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Long-term management of inflammatory skin diseases is challenging because of side effects from repeated use of systemic treatments or topical corticosteroids. This study sought to identify the mechanisms and developmental therapeutics for these diseases using genetic models and pharmacological approaches. We found that mice overexpressing SMAD7 in keratinocytes but not mice overexpressing the N-terminal domain of SMAD7 (i.e., N-SMAD7) were resistant to imiquimod-induced T helper 1/17- and T helper 2-type inflammation. We generated a Tat-PYC-SMAD7 (truncated SMAD7 protein encompassing C-terminal SMAD7 and PY motif fused with cell-penetrating Tat peptide). Topically applied Tat-PYC-SMAD7 to inflamed skin entered cells upon contact and attenuated imiquimod-, 2,4-dinitrofluorobenzene-, and tape-stripping-induced inflammation. RNA-sequencing analyses of mouse skin exposed to these insults showed that in addition to inhibiting TGFβ/NF-κB, SMAD7 blunted IL-22/signal transducer and activator of transcription 3 activation and associated pathogenesis, which is due to SMAD7 transcriptionally upregulating IL-22 antagonist IL-22RA2. Mechanistically, SMAD7 facilitated nuclear translocation and DNA binding of C/EBPβ to IL22RA2 promoter for IL22RA2 transactivation. Consistent with the observations in mice mentioned earlier, transcript levels of IL22RA2 were increased in human atopic dermatitis and psoriasis lesions with clinical remission. Our study identified the anti-inflammation functional domain of SMAD7 and suggests the mechanism and feasibility for developing SMAD7-based biologics as a topical therapy for skin inflammatory disorders.

PURPOSE: Recent studies reported therapeutic effects of Smad7 on oral mucositis in mice without compromising radiation therapy-induced cancer cell killing in neighboring oral cancer. This study aims to assess whether a Smad7-based biologic can treat oral mucositis in a clinically relevant setting by establishing an oral mucositis model in dogs and analyzing molecular targets. METHODS AND MATERIALS: We created a truncated human Smad7 protein fused with the cell-penetrating Tat tag (Tat-PYC-Smad7). We used intensity modulated radiation therapy to induce oral mucositis in dogs and applied Tat-PYC-Smad7 to the oral mucosa in dose-finding studies after intensity modulated radiation therapy. Clinical outcomes were evaluated. Molecular targets were analyzed in biopsies and serum samples. RESULTS: Tat-PYC-Smad7 treatment significantly shortened the duration of grade 3 oral mucositis based on double-blinded Veterinary Radiation Therapy Oncology Group scores and histopathology evaluations. Topically applied Tat-PYC-Smad7 primarily penetrated epithelial cells and was undetectable in serum. NanoString nCounter Canine IO Panel identified that, compared to the vehicle samples, top molecular changes in Tat-PYC-Smad7 treated samples include reductions in inflammation and cell death and increases in cell growth and DNA repair. Consistently, immunostaining shows that Tat-PYC-Smad7 reduced DNA damage and neutrophil infiltration with attenuated TGF-β and NFκB signaling. Furthermore, IL-1β and TNF-α were lower in Tat-PYC-Smad7 treated mucosa and serum samples compared to those in vehicle controls. CONCLUSIONS: Topical Tat-PYC-Smad7 application demonstrated therapeutic effects on oral mucositis induced by intensity modulated radiation therapy in dogs. The local effects of Tat-PYC-Smad7 targeted molecules involved in oral mucositis pathogenesis as well as reduced systemic inflammatory cytokines.

It is important to understand the unique experiences and perspectives of older adults who were required to incorporate critical adaptive behaviors during the onset of the COVID-19 pandemic. An anonymous, cross-sectional survey was administered online through Qualtrics Survey Software in June 2020 to 1405 adults between the ages of 18 and 86. Differences in adaptability between older adults and young/middle-aged adults were analyzed. This study found that older adults (n = 132) utilized different sources of information than young/middle-aged adults; they were more likely to read the newspaper or listen to the radio, and less likely to rely on social media for information. Older respondents in this study reported coping with the COVID-19 outbreak better than young/middle-aged respondents, were less likely to report that they were personally affected by the virus, and were less likely to feel overwhelmed by the amount of information about COVID-19. The findings of this study highlight adaptability and resilience in older adults not found in young/middle-aged adults and provide an important step in identifying policy and practice suggestions to reduce negative repercussions for older adults experiencing the current crisis, as well as future generations of older adults who might experience similar events. [ABSTRACT FROM AUTHOR]

