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Many forms of damage to cochlear sensory cells involve reactive oxygen species (ROS). We previously screened 81 antioxidants in vitro for the ability to reduce cochlear hair cell (HC) damage by the ototoxic aminoglycoside gentamicin. Only 13 antioxidants produced significant reduction in HC loss, with the quinone antioxidants seratrodast and idebenone being most protective. Why so few antioxidants were protective is unclear, but most antioxidants have other properties that could enhance or detract from protection. In particular, seratrodast is a potent thromboxane A2 (TXA2) antagonist, while idebenone also strongly supports cell metabolism by enhancing mitochondrial function. We therefore asked whether a different TXA2 inhibitor (SQ-29548) or mitochondrial function enhancer (mitochonic acid) exhibited any HC protective ability in the same assay. In both cases, no significant protection from gentamicin was observed, indicating that the ROS scavenging activity of seratrodast and idebenone accounted for HC protection. Additionally, to assess the generality of HC protection by the two antioxidants, we assessed their potential for protection against cisplatin, an ototoxic anti-cancer drug that produces HC damage through a different mechanism than aminoglycosides, but which also involves ROS. High-dose seratrodast tested protected HCs from cisplatin damage, but not to the extent observed for gentamicin. High-dose idebenone was also protective, but even less than for seratrodast. Neither mitochonic acid nor SQ-29548 was protective against cisplatin. The results indicate that seratrodast and idebenone provide HC protection from gentamicin and cisplatin due to their free radical scavenging properties, but protection from cisplatin was less effective, presumably due to its different mechanism of ototoxicity.

Statin therapy lowers not only low-density lipoprotein (LDL) cholesterol levels, but also levels of C-reactive protein (CRP), a marker of inflammation. This study examined the independent effects of decreasing LDL cholesterol and CRP levels on subsequent coronary risk in patients with acute coronary syndromes who were receiving pravastatin or atorvastatin. Lowering CRP levels reduced coronary risk irrespective of the extent of LDL cholesterol lowering. Patients with the lowest risk had the lowest levels of both LDL cholesterol and CRP after 30 days of statin therapy. This study examined the independent effects of decreasing LDL cholesterol and CRP levels on subsequent coronary risk in patients with acute coronary syndromes who were receiving statin therapy. Statin therapy lowers the risk of cardiovascular events by reducing plasma cholesterol levels, and practice guidelines for patients with known cardiovascular disease emphasize the importance of reaching target goals for low-density lipoprotein (LDL) cholesterol. 1 However, we have shown that statin therapy results in a greater clinical benefit when levels of the inflammatory biomarker C-reactive protein (CRP) are elevated 2 , 3 and that statins lower CRP levels in a manner largely independent of LDL cholesterol levels. 3 – 6 These findings, along with basic laboratory evidence, have led to the hypothesis that, in addition to being potent lipid-lowering agents, statins may also have antiinflammatory . . .

The Plasmodium falciparum lactate dehydrogenase enzyme (PfLDH) has been considered as a potential molecular target for antimalarials due to this parasite's dependence on glycolysis for energy production. Because the LDH enzymes found in P. vivax, P. malariae and P. ovale (pLDH) all exhibit ∼90% identity to PfLDH, it would be desirable to have new anti-pLDH drugs, particularly ones that are effective against P. falciparum, the most virulent species of human malaria. Our present work used docking studies to select potential inhibitors of pLDH, which were then tested for antimalarial activity against P. falciparum in vitro and P. berghei malaria in mice. A virtual screening in DrugBank for analogs of NADH (an essential cofactor to pLDH) and computational studies were undertaken, and the potential binding of the selected compounds to the PfLDH active site was analyzed using Molegro Virtual Docker software. Fifty compounds were selected based on their similarity to NADH. The compounds with the best binding energies (itraconazole, atorvastatin and posaconazole) were tested against P. falciparum chloroquine-resistant blood parasites. All three compounds proved to be active in two immunoenzymatic assays performed in parallel using monoclonals specific to PfLDH or a histidine rich protein (HRP2). The IC(50) values for each drug in both tests were similar, were lowest for posaconazole (<5 µM) and were 40- and 100-fold less active than chloroquine. The compounds reduced P. berghei parasitemia in treated mice, in comparison to untreated controls; itraconazole was the least active compound. The results of these activity trials confirmed that molecular docking studies are an important strategy for discovering new antimalarial drugs. This approach is more practical and less expensive than discovering novel compounds that require studies on human toxicology, since these compounds are already commercially available and thus approved for human use.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common life-threatening monogenetic diseases characterized by progressive enlargement of fluid-filled renal cysts. Our previous study has shown that Ganoderma triterpenes (GT) retards PKD renal cyst development. In the present study we identified the effective ingredient of GT in suppression of kidney cyst development. Using an in vitro MDCK cystogenesis model, we identified ganoderic acid A (GA-A) as the most promising candidate among the 12 ganoderic acid (GA) monomers. We further showed that GA-A (6.25−100 μM) significantly inhibited cyst growth in MDCK cyst model and embryonic kidney cyst model in vitro, and the inhibitory effect was reversible. In kidney-specific Pkd1 knockout (kPKD) mice displaying severe cystic kidney disease, administration of GA-A (50 mg· kg −1  ·d −1 , sc) significantly attenuated renal cyst development. In both MDCK cells and kidney of kPKD mice, we revealed that GA-A dose-dependently downregulated the Ras/MAPK signaling pathway. The expression of proliferating cell nuclear antigen (PCNA) was also suppressed, suggesting a possible effect of GA-A on cell proliferation. These experimental data suggest that GA-A may be the main ingredient of GT as a potential therapeutic reagent for treating ADPKD.

