriguingly, IRAK4 inhibitor (IRAK4i) rescues the SARS-CoV-2-induced cytotoxic effect in ACE2+HEK 293 cells. Moreover, the inflammatory reprogramming of MÏ´s by Spike protein was blunted by IRAK4i through IRF5 and IRF7, along with the reduction of monokines, IL-6, IL-8, TNFα, and CCL2. Notably, in Spike protein-stimulated MÏ´s, suppression of the inflammatory markers by IRAK4i was coupled with the rebalancing of oxidative phosphorylation over metabolic activity. This metabolic adaptation promoted by IRAK4i in Spike protein-activated MÏ´s was shown to be in part through constraining PFKBF3, HIF1α, cMYC, LDHA, lactate expression, and reversal of citrate and succinate buildup. IRAK4 knockdown could comparably impair Spike protein-enhanced inflammatory and metabolic imprints in human MÏ´s as those treated with ACE2, TLR2, and TLR7 siRNA. Extending these results, in murine models, where human SARS-CoV-2 Spike protein was not recognized by mouse ACE2, TLRs were responsible for the inflammatory and glycolytic responses instigated by Spike protein and were dysregulated by IRAK4i therapy. In conclusion, IRAK4i may be a promising strategy for severe COVID-19 patients by counter-regulating ACE2 and TLR-mediated MÏ´ hyperactivation. IRAK4i therapy counteracts MÏ´ inflammatory and glycolytic reprogramming triggered by Spike protein. This study illustrates that SARS-CoV-2 Spike protein activates IRAK4 signaling via ACE2 as well as TLR2 and TLR7 sensing in human MÏ´s. Remarkably, IRAK4i treatment can dysregulate both ACE-dependent and independent (via TLR sensing) SARS-CoV-2 Spike protein-activated inflammatory and metabolic imprints.

Viruses of the oral cavity: Prevalence, pathobiology and association with oral diseases.

The human oral cavity contains a plethora of habitats and tissue environments, such as teeth, tongue, and gingiva, which are home to a rich microbial flora including bacteria, fungi, and viruses. Given the exposed nature of the mouth, oral tissues constantly encounter infectious agents, forming a complex ecological community. In the past, the discussion of microbiological aspects of oral disease has traditionally focused on bacteria and fungi, but viruses are attracting increasing attention as pathogens in oral inflammatory diseases. Therefore, understanding viral prevalence, pathogenicity, and preference regarding oral tissues is critical to understanding the holistic effects of viruses on oral infections. Recent investigations have demonstrated the abundance of certain viruses in oral inflammatory diseases, suggesting an association between viruses and disease. Human herpesviruses are the most extensively studied viruses in different oral inflammatory diseases. However, challenges in viral detection and the lack of reproducible in vitro and in vivo infection models have limited our progress in understanding viruses and their contribution to oral diseases. This review presents a summary of major mammalian viruses and associated diseases in the human oral cavity. The emergence of a recent pathogen SARS-CoV-2 and its tropism for salivary and periodontal tissues further highlights the relevance of the oral cavity in host-pathogen interaction. Understanding how these different viruses present clinically and influence oral health will advance our understanding of multifactorial oral diseases and their association with viruses.

Metabolic regulation of RA macrophages is distinct from RA fibroblasts and blockade of glycolysis alleviates inflammatory phenotype in both cell types.

