No abstract

Inflammation plays an important role in the development of rheumatoid arthritis (RA). NR4A1 is an anti-inflammatory orphan nuclear receptor involved in protection from inflammatory stimuli in RA. In this study we have explored the anti-inflammatory potential of the FDAapproved drug 9-aminoacridine (9AA) and the natural compound caffeic acid (CA) conjugated to nanomicelles for the treatment of RA. We have synthesized methoxy polyethylene glycol polycaprolactone block copolymer (mPEG-b-PCL) by ring opening polymerization of ε-caprolactone. Then, we conjugated the hydrophilic caffeic acid (CA) with mPEG-b-PCL micelles via Steglich esterification and incorporated the 9AA drug. These nanomicelles were formulated by the solvent evaporation method with a size distribution around 190 nm and showed maximum drug loading capacity along with sustained drug release behavior. Furthermore, we tested the therapeutic potential of the formulated 9AA-encapsulated CAconjugated nanomicelles (9AA-NMs) against an experimental RA model. We observed promising results which showed alleviation of arthritic symptoms by reducing inflammation, joint damage, bone erosion, and swelling. Further, collagen destruction was significantly reduced in articular cartilage, as shown by safranin-O and toluidine blue staining. The protective mechanism might be due to the simultaneous inhibition of NF-κB by 9AA and CA, whereas the activation of NR4A1 by 9AA leads to the suppression of HIF-1α. This combined therapeutic effect of 9AA and CA has enhanced the therapeutic efficacy of 9AA-NM and markedly reduced the severity of inflammatory arthritis. Unlike existing drugs for pain management and with limited efficacy, 9AA-NM exerted a disease-relevant activation/blockade that alleviated inflammation and exhibited marked therapeutic efficacy against RA.

Ischemia−reperfusion (I/R) injury is a disease process that affects several vital organs. There is widespread agreement that the NLRP3 inflammasome pathway plays a crucial role in the development of I/R injury. We have developed transferrinconjugated, pH-responsive nanomicelles for the entrapment of MCC950 drug. These nanomicelles specifically bind to the transferrin receptor 1 (TFR1) expressed on the cells of the blood−brain barrier (BBB) and thus help the cargo to cross the BBB. Furthermore, the therapeutic potential of nanomicelles was assessed using in vitro, in ovo, and in vivo models of I/R injury. Nanomicelles were injected into the common carotid artery (CCA) of a middle cerebral artery occlusion (MCAO) rat model to achieve maximum accretion of nanomicelles into the brain as blood flows toward the brain in the CCA. The current study reveals that the treatment with nanomicelles significantly alleviates the levels of NLRP3 inflammasome biomarkers which were found to be increased in oxygen−glucose deprivation (OGD)-treated SH-SY5Y cells, the I/Rdamaged right vitelline artery (RVA) of chick embryos, and the MCAO rat model. The supplementation with nanomicelles significantly enhanced the overall survival of MCAO rats. Overall, nanomicelles exerted therapeutic effects against I/R injury, which might be due to the suppression of the activation of the NLRP3 inflammasome.

No abstract

HIV-associated lipodystrophy (HIVLD) is a metabolic condition with an irregularity in the production of lipoprotein particles, and its occurrence varies among HIV-infected patients. MTP and ABCG2 genes have a role in the transport of lipoproteins. The polymorphisms of MTP -493G/T and ABCG2 34G/A affect its expression and influence the secretion and transportation of lipoproteins. Hence, we investigated the MTP -493G/T and ABCG2 34G/A polymorphisms in 187 HIV-infected patients (64 with HIVLD and 123 without HIVLD) along with 139 healthy controls using polymerase chain reaction (PCR)-restriction fragment length polymorphism and expression analysis using real-time PCR. ABCG2 34A allele showed an insignificantly reduced risk of LDHIV severity [P = 0.07, odds ratio (OR) = 0.55]. MTP -493T allele exhibited a non-significantly reduced risk for the development of dyslipidemia (P = 0.08, OR = 0.71). In patients with HIVLD, the ABCG2 34GA genotype was linked with impaired low-density lipoprotein levels and showed a reduced risk for LDHIV severity (P = 0.04, OR = 0.17). In patients without HIVLD, the ABCG2 34GA genotype was associated with impaired triglyceride levels with marginal significance and showed an increased risk for the development of dyslipidemia (P = 0.07, OR = 2.76). The expression level of MTP gene was 1.22-fold decreased in patients without HIVLD compared with that in patients with HIVLD. ABCG2 gene was upregulated 2.16-fold in patients with HIVLD than in patients without HIVLD. In conclusion, MTP -493C/T polymorphism influences the expression level of MTP in patients without HIVLD. Individuals without HIVLD having ABCG2 34GA genotype with impaired triglyceride levels may facilitate dyslipidemia risk.