α7-Nicotinic acetylcholine receptor (α7nAChR) agonists confer protection against a wide variety of cytotoxic insults and suppress oxidative stress and apoptosis in various cell systems, including hepatocytes. We recently demonstrated that nicotine, when combined with a high-fat diet (HFD), triggers oxidative stress, activates hepatocyte apoptosis, and exacerbates HFD-induced hepatic steatosis in male mice. This study evaluates whether PNU-282987 (PNU), a specific α7nAChR agonist, is effective in preventing nicotine plus HFD-induced hepatic steatosis. Adult C57BL6 male mice were fed a normal chow diet or HFD with 60% of calories derived from fat and received twice-daily intraperitoneal injections of 0.75 mg/kg body weight (BW) of nicotine, PNU (0.26 mg/kg BW), PNU plus nicotine, or saline for 10 weeks. PNU treatment was effective in attenuating nicotine plus HFD-induced increase in hepatic triglyceride levels, hepatocyte apoptosis, and hepatic steatosis. The preventive effects of PNU on nicotine plus HFD-induced hepatic steatosis were mediated by suppression of oxidative stress and activation of adenosine 5'-monophosphate-activated protein kinase (AMPK) together with inhibition of its downstream target sterol regulatory element binding protein 1c (SREBP1c), fatty acid synthase (FAS), and acetyl-coenzyme A-carboxylase (ACC). We conclude that the α7nAChR agonist PNU protects against nicotine plus HFD-induced hepatic steatosis in obese mice. PNU appears to work at various steps of signaling pathways involving suppression of oxidative stress, activation of AMPK, and inhibition of SREBP1c, FAS, and ACC. α7nAChR agonists may be an effective therapeutic strategy for ameliorating fatty liver disease, especially in obese smokers.

The human papillomavirus (HPV) is a major public health concern affecting both females and males. HPV is associated with cervical, anal, head and neck cancers. About 99% of all cervical cancers are related to HPV. HPV vaccines, Gardasil, Cervarix, and Gardasil 9 are used in the primary prevention of HPV related cancers. Gardasil and Gardasil 9 are available for use in both females and males ages 9 to 26, while Cervarix is available for females ages 9 to 25. Gardasil 9 was approved by the FDA for prevention against additional HPV types. Despite the availability of this preventative measure against cervical cancer, the rate of HPV vaccination in the United States remains lower than that of other industrialized nations. The purpose of this study is to elucidate mechanisms to help increase the HPV vaccination rate by using education as a tool; by simplifying the president report so that lay person can understand the information presented in the report. Through the quantitative examination of the data from the states with the lowest and highest vaccination rates, using SPSS statistical analysis; we analyzed several factors involved with the low uptake of the vaccines. The results collected show that socioeconomic status, misconceptions about HPV, and misconceptions about the safety of the vaccines were identified as possible obstacles to the effective uptake of HPV vaccinations. The proposals made by the President’s Cancer Panel to accelerate the uptake of vaccines include, increasing coverage of the vaccines through government-sponsored programs, and the Affordable Care Act; increasing accessibility to vaccines through pharmacies, schools, and clinics; and disseminating more information on HPV to healthcare providers, parents, caregivers, and patients. Allowing greater accessibility to the vaccines for all populations regardless of income, education, and eliminating misconceptions of the vaccines would play a significant role in eliminating cancer.