Recent studies have shown the significance of metabolic reprogramming in immune and stromal cell function. Yet, the metabolic reconfiguration of RA macrophages (MΦs) is incompletely understood during active disease and in crosstalk with other cell types in experimental arthritis. This study elucidates a distinct regulation of glycolysis and oxidative phosphorylation in RA MΦs compared to fibroblast (FLS), although PPP (Pentose Phosphate pathway) is similarly reconfigured in both cell types. 2-DG treatment showed a more robust impact on impairing the RA M1 MΦ-mediated inflammatory phenotype than IACS-010759 (IACS, complexli), by reversing ERK, AKT and STAT1 signaling, IRF8/3 transcription and CCL2 or CCL5 secretion. This broader inhibitory effect of 2-DG therapy on RA M1 MΦs was linked to dysregulation of glycolysis (GLUT1, PFKFB3, LDHA, lactate) and oxidative PPP (NADP conversion to NADPH), while both compounds were ineffective on oxidative phosphorylation. Distinctly, in RA FLS, 2-DG and IACS therapies constrained LPS/IFNγ-induced AKT and JNK signaling, IRF5/7 and fibrokine expression. Disruption of RA FLS metabolic rewiring by 2-DG or IACS therapy was accompanied by a reduction of glycolysis (HIF1α, PFKFB3) and suppression of citrate or succinate buildup. We found that 2-DG therapy mitigated CIA pathology by intercepting joint F480+iNOS+MΦ, Vimentin+ fibroblast and CD3+T cell trafficking along with downregulation of IRFs and glycolytic intermediates. Surprisingly, IACS treatment was inconsequential on CIA swelling, cell infiltration, M1 and Th1/Th17 cytokines (IFN-γ/IL-17) and joint glycolytic mediators. Collectively, our results indicate that blockade of glycolysis is more effective than inhibition of complex 1 in CIA, in part due to its effectiveness on the MΦ inflammatory phenotype.

Covid-19 and oral diseases: Crosstalk, synergy or association?

The coronavirus disease 2019 (Covid-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that clinically affects multiple organs of the human body. Cells in the oral cavity express viral entry receptor angiotensin-converting enzyme 2 that allows viral replication and may cause tissue inflammation and destruction. Recent studies have reported that Covid-19 patients present oral manifestations with multiple clinical aspects. In this review, we aim to summarise main signs and symptoms of Covid-19 in the oral cavity, its possible association with oral diseases, and the plausible underlying mechanisms of hyperinflammation reflecting crosstalk between Covid-19 and oral diseases. Ulcers, blisters, necrotising gingivitis, opportunistic coinfections, salivary gland alterations, white and erythematous plaques and gustatory dysfunction were the most reported clinical oral manifestations in patients with Covid-19. In general, the lesions appear concomitant with the loss of smell and taste. Multiple reports show evidences of necrotic/ulcerative gingiva, oral blisters and hypergrowth of opportunistic oral pathogens. SARS-CoV-2 exhibits tropism for endothelial cells and Covid-19-mediated endotheliitis can not only promote inflammation in oral tissues but can also facilitate virus spread. In addition, elevated levels of proinflammatory mediators in patients with Covid-19 and oral infectious disease can impair tissue homeostasis and cause delayed disease resolution. This suggests potential crosstalk of immune-mediated pathways underlying pathogenesis. Interestingly, few reports suggest recurrent herpetic lesions and higher bacterial growth in Covid-19 subjects, indicating SARS-CoV-2 and oral virus/bacteria interaction. Larger cohort studies comparing SARS-CoV-2 negative and positive subjects will reveal oral manifestation of the virus on oral health and its role in exacerbating oral infection.

Stigmasterol protects rats from collagen induced arthritis by inhibiting proinflammatory cytokines.

Rheumatoid arthritis (RA) is an autoimmune disorder, in which imbalance in synthesis and production of inflammatory cytokines promotes cartilage and bone destruction. Out of the numerous factors contributing to RA prognosis, the transcription factor NF-kBp65 and p38 mitogen-activated protein kinase (p38MAPK) signaling module has been well implicated as a key regulator of inflammation and downstream signaling events in RA. Stigmasterol (STG) is a natural plant based product exhibiting anti-inflammatory activity, however, the mechanism through which it exhibits anti-inflammatory activity has not been completely understood. The current study aimed to understand the mechanisms underlying the anti-inflammatory effect of STG in the treatment of RA in collagen-induced arthritic (CIA) model of arthritis. Our results showed that STG improved the clinical severity in CIA rats compared to control. The therapeutic effects were related with reduced joint destruction and improved histological alterations. Furthermore, treatment of STG also significantly suppresses the expression of proinflammatory mediators (TNF-α, IL-6, IL-1ß, iNOS and COX-2) and increases the expression of anti-inflammatory cytokine (IL-10) through down-regulating the expression of NF-kBp65 (inhibiting p-IKB-α activation) and p38MAPK in joints. In agreement with our results, we can suggest that high therapeutic efficacy of STG against CIA induced inflammation in rats are attributed through the suppressing proinflammatory cytokines.