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The risk of cardiovascular disease has been reported to have a linear relationship with LDL levels. Additionally, the currently recommended LDL target goal of 70 mg/dl does not diminish the CV risk entirely leaving behind some residual risk. Previous attempts to maximally lower the LDL levels with statin monotherapy have met dejection due to the increased side effects associated with the treatment. Nevertheless, with the new advancements in clinical medicine, it has now become possible to bring down the LDL levels to as low as 15 mg/dl using PCSK9 monoclonal antibodies alone or in combination with statins. The development of inclisiran, siRNA silencer targeting PCSK9 gene, is a one step forward in these endeavors. Moreover, various studies aiming to lower the CV risk and mortality by lowering LDL levels have demonstrated encouraging results. The current challenge is to explore this arena to redefine the target LDL levels, if required, to avoid any suboptimal treatment. After thorough literature search in the PubMed, Embase, Scopus, and Google Scholar, we present this article to provide a brief overview of the safety and efficacy of lowering LDL below the current goal.

Background and PurposeInhibition of diacylglycerol lipase (DGL) prevents LPS-induced pro-inflammatory responses in mouse peritoneal macrophages. Thus, the present study tested whether DGL inhibition reverses allodynic responses of mice in the LPS model of inflammatory pain, as well as in neuropathic pain models. Experimental ApproachInitial experiments examined the cellular expression of DGL and inflammatory mediators within the LPS-injected paw pad. DAGL- (-/-) mice or wild-type mice treated with the DGL inhibitor KT109 were assessed in the LPS model of inflammatory pain. Additional studies examined the locus of action for KT109-induced antinociception, its efficacy in chronic constrictive injury (CCI) of sciatic nerve and chemotherapy-induced neuropathic pain (CINP) models. Key ResultsIntraplantar LPS evoked mechanical allodynia that was associated with increased expression of DGL, which was co-localized with increased TNF- and prostaglandins in paws. DAGL- (-/-) mice or KT109-treated wild-type mice displayed reductions in LPS-induced allodynia. Repeated KT109 administration prevented the expression of LPS-induced allodynia, without evidence of tolerance. Intraplantar injection of KT109 into the LPS-treated paw, but not the contralateral paw, reversed the allodynic responses. However, i.c.v. or i.t. administration of KT109 did not alter LPS-induced allodynia. Finally, KT109 also reversed allodynia in the CCI and CINP models and lacked discernible side effects (e.g. gross motor deficits, anxiogenic behaviour or gastric ulcers). Conclusions and ImplicationsThese findings suggest that local inhibition of DGL at the site of inflammation represents a novel avenue to treat pathological pain, with no apparent untoward side effects. United States Department of Health & Human Services - DA009789 - DA017259 - DA032933 - DA033934-01A1 DA035864 - DA038493-01A1 National Institutes of Health (NIH) - USA NIH-NINDS Center core grant - 5P30NS047463 United States Department of Health & Human Services National Institutes of Health (NIH) - USA - P30NS047463 NIH National Institute of Neurological Disorders & Stroke (NINDS) United States Department of Health & Human Services National Institutes of Health (NIH) - USA - R01DA032933 - K99DA035864 - P01DA017259 - P01DA009789 - F32DA038493 - R00DA035864 - P30DA033934 NIH National Institute on Drug Abuse (NIDA) European Commission

VCU Theses and Dissertations

VCU Theses and Dissertations

NalC is a TetR type regulator that represses the multidrug efflux pump MexAB-OprM in Pseudomonas aeruginosa. Here we explain the mechanism of NalC mediated regulation of MexAB-OprM. We show that NalC non-covalently binds chlorinated phenols and chemicals containing chlorophenol sidechains such as triclosan. NalC-chlorinated phenol binding results in its dissociation from promoter DNA and up-regulation of NalC’s downstream targets, including the MexR antirepressor ArmR. ArmR up-regulation and MexR-ArmR complex formation have previously been shown to upregulate MexAB-OprM. In vivo mexB and armR expression analyses were used to corroborate in vitro NalC chlorinated phenol binding. We also show that the interaction between chlorinated phenols and NalC is reversible, such that removal of these chemicals restored NalC promoter DNA binding. Thus, the NalC-chlorinated phenol interaction is likely a pertinent physiological mechanism that P. aeruginosa uses to control expression of the MexAB-OprM efflux pump.

The authors analyze the determinants of firm productivity in a group of Mexican firms. In particular, they test the contribution of external factors such as trade and knowledge diffusion, the availability of infrastructure, informal knowledge exchange, competitive environment, and business regulatory climate. The authors find that one factor consistently emerges as an important proximate source of productivity-access to informal networks. Interaction in the form of"business lunches"with local buyers and suppliers, competitors, government officials, and other professionals have a significant and positive effect on a firm's productivity. Access to regulators and agents of backward and forward linkages are important in settings where information on business practices and regulations is not publicly disclosed. The results complement predictions of traditional growth theory-in addition to technology and learning being the driving force of firm productivity, proximity to influential individuals who can grant favors or provide information advantage on business and trade practices have significant productivity impacts.

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