Significant advancements in the development of immunosuppressive agents have resulted in longer lifespans for solid organ transplants recipients (SOTRs) over time. A multidrug approach involving immunosuppressive therapies with different mechanisms of action is commonly used to prevent or treat graft rejection. Early protocols in the 1970s included immunosuppressants prednisone, azathioprine, and cyclophosphamide. The later discovery and incorporation of calcineurin inhibitors (CNIs) such as cyclosporine (CsA) and tacrolimus began a new era in immunopharmacology. Its immunosuppressive power significantly improved graft and patient survival rates in comparison to its predecessors. 1-5 Yet despite the advantages of graft and patient survival, SOTRs face consequences of long-term immunosuppression on a variety of organ systems, including the skin. Ultraviolet (UV)-induced skin cancers comprise a major problem in SOTRS. 6-10 Early clinical studies suggest that immunosuppressive drugs (including corticosteroids, azathioprine, CsA, and tacrolimus) increase the incidence of skin cancer, 11 while more recent studies report that CNIs increase skin cancer risk to a greater extent than other immunosuppressive agents. 12-14 Increased skin cancer incidence associated with immunosuppression therapy was originally attributed to the organ recipient's diminished immune surveillance system. Although this rationale is quite plausible, it has become increasingly clear that immunosuppressant action is far more complex. Each drug may act

Recently, research has directed its interests into identifying molecular pathways implicated in calcineurin inhibitor (CNI)-induced renal fibrosis. An emerging body of studies investigating calcineurin (CnA) activity has identified distinct actions of two main ubiquitously expressed isoforms: CnAα and CnAβ. CNIs have the capacity to inhibit both of these CnA isoforms. In the kidney, CnAα is required for development, whereas CnAβ predominantly modulates the immune response and glomerular hypertrophic signaling powered by activation of the transcription factor, Nuclear Factor of Activated T lymphocytes (NFAT). Interestingly, data has shown that a loss of CnAα activity contributes to the expression of profibrotic proteins in the kidney. Although this finding is of great significance, follow-up studies are needed to identify how loss of the CnAα isoform causes progressive renal damage. Additionally, it is also necessary to identify downstream mediators of CnAα signaling that assist in upregulation of these profibrotic proteins. The goal of this review is to provide insight into strides taken to close the gap in elucidating CnA isoform-specific mechanisms of CNI-induced renal fibrosis. It is with hope that these contributions will lead to the development of newer generation CNIs that effectively blunt the immune response while circumventing extensive renal damage noted with long-term CNI use.

Background: Calcineurin inhibitors (CNIs) are vital immunosuppressive therapies in the management of inflammatory conditions. A long-term consequence is nephrotoxicity. In the kidneys, the primary, catalytic calcineurin (CnA) isoforms are CnAα and CnAβ. While the renal phenotype of CnAα-/- mice substantially mirrors CNI-induced nephrotoxicity, the mechanisms downstream of CnAa are poorly understood. Hypothesis: Since NADPH oxidase-2 (Nox2)-derived oxidative damage is implicated in CNI-induced nephrotoxicity, we hypothesized that CnAα inhibition drives Nox2 upregulation and promotes oxidative stress. Experimental Design: To test the hypothesis, Nox2 regulation was investigated in kidneys from CnAα-/-, CnAβ-/- and WT littermate mice. To identify the downstream mediator of CnAα, NFAT and NFκB regulation was examined. To test if Nox2 is transcriptionally regulated via a NFκB pathway, CnAα-/- and WT renal fibroblasts were treated with the NFκB inhibitor, caffeic acid phenethyl ester. Results: Our findings showed that CsA treatment induced Nox2 upregulation and oxidative stress. Further, Nox2 upregulation and elevated ROS generation occurred only in CnAα-/- mice. In these mice, NFκB but not NFAT activity was increased. In CnAα-/- renal fibroblasts, NFκB inhibition prevented Nox2 upregulation and ROS generation. Conclusions: These findings indicate that 1) CnAα loss stimulates Nox2 upregulation, 2) NFκB is a novel CnAα-regulated transcription factor and 3) NFκB mediates CnAα-induced Nox2 and ROS upregulation. Significance: Our results demonstrate that CnAα plays a key role in Nox2 and ROS generation. Further, these novel findings provide evidence of divergent CnA isoform signaling pathways. Finally, this study advocates for CnAα-sparing CNIs, ultimately circumventing the CNI nephrotoxicity.