Carboxyl-terminal-binding protein-1 (CtBP1) is a transcriptional corepressor with multiple in vitro targets, but its in vivo functions are largely unknown. We generated keratinocyte-specific CtBP1 transgenic mice with a keratin-5 promoter (K5.CtBP1) to probe the pathological roles of CtBP1. At transgene expression levels comparable to endogenous CtBP1 in acute skin wounds, the K5.CtBP1 epidermis displayed hyperproliferation, loss of E-cadherin, and failed terminal differentiation. Known CtBP1 target genes associated with these processes, e.g., p21, Brca1, and E-cadherin, were downregulated in K5.CtBP1 skin. Surprisingly, K5.CtBP1 pups also exhibited a hair loss phenotype. We found that expression of the Distal-less 3 (Dlx3), a critical regulator of hair follicle differentiation and cycling, was decreased in K5.CtBP1 mice. Molecular studies revealed that CtBP1 directly suppressed Dlx3 transcription. Consistently, K5.CtBP1 mice displayed abnormal hair follicles with decreased expression of Dlx3 downstream targets Gata3, Hoxc13, and hair keratins. In summary, this CtBP1 transgenic model provides in vivo evidence for certain CtBP1 functions predicted from in vitro studies, reveals--to our knowledge--previously unreported functions and transcriptional activities of CtBP1 in the context of epithelial-mesenchymal interplay, and suggests that CtBP1 has a pathogenic role in hair follicle morphogenesis and differentiation.

Objective: To measure comprehensiveness of California campus tobacco policies. Participants: Sixteen campuses representing different regions, institution types, and policies. Research occurred June-August 2013. Methods: Comprehensiveness was scored using American College Health Association's (ACHA) "Position Statement on Tobacco." The Institutional Grammar Tool was used to breakdown policy statements into Strategies, Norms, or Rules. Differences in ACHA score and number of Strategies, Norms, and Rules were assessed by region, policy, and institution type. Results: Median ACHA score was 0.35 (scale of 0-1). Schools with 100% tobacco-free policies had highest ACHA scores, but failed to address relationships between schools and tobacco companies. Less than half the schools assessed (7/16) had Rules (enforceable penalties related to policies). In 67% of the policy statements, individuals doing the action were implied (not specifically stated). Conclusion: Campuses should address ACHA recommendations related to campus relationships with tobacco companies, include enforceable rules, and specify individuals and entities covered by policy.

This study reports results from a national Internet-based survey administered anonymously to a cross-section of social work faculty in the United States. Drawn from a sampling frame of 700 accredited or in candidacy schools, data were collected between November 2010 and March 2011. We investigate the role of sex, sexual orientation, race, religious affiliation and beliefs, religiosity, political ideology, sexism, and interest in sexuality/LGBTQ issues. Race, religiosity, political ideology, and sexism are associated with sexual prejudice, which was endorsed among a small percentage (14%) of the sample (n?=?303). Outcome scores were not statistically different based on the targets' sex. Strategies are recommended to reduce sexual prejudice among social work faculty and to increase institutional support for acceptance in the academy.

Social work students have reported in previous studies that they receive insufficient coursework and training to work effectively with older adults. A critical factor in these deficiencies may be the level of knowledge of social work faculty. This study sought to assess social work faculty's knowledge of aging using the Knowledge of Aging for Social Workers (KASW) quiz. Using systematic random sampling, schools of social work in the United States were selected, and individual faculty members were invited by e-mail to participate in an online survey. Results show that social work faculty's ("N" = 609) knowledge about aging was found to be either less or comparable to other study populations. Knowledge levels were related to having an interest in policy, educational level, teaching aging courses on a regular basis, and confidence level in covering aging content. This study is the first to investigate social work faculty knowledge about aging and older adults. It may offer insight as to faculty competencies, which can have direct implications for student learning and interest in gerontology. (Contains 4 tables.)

Ageist attitudes toward older adults have been recognized as barriers to recruiting and training competent social workers. This article provides a systematic review of the literature that focused on social workers' and social work students' attitudes toward older adults and working with older adults. The authors sought empirical studies that used an attitudinal measure of ageism with a social work sample, and a total of 20 articles met the criteria. Characteristics of the studies' participants, methodology, instruments, and results were evaluated. This article discusses the findings and offers implications for future research. (Contains 1 table.)

