The sodium channel NaV1.7 is a master regulator of nociceptive neuronal firing. Mutations in this channel can result in painful conditions as well as produce insensitivity to pain. Despite being recognized as a "poster child" for nociceptive signaling and human pain, targeting NaV1.7 has not yet produced a clinical drug. Recent work has illuminated the NaV1.7 interactome, offering insights into the regulation of these channels and identifying potentially new druggable targets. Amongst the regulators of NaV1.7 is the cytosolic collapsin response mediator protein 2 (CRMP2). CRMP2, modified at Lysine 374 (K374) by addition of a small ubiquitin-like modifier (SUMO), bound NaV1.7 to regulate its membrane localization and function. Corollary to this, preventing CRMP2 SUMOylation was sufficient to reverse mechanical allodynia in rats with neuropathic pain. Notably, loss of CRMP2 SUMOylation did not compromise other innate functions of CRMP2. To further elucidate the in vivo role of CRMP2 SUMOylation in pain, we generated CRMP2 K374A knock-in (CRMP2 K374A/K374A ) mice in which Lys374 was replaced with Ala. CRMP2 K374A/K374A mice had reduced NaV1.7 membrane localization and function in female, but not male, sensory neurons. Behavioral appraisal of CRMP2 K374A/K374A mice demonstrated no changes in depressive or repetitive, compulsive-like behaviors, and a decrease in noxious thermal sensitivity. No changes were observed in CRMP2 K374A/K374A mice to inflammatory, acute, or visceral pain. In contrast, in a neuropathic model, CRMP2 K374A/K374A mice failed to develop persistent mechanical allodynia. Our study suggests that CRMP2 SUMOylation-dependent control of peripheral NaV1.7 is a hallmark of chronic, but not physiological, neuropathic pain.

Defensins are antimicrobial peptides expressed by plants and animals. In mammals there are three subfamilies of defensins, distinguished by structural features: α, β and θ. Alpha and β-defensins are linear peptides with broad anti-microbial activity that are expressed by many mammals including humans. In contrast, θ-defensins are cyclic anti-microbial peptides made by several non-human primates but not humans. All three defensin types have anti-HIV-1 activity, but their mechanisms of action differ. We studied the anti-HIV-1 activity of one defensin from each group, HNP-1 (α), HBD-2 (β) and RTD-1 (θ). We examined how each defensin affected HIV-1 infection and demonstrated that the cyclic defensin RTD-1 inhibited HIV-1 entry, while acyclic HNP-1 and HBD-2 inhibited HIV-1 replication even when added 12 hours post-infection and blocked viral replication after HIV-1 cDNA formation. We further found that all three defensins downmodulated CXCR4. Moreover, RTD-1 inactivated X4 HIV-1, while HNP-1 and HBD-2 inactivated both X4 and R5 HIV-1. The data presented here show that acyclic and cyclic defensins block HIV-1 replication by shared and diverse mechanisms. Moreover, we found that HNP-1 and RTD-1 directly inhibited firefly luciferase enzymatic activity, which may affect the interpretation of previously published data.

