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Severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) has first emerged from China in December 2019 and causes coronavirus induced disease 19 (COVID19). Since then researchers worldwide have been struggling to detect the possible pathogenesis of this disease. COVID19 showed a wide range of clinical behavior from asymptomatic to severe acute respiratory disease syndrome. However, the etiology of susceptibility to severe lung injury is not yet fully understood. Angiotensin-converting enzyme1 (ACE1) convert angiotensin I into Angiotensin II that was further metabolized by ACE 2 (ACE2). The binding ACE2 receptor to SARS-CoV-2 facilitate its enter into the host cell. The interaction and imbalance between ACE1 and ACE2 play a crucial role in the pathogenesis of lung injury. Thus, the aim of this study was to investigate the association of ACE1 I/D polymorphism with severity of Covid-19. The study included RT-PCR confirmed 269 cases of Covid-19. All cases were genotyped for ACE1 I/D polymorphism using polymerase chain reaction and followed by statistical analysis (SPSS, version 15.0). We found that ACE1 DD genotype, frequency of D allele, older age (≥46 years), unmarried status, and presence of diabetes and hypertension were significantly higher in severe COVID19 patient. ACE1 ID genotype was significantly independently associated with high socio-economic COVID19 patients (OR: 2.48, 95% CI: 1.331–4.609). These data suggest that the ACE1 genotype may impact the incidence and clinical outcome of COVID-19 and serve as a predictive marker for COVID-19 risk and severity.

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UVB-induced DNA damage plays a critical role in development of photoimmunosuppression. The purpose of this study was to determine whether repair of UVB-induced DNA damage is regulated by Toll-like receptor-4 (TLR4). When TLR4 gene knockout (TLR4-/-) and TLR4 competent (TLR4+/+) mice were subjected to 90 mJ/cm2 UVB radiation locally, DNA damage in the form of CPD, were repaired more efficiently in the skin and bone marrow dendritic cells (BMDC) of TLR4-/- mice in comparison to TLR4+/+ mice. Expression of DNA repair gene XPA (Xeroderma pigmentosum complementation group A) was significantly lower in skin and BMDC of TLR4+/+ mice than TLR4-/- mice after UVB exposure. When cytokine levels were compared in these strains after UVB exposure, BMDC from UV-irradiated TLR4-/- mice produced significantly more interleukin (IL)-12 and IL-23 cytokines (p<0.05) than BMDC from TLR4+/+ mice. Addition of anti-IL-12 and anti-IL-23 antibodies to BMDC of TLR4-/- mice (before UVB exposure) inhibited repair of CPD, with a concomitant decrease in XPA expression. Addition of TLR4 agonist to TLR4+/+ BMDC cultures decreased XPA expression and inhibited CPD repair. Thus, strategies to inhibit TLR4 may allow for immunopreventive and immunotherapeutic approaches for managing UVB-induced cutaneous DNA damage and skin cancer.

Malaysian tualang honey possesses strong antioxidant and anti-inflammatory properties. Here, we evaluated the effect of tualang honey on early biomarkers of photocarcinogenesis employing PAM212 mouse keratinocyte cell line. Keratinocytes were treated with tualang honey (1.0%, v/v) before a single UVB (150 mJ/cm2) irradiation. We found that treatment of tualang honey inhibited UVB-induced DNA damage, and enhanced repair of UVB-mediated formation of cyclobutane pyrimidine dimers (CPDs) and 8-oxo-7, 8-dihydro-2′-deoxyguanosine (8-oxodG). Treatment of tualang honey inhibited UVB-induced nuclear translocation of NF-κB, and degradation of IκBα in murine keratinocyte cell line. Treatment of tualang honey also inhibited UVB-induced inflammatory cytokines and inducible nitric oxide synthase protein expression. Furthermore, treatment of tualang honey inhibited UVB-induced COX-2 expression and PGE2 production. Taken together, we provide evidence that treatment of tualang honey to keratinocytes affords substantial protection from the adverse effects of UVB radiation via modulation in early biomarkers of photocarcinogenesis and provide suggestion for its photochemopreventive potential.

Acid (HCl) aspiration during anesthesia may lead to acute lung injury. There is no effective therapy. We hypothesized that HCl instilled intratracheally in C57BL/6 mice results in the formation of low-molecular weight hyaluronan (L-HA), which activates RhoA and Rho kinase (ROCK), causing airway hyperresponsiveness (AHR) and increased permeability. Furthermore, instillation of high-molecular weight hyaluronan (H-HA; Yabro) will reverse lung injury. We instilled HCl in C57BL/6 wild-type (WT), myeloperoxidase gene-deficient (MPO) mice, and CD44 gene-deficient (CD44) mice. WT mice were also instilled intranasally with H-HA (Yabro) at 1 and 23 h post-HCl. All measurements were performed at 1, 5, or 24 h post-HCl. Instillation of HCl in WT but not in CD44 resulted in increased inflammation, AHR, lung injury, and L-HA in the bronchoalveolar lavage fluid (BALF) 24 h post-HCl; L-HA levels and lung injury were significantly lower in HCl-instilled MPO mice. Isolated perfused lungs of HCl instilled WT but not of CD44 mice had elevated values of the filtration coefficient ( K). Addition of L-HA on the apical surface of human primary bronchial epithelial cell monolayer decreased barrier resistance ( R). H-HA significantly mitigated inflammation, AHR, and pulmonary vascular leakage at 24 h after HCl instillation and mitigated the increase of K and R as well as ROCK2 phosphorylation. Increased H- and L-HA levels were found in the BALF of mechanically ventilated patients but not in healthy volunteers. HCl instillation-induced lung injury is mediated by the L-HA-CD44-RhoA-ROCK2 signaling pathway, and H-HA is a potential novel therapeutic agent for acid aspiration-induced lung injury.

UVB radiation contributes to both direct and indirect damage to the skin including the generation of free radicals and reactive oxygen species (ROS), inflammatory responses, immunosuppression, and gene mutations, which can ultimately lead to photocarcinogenesis. A plant-derived flavonoid, baicalin, has been shown to have antioxidant, anti-inflammatory, and free radical scavenging activities. Previous studies from our laboratory have shown that in murine skin, Toll like receptor-4 (TLR4) enhanced both UVB-induced DNA damage and inflammation. The aim of the current study is to investigate the efficacy of baicalin against TLR4-mediated processes in the murine keratinocyte PAM 212 cell line. Our results demonstrate that treating keratinocytes with baicalin both before and after UV radiation (100 mJ/cm2) significantly inhibited the level of intracellular ROS and decreased cyclobutane pyrimidine dimers (CPDs) and 8-Oxo-2′-deoxyguanosine (8-oxo-dG)—markers of DNA damage. Furthermore, cells treated with baicalin demonstrated an inhibition of TLR4 and its downstream signaling molecules, MyD88, TRIF, TRAF6, and IRAK4. TLR4 pathway inhibition resulted in NF-κB inactivation and down-regulation of iNOS and COX-2 protein expression. Taken together, baicalin treatment effectively protected keratinocytes from UVB-induced inflammatory damage through TLR pathway modulation.