The concept and act of “aging” can often carry a negative connotation in many Western societies; however, research suggests collective perceptions may be shifting as people are living longer lives. This cross-sectional study using survey methodology sought to understand how older people (N = 477) perceive their age by analyzing the responses of closed- and open-ended questions through summative content analysis. The mean age of participants was 63 years, and the average age that they felt was approximately 10 years younger. The seven themes for why individuals did not feel old ranged from maintaining an active and engaged lifestyle to “I don’t act or look old,” and the seven themes for why individuals felt old ranged from stopped or changed activities to nearing death. The findings illuminate how subjective age is shaped by perceptions of what it means to be old, and the ways in which these micronarratives are reflective of larger macronarratives surrounding age and aging. [ABSTRACT FROM AUTHOR]

We report that K5.Smad7 mice, which express a Smad7 transgene under the control of a keratin 5 promoter, were resistant to radiation-induced oral mucositis, a painful oral ulceration. In addition to nuclear factor κB (NF- κB) activation, which is known to contribute to oral mucositis, we found activated transforming growth factor β (TGF- β) signaling in cells from this condition. Smad7 dampened both pathways to attenuate inflammation, growth inhibition and apoptosis. Additionally, Smad7 promoted oral epithelial migration to close the wound. Further analyses revealed that TGF-β signaling Smads and their co-repressor C-terminal binding protein 1 (CtBP1) transcriptionally repressed Rac1, and that Smad7 abrogated this repression. Knocking down Rac1 expression in mouse keratinocytes abrogated Smad7-induced migration. Topical application of Smad7 protein conjugated with a cell-permeable Tat tag to oral mucosa showed prophylactic and therapeutic effects on radiation-induced oral mucositis in mice. Thus, we have identified new molecular mechanisms involved in oral mucositis pathogenesis, and our data suggest an alternative therapeutic strategy to block multiple pathological processes in this condition., Oral mucositis, marked by severe oral ulcerations, is a common adverse effect of large-dose radiation used before bone-marrow transplantation or craniofacial radiotherapy for cancer (1), (2). Severe oral mucositis can [...]

The transient receptor potential vanilloid type 1 (TRPV1) channel is a ligand-gated cation channel expressed by sensory nerves. P2Y receptors are G protein-coupled receptors that are also expressed by TRPVl-positive sensory neurons. Therefore, we studied interactions between P2Y receptors and TRPV1 function on kidney projecting sensory neurons. Application of Fast Blue (FB) to nerves surrounding the renal artery retrogradely labeled neurons in dorsal root ganglia of rats. Whole cell recording was performed on FB-labeled neurons maintained in primary culture. Capsaicin was used to activate TRPV1. Four types of kidney projecting neurons were identified based on capsaicin responses: 1) desensitizing (35%), 2) nondesensitizing (29%), 3) silent (3%), and 4) insensitive (30%). Silent neurons responded to capsaicin only after ATP (100 [micro]M) pretreatment. ATP reversed desensitization in desensitizing neurons. Insensitive neurons never responded to capsaicin. UTP, a P2Y purinoceptor 2 ([P2Y.sub.2])/[P2Y.sub.4] receptor agonist, reversed capsaicin-induced TRPV1 desensitization. 2-methyl-thio-ATP (2Me-S-ATP), a [P2Y.sub.1] receptor agonist, did not change desensitization. MRS 2179 and pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), drugs that block [P2Y.sub.1] receptors, did not block ATP-induced resensitization of TRPV1. Suramin, a [P2Y.sub.2] receptor antagonist, blocked resensitization caused by UTP. Immunocytochemical studies showed that FB-labeled neurons coexpressed [P2Y.sub.2] receptors and TRPV1. We conclude that [P2Y.sub.2] receptor activation can maintain TRPV1 function perhaps during sustained episodes of activity of kidney projecting sensory neurons. dorsal root ganglia; capsaicin; desensitization; retrograde labeling doi: 10.1152/ajpregu.00235.2009.