Statins are highly effective and widely prescribed cholesterol lowering drugs. However, statins cross the blood-brain barrier and decrease neural cholesterol in animal models, raising concern that long-term statin use may impact cholesterol-dependent structures and functions in the brain. Cholesterol is a fundamental component of cell membranes and experimentally decreasing membrane cholesterol has been shown to alter cell morphology in vitro. In addition, brain regions that undergo adult neurogenesis rely on local brain cholesterol for the manufacture of new neuronal membranes. Thus neurogenesis may be particularly vulnerable to long-term statin use. Here we asked whether oral statin treatment impacts neurogenesis in juveniles, either by decreasing numbers of new cells formed or altering the structure of new neurons. The use of statins in children and adolescents has received less attention than in older adults, with few studies on potential unintended effects in young brains. We examined neurons in the juvenile zebra finch songbird in telencephalic regions that function in song perception and memory (caudomedial nidopallium, NCM) and song production (HVC). Birds received either 40 mg/kg of atorvastatin in water or water vehicle once daily for 2–3 months until they reached adulthood. We labeled newborn cells using systemic injections of bromodeoxyuridine (BrdU) and quantified cells double-labeled with antibodies for BrdU and the neuron-specific protein Hu 30–32 days post mitosis. We also quantified a younger cohort of new neurons in the same birds using antibody to the neuronal protein doublecortin (DCX). We then compared numbers of new neurons and soma morphology of BrdU + /Hu+ neurons between statin-treated and control birds. We did not find an effect of statins on the density of newly formed neurons in either brain region, suggesting that statin treatment did not impact neurogenesis or young neuron survival in our paradigm. However, we found that neuronal soma morphology differed significantly between statin-treated and control birds. Somata of BrdU + /Hu+ (30–32 day old) neurons were flatter and had more furrowed contours in statin-treated birds relative to controls. In a larger, heterogeneous cohort of non-birthdated BrdU-/Hu+ neurons, largely born prior to statin treatment, somata were smaller in statin-treated birds than in controls. Our findings indicate that atorvastatin may affect neural cytoarchitecture in both newly formed and mature neurons, perhaps as a consequence of decreased cholesterol availability in the brain.

Background Species-specific differences in tolerance to infection are exemplified by the high susceptibility of humans to enterohemorrhagic Escherichia coli (EHEC) infection, whereas mice are relatively resistant to this pathogen. This intrinsic species-specific difference in EHEC infection limits the translation of murine research to human. Furthermore, studying the mechanisms underlying this differential susceptibility is a difficult problem due to complex in vivo interactions between the host, pathogen, and disparate commensal microbial communities. Results We utilize organ-on-a-chip (Organ Chip) microfluidic culture technology to model damage of the human colonic epithelium induced by EHEC infection, and show that epithelial injury is greater when exposed to metabolites derived from the human gut microbiome compared to mouse. Using a multi-omics approach, we discovered four human microbiome metabolites—4-methyl benzoic acid, 3,4-dimethylbenzoic acid, hexanoic acid, and heptanoic acid—that are sufficient to mediate this effect. The active human microbiome metabolites preferentially induce expression of flagellin, a bacterial protein associated with motility of EHEC and increased epithelial injury. Thus, the decreased tolerance to infection observed in humans versus other species may be due in part to the presence of compounds produced by the human intestinal microbiome that actively promote bacterial pathogenicity. Conclusion Organ-on-chip technology allowed the identification of specific human microbiome metabolites modulating EHEC pathogenesis. These identified metabolites are sufficient to increase susceptibility to EHEC in our human Colon Chip model and they contribute to species-specific tolerance. This work suggests that higher concentrations of these metabolites could be the reason for higher susceptibility to EHEC infection in certain human populations, such as children. Furthermore, this research lays the foundation for therapeutic-modulation of microbe products in order to prevent and treat human bacterial infection.