The sodium channel NaV1.7 is a master regulator of nociceptive neuronal firing. Mutations in this channel can result in painful conditions as well as produce insensitivity to pain. Despite being recognized as a "poster child" for nociceptive signaling and human pain, targeting NaV1.7 has not yet produced a clinical drug. Recent work has illuminated the NaV1.7 interactome, offering insights into the regulation of these channels and identifying potentially new druggable targets. Amongst the regulators of NaV1.7 is the cytosolic collapsin response mediator protein 2 (CRMP2). CRMP2, modified at Lysine 374 (K374) by addition of a small ubiquitin-like modifier (SUMO), bound NaV1.7 to regulate its membrane localization and function. Corollary to this, preventing CRMP2 SUMOylation was sufficient to reverse mechanical allodynia in rats with neuropathic pain. Notably, loss of CRMP2 SUMOylation did not compromise other innate functions of CRMP2. To further elucidate the in vivo role of CRMP2 SUMOylation in pain, we generated CRMP2 K374A knock-in (CRMP2 K374A/K374A ) mice in which Lys374 was replaced with Ala. CRMP2 K374A/K374A mice had reduced NaV1.7 membrane localization and function in female, but not male, sensory neurons. Behavioral appraisal of CRMP2 K374A/K374A mice demonstrated no changes in depressive or repetitive, compulsive-like behaviors, and a decrease in noxious thermal sensitivity. No changes were observed in CRMP2 K374A/K374A mice to inflammatory, acute, or visceral pain. In contrast, in a neuropathic model, CRMP2 K374A/K374A mice failed to develop persistent mechanical allodynia. Our study suggests that CRMP2 SUMOylation-dependent control of peripheral NaV1.7 is a hallmark of chronic, but not physiological, neuropathic pain. IntroductionThe voltage-gated sodium channel NaV1.7 is a "poster child" target in pain signaling: gain-of-function mutations in the human NaV1.7 gene SCN9A can produce sensory neuron hyperexcitability associated with severe pain as well as insensitivity to pain [16]. While other sodium channels regulate the propagation of action potentials along nerves, NaV1.7 is upstream and defines the threshold at which an action potential will be elicited [44].Alterations of NaV1.7 trafficking are important in the etiology of neuropathic pain. Mapping the NaV1.7 interactome has shed light on novel proteins involved in regulation of trafficking and degradation of NaV1.7 [10; 35]. In neuropathic pain, the expression of proteins regulating trafficking of voltage gated sodium channels (VGSCs) is dysregulated [4; 38]. In particular, upregulation of the VGSC β-subunits [4] and downregulation of Nedd4-2 (an E3 ubiquitin ligase)[38] following a spared nerve injury (SNI) [15], converge to functionally upregulate NaV1.7.We identified the collapsin response mediator protein 2 (CRMP2) as a regulator of NaV1.7 function [17-19; 22; 48]. Our laboratory uncovered the logical coding of CRMP2's cellular actions [11; 51]. The argument path underlying NaV1.7 regulation is defined by "IF CRMP2 is phosphorylated by cycli...

Congestive heart failure is one of the most prevalent and deadly complications of type 2 diabetes that is frequently associated with pulmonary dysfunction. Among many factors that contribute to development and progression of diabetic complications is angiotensin II Ang2). Activation of pathological arm of renin-angiotensin system results in increased levels of Ang2 and signaling through angiotensin type 1 receptor. This pathway is well recognized for its role in induction of oxidative stress (OS), inflammation, hypertrophy and fibrosis. Angiotensin (1-7) [A(1-7)], through activation of Mas receptor, opposes the actions of Ang2 which can result in the amelioration of diabetic complications; enhancing the overall welfare of diabetic patients. In this study, 8 week-old db/db mice were administered A(1-7) daily via subcutaneous injections. After 16 weeks of treatment, echocardiographic assessment of heart function demonstrated significant improvement in cardiac output, stroke volume and shortening fraction in diabetic animals. A(1-7) also prevented cardiomyocyte hypertrophy, apoptosis, lipid accumulation, and decreased diabetes-induced fibrosis and OS in the heart tissue. Treatment with A(1-7) reduced levels of circulating proinflammatory cytokines that contribute to the low grade inflammation observed in diabetes. In addition, lung pathologies associated with type 2 diabetes, including fibrosis and congestion, were decreased with treatment. OS and macrophage infiltration were also reduced in the lungs after treatment with A(1-7). Long-term administration of A(1-7) to db/db mice is effective in improving heart and lung function in db/db mice. Treatment prevented pathological remodeling of the tissues and reduced OS, fibrosis and inflammation.