Wang Y, Wang DH. Aggravated renal inflammatory responses in TRPV1 gene knockout mice subjected to DOCA-salt hypertension. Am J Physiol Renal Physiol 297: F 1550-F 1559, 2009. First published September 30, 2009; doi: 10.1152/ajprenal.00012.2009.--To test the hypothesis that deletion of the transient receptor potential vanilloid type 1 (TRPV1) channel exaggerates hypertension-induced renal inflammatory response, wild-type (WT) or TRPVI-null mutant ([TRPV1.sup.-/-]) mice were subjected to uninephrectomy and deoxycorticosterone acetate (DOCA)-salt treatment for 4 wk. Mean arterial pressure (MAP) determined by radiotelemetry increased in DOCA-salt-treated WT or [TRPV1.sup.-/-] mice, whereas there was no difference in MAP between two strains at the baseline or after DOCA-salt treatment. DOCA-salt treatment increased urinary excretion of albumin and 8-isoprostane in both WT and [TRPV1.sup.-/-] mice, and the increases were greater in magnitude in the latter strain. Periodic acid-Schiff and Mason's trichrome staining showed that kidneys of DOCA-salt-treated [TRPV1.sup.-/-] mice exhibited more severe glomerulosclerosis and tubulointerstitial injury compared with DOCA-salt-treated WT mice. NF-[kappa]B assay showed that DOCA-salt treatment increased renal activated NF-[kappa]B concentrations in [TRPV1.sup.-/-] mice compared with WT mice. Immunostaining and ELISA assay revealed that DOCA-salt-treated [TRPV1.sup.-/-] mice had enhanced renal infiltration of monocyte/macrophage and lymphocyte, as well as increased renal levels of proinflammatory cytokine (TNF-[alpha], IL-6) and chemokine (MCP-1) compared with DOCA-salt-treated WT mice. Renal ICAM-1 but not VCAM-1 expression was also greater in DOCA-salt-treated [TRPV1.sup.-/-] than WT mice. Dexamethasone (DEXA), an immunosuppressive drug, conveyed a renoprotective effect that was greater in DOCA-salt-treated TRPV1 / compared with WT mice. These data show that renal inflammation is exacerbated in DOCA-salt hypertension when TRPV1 gene is deleted and that the deterioration is ameliorated by DEXA treatment, indicating that TRPV1 may act as a potential regulator of the inflammatory process to lessen renal injury in DOCA-salt hypertension. transient receptor potential vanilloid type 1 channel; deoxycorticosterone; dexamethasone doi: 10.1152/ajprenal.00012.2009

Zhong B, Wang DH. Protease-activated receptor 2-mediated protection of myocardial ischemia-reperfusion injury: role of transient receptor potential vanilloid receptors. Am J Physiol Regul Integr Comp Physiol 297: R1681-R1690, 2009. First published October 7, 2009; doi: 10.1152/ajpregu.90746.2008.--Activation of the protease-activated receptor 2 (PAR2) or the transient receptor potential vanilloid type 1 (TRPVI) channels expressed in cardiac sensory afferents containing calcitonin gene-related peptide (CGRP) and/or substance P (SP) has been proposed to play a protective role in myocardial ischemia-reperfusion (I/R) injury. However, the interaction between PAR2 and TRPV1 is largely unknown. Using gene-targeted TRPVI-null mutant (TRPV[1.sup.-/-]) or wild-type (WT) mice, we test the hypothesis that TRPV1 contributes to PAR2-mediated cardiac protection via increasing the release of CGRP and SP. Immunofluorescence labeling showed that TRPV1 coexpressed with PAR2, PKC-[epsilon], or PKAc in cardiomyocytes, cardiac blood vessels, and perivascular nerves in WT but not TRPV[1.sup.-/-] hearts. WT or TRPV[1.sup.-/-] hearts were Langendorff perfused with the selective PAR2 agonist, SLIGRL, in the presence or absence of various antagonists, followed by 35 min of global ischemia and 40 min of reperfusion (I/R). The recovery rate of coronary flow, the maximum rate of left ventricular pressure development, left ventricular end-diastolic pressure, and left ventficular developed pressure were evaluated after I/R. SLIGRL improved the recovery of hemodynamic parameters, decreased lactate dehydrogenase release, and reduced the infarct size in both WT and TRPV[1.sup.-/-] hearts (P < 0.05). The protection of SLIGRL was significantly surpassed for WT compared with TRPV[1.sup.-/-] hearts (P < 0.05). [CGRP.sub.8-37], a selective CGRP receptor antagonist, RP67580, a selective neurokinin-1 receptor antagonist, PKC-[epsilon] V1-2, a selective PKC-[epsilon] inhibitor, or H-89, a selective PKA inhibitor, abolished SLIGRL protection by inhibiting the recovery of the rate of coronary flow, maximum rate of left ventricular pressure development, and left ventricular developed pressure, and increasing left ventricular end-diastolic pressure in WT but not TRPV[1.sup.-/-] hearts. Radioimmunoassay showed that SLIGRL increased the release of CGRP and SP in WT but not TRPV[1.sup.-/-] hearts (P < 0.05), which were prevented by PKC-[epsilon] V1-2 and H-89. Thus our data show that PAR2 activation improves cardiac recovery after I/R injury in WT and TRPV[1.sup.-/-] hearts, with a greater effect in the former, suggesting that PAR2-mediated protection is TRPV1 dependent and independent, and that dysfunctional TRPV1 impairs PAR2 action. PAR2 activation of the PKC-[epsilon] or PKA pathway stimulates or sensitizes TRPVI in WT hearts, leading to the release of CGRP and SP that contribute, at least in part, to PAR2-induced cardiac protection against I/R injury. transient receptor potential vanilloid 1; protease-activated receptors; protein kinase C-[epsilon]; ischemia-reperfusion; substance P; calcitonin gene-related peptide; gene knockout doi: 10.1152/ajpregu.90746.2008

N-oleoyldopamine (OLDA), a bioactive lipid originally found in the mammalian brain, is an endo-vanilloid that selectively activates the transient receptor potential vanilloid type 1 (TRPV1) channel. This study tests the hypothesis that OLDA protects the heart against ischemia and reperfusion (I/R) injury via activation of the TRPV1 in wild-type (WT) but not in genetargeted TRPV1-null mutant ([TRPV1.sup.-/-]) mice. Hearts of WT or [TRPV1.sup.-/-] mice were Langendorffly perfused with OLDA (2 X [10.sup.-9] M) in the presence or absence of CGRP8-37 (1 x [10.sup.-6] M), a selective calcitonin gene-related peptide (CGRP) receptor antagonist; RP-67580 (1 X [10.sup.-6] M), a selective neurokinin-1 receptor antagonist; chelerythrine (5 X [10.sup.-6] M), a selective protein kinase C (PKC) antagonist; or tetrabutylammonium (TBA, 5 x [10.sup.-4] M), a nonselective [K.sup.+] channel antagonist, followed by 35 min of global ischemia and 40 min of reperfusion (I/R). Left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), coronary flow (CF), and left ventricular peak positive dP/dt (+dP/dt) were evaluated after I/R. OLDA improved recovery of cardiac function after I/R in WT but not [TRPV1.sup.-/-] hearts by increasing LVDP, CF, and +dP/dt and by decreasing LVEDP. CGRP8-37, RP-67580, chelerythrine, or TBA abolished the protective effect of OLDA in WT hearts. Radioirmnunoassay showed that the release of substance P (SP) and CGRP after OLDA treatment was higher in WT than in [TRPV1.sup.-/-] hearts, which was blocked by chelerythrine or TBA. Thus OLDA exerts a cardiac protective effect during I/R injury in WT hearts via CGRP and SP release, which is abolished by PKC or [K.sup.+] channel antagonists. The protective effect of OLDA is void in [TRPV1.sup.-/-] hearts, supporting the notion that TRPV1 mediates OLDA-induced protection against cardiac I/R injury. N-oleoyldopamine; transient receptor potential vanilloid 1; ischemia-reperfusion; substance P; calcitonin gene-related peptide; protein kinase C antagonist; potassium ion channel antagonist; gene knockout

This study was designed to test the hypothesis that the transient receptor potential vanilloid type 1 (TRPV1) channel, expressed primarily in sensory nerves, and substance P (SP), released by sensory nerves, play a protective role against lipopolysaccharide (LPS)-induced hypotension. LPS (10 mg/kg iv) elicited tachycardia and hypotension in anesthetized male Wistar rats, which peaked at 10 min and gradually recovered 1 h after the injection. Blockade of TRPV1 with its selective antagonist capsazepine (CAPZ, 3 mg/kg iv) impaired recovery given that the fall in mean arterial pressure (MAP) was greater 1 h after CAPZ plus LPS injections compared with LPS injection alone (45 [+ or -] 5 vs. 25 [+ or -] 4 mmHg, P < 0.05). Blockade of the neurokinin 1 (NK1) receptor with its selective antagonists RP-67580 (5 mg/kg iv) or L-733,060 (4 mg/kg iv) prevented recovery, considering that falls in MAP were not different 1 h after injections of NKI antagonists plus LPS from their peak decreases (66 [+ or -] 9 vs. 74 [+ or -] 5 mmHg or 60 [+ or -] 7 vs. 69 [+ or -] 3 mmHg, respectively, P > 0.05). LPS increased plasma SP, norepinephrine (NE), and epinephrine (Epi) levels compared with vehicles, and the increases in plasma SP, NE, and Epi were significantly inhibited by CAPZ or RP-67580. The survival rate at 24 or 48 h after LPS injection (20 mg/kg ip) was lower in conscious rats pre-treated with CAPZ or RP-67580 compared with rats treated with LPS alone (P < 0.05). Thus our results show that the TRPV1, possibly via triggering release of SP which activates the NK1 and stimulates the sympathetic axis, plays a protective role against endotoxin-induced hypotension and mortality, suggesting that TRPV1 receptors are essential in protecting vital organ perfusion and survival during the endotoxic condition. endotoxin; transient receptor potential vanilloid type 1 channel; substance