IMPORTANCE The association between exposure to hormone-modulating therapy (HMT) as breast cancer treatment and neurodegenerative disease (NDD) is unclear. OBJECTIVE To determine whether HMT exposure is associated with the risk of NDD in women with breast cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study used the Humana claims data set from January 1, 2007, to March 31, 2017. The Humana data set contains claims from privatepayer and Medicare insurance data sets from across the United States with a population primarily residing in the Southeast. Patient claims records were surveyed for a diagnosis of NDD starting 1 year after breast cancer diagnosis for the duration of enrollment in the claims database. Participants were 57 843 women aged 45 years or older with a diagnosis of breast cancer. Patients were required to be actively enrolled in Humana claims records for 6 months prior to and at least 3 years after the diagnosis of breast cancer. The analyses were conducted between January 1 and 15, 2020. EXPOSURE Hormone-modulating therapy (selective estrogen receptor modulators, estrogen receptor antagonists, and aromatase inhibitors). MAIN OUTCOMES AND MEASURES Patients receiving HMT for breast cancer treatment were identified. Survival analysis was used to determine the association between HMT exposure and diagnosis of NDD. A propensity score approach was used to minimize measured and unmeasured selection bias.

Introduction The impact of menopausal hormone therapy (HT) on age‐associated Alzheimer's and neurodegenerative diseases (NDDs) remains unresolved. To determine the effect of HT, formulation, type, and duration on risk of NDDs, a retrospective analysis was performed using a 10‐year Humana claims dataset. Methods Study population included women aged 45 years or older with or without claim records of HT medications. Patients diagnosed with NDDs including Alzheimer's disease (AD), Parkinson's disease (PD), dementia, multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) were identified. Relative risk (RR) ratios and 95% confidence intervals (CI) for combined NDDs, or AD, PD, dementia, MS, and ALS were determined. Cumulative hazard ratios were determined to investigate the association between HT and NDDs at different age groups. Results In 379,352 women with or without claim records of HT, use of HT was associated with significantly reduced risk for combined NDDs (RR 0.42, 95% CI 0.40–0.43, P < 0.001). Average follow‐up time was 5.1 [2.3] years. Formulations containing natural steroids 17β‐estradiol and/or progesterone were associated with greater reduction in NDD risk. Oral‐ HT users showed significantly reduced RRs (0.42, 0.41–0.44, P < 0.001) for combined NDDs compared to non‐HT users. The RRs for transdermal‐HT users were significantly decreased for all‐cause dementia (0.73, 0.60–0.88, P = 0.001) and MS (0.55, 0.36–0.84, P = 0.005). Greatest reduction in risk of NDD, AD, and dementia emerged in patients aged 65 years or older. Further, the protective effect of long‐term therapy (>1 year) on combined NDDs, AD, PD, and dementia was greater compared to short‐term therapy (≤1 year). Discussion HT was associated with reduced risk of all NDDs including AD and dementia, with greater duration of therapy and natural steroid formulations associated with greater efficacy. These findings advance precision HT to prevent NDDs including AD.

BackgroundPulmonary diseases are often complicated and have diverse etiologies. One common factor is the lack of therapeutics available for these diseases. The goal of this study was to investigate the impact of Renin-Angiotensin System (RAS)-modifying medications on incidence and time to pulmonary complications.MethodsA retrospective analysis was conducted using claims data from a US commercial insurance company (2007–2013). The study consisted of patients with an emerging hypertension (HTN) diagnosis. Cox analysis was used to look at the effect of angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) in this population. The events included pneumonia and influenza (infectious), Chronic obstructive pulmonary disease (COPD) and allied conditions (inflammatory), and other diseases (structural).ResultsA total of 215,225 patients were followed in the study. These fell into three groups depending on the first prescribed anti-hypertension medication; ACE-Is (47.21%), ARBs (11.40%) and calcium channel blockers (CCBs)/Diuretics-Control (41.39%). The use of ACE-I as first treatment significantly reduced the incidence of infectious (Hazard Ratio (HR) 0.886, 95% Confidence Interval (95% CI) 0.859–0.886), inflammatory (HR 0.924, 95% CI 0.906–0.942) and structural outcomes (HR 0.865, 95% CI 0.847–0.885); it also increased the time (delayed) to diagnosis with prolonged treatment. Primary ARB use only significantly lowered the incidence of structural outcomes (HR 0.900, 95% CI 0.868–0.933); prolonged treatment did reduce incidence of all three diagnosis groups and significantly delayed disease onset.ConclusionsThere is an association between the use of ACE-Is and ARBs and a delay in the progression of pulmonary complications in vulnerable populations. Research into the RAS may identify future therapies for patients with potential chronic pulmonary conditions.

No abstract