Excessive exposure to UV, especially UVB, is the most important risk factor for skin cancer and premature skin aging. The identification of the specialized pro-resolving lipid mediators (SPMs) challenged the preexisting paradigm of how inflammation ends. Rather than a passive process, the resolution of inflammation relies on the active production of SPMs, such as Lipoxins (Lx), Maresins, protectins, and Resolvins. LXA4 is an SPM that exerts its action through ALX/FPR2 receptor. Stable ALX/FPR2 agonists are required because SPMs can be quickly metabolized within tissues near the site of formation. BML-111 is a commercially available synthetic ALX/FPR2 receptor agonist with analgesic, antioxidant, and anti-inflammatory properties. Based on that, we aimed to determine the effect of BML-111 in a model of UVB-induced skin inflammation in hairless mice. We demonstrated that BML-111 ameliorates the signs of UVB-induced skin inflammation by reducing neutrophil recruitment and mast cell activation. Reduction of these cells by BML-111 led to lower number of sunburn cells formation, decrease in epidermal thickness, collagen degradation, cytokine production (TNF-α, IL-1β, IL-6, TGF, and IL-10), and oxidative stress (observed by an increase in total antioxidant capacity and Nrf2 signaling pathway), indicating that BML-111 might be a promising drug to treat skin disorders.

Background. 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) exhibit against antiviral activity against human immunodeficiency virus type 1 (HIV-1) in vitro and may modulate the immune response to HIV infection. Studies evaluating the antiviral activity of statins have yielded conflicting results. Methods. We conducted a randomized, double-blind, placebo-controlled crossover trial to investigate the effect of atorvastatin on HIV-1 RNA (primary objective) and cellular markers of immune activation (secondary objective). HIV-infected individuals not receiving antiretroviral therapy were randomized to receive either 8 weeks of atorvastatin (80 mg) or placebo daily. After a 4-6 week washout phase, participants switched treatment assignments. The study had 80% power to detect a 0.3 log₁₀ decrease in HIV-1 RNA level. Expression of CD38 and HLA-DR on CD4⁺ and CD8⁺ T cells was used to measure immune activation. Results. Of 24 randomized participants, 22 completed the study. Although HIV-1 RNA level was unaffected by the intervention (-0.13 log₁₀ copies/mL; P = .85), atorvastatin use resulted in reductions in circulating proportions of CD4⁺ HLA-DR⁺ (-2.5%; P = .02), CD8⁺ HLA-DR⁺ (-5%; P = .006), and CD8⁺ HLA-DR⁺ CD38⁺ T cells (-3%; P = .03). Reductions in immune activation did not correlate with declines in serum levels of low-density lipoprotein cholesterol. Conclusions. Short-term use of atorvastatin was associated with modest but statistically significant reductions in the proportion of activated T lymphocytes.

Currently, the discovery of effective chemotherapeutic agents poses a major challenge to the field of cancer biology. The present study focuses on enhancing the therapeutic and anti cancer properties of atorvastatin calcium loaded BSA (ATV-BSA) nanoparticles in vitro. BSA-ATV nanoparticles were prepared using desolvation technique. The process parameters were optimized based on the amount of desolvating agent, stabilization conditions as well as the concentration of the cross linker. The anti cancer properties of the protein coated ATV nanoparticles were tested on MiaPaCa-2 cell lines. In vitro release behavior of the drug from the carrier suggests that about 85% of the drug gets released after 72 hrs. Our studies show that ATV-BSA nanoparticles showed specific targeting and enhanced cytotoxicity to MiaPaCa-2 cells when compared to the bare ATV. We hereby propose that the possible mechanism of cellular uptake of albumin bound ATV could be through caveolin mediated endocytosis. Hence our studies open up new facet for an existing cholesterol drug as a potent anti-cancer agent.

Objective Hypercholesterolaemia, a risk factor for atherosclerosis (ATH), has been suggested to have a role in the development of osteoarthritis (OA). To test this hypothesis, the effect of cholesterol and different cholesterol-lowering treatments on OA was investigated in a mouse model resembling human lipoprotein metabolism. Methods Female ApolipoproteinE*3Leiden.human Cholesteryl Ester Transfer Protein mice received a western-type diet with 0.1% (w/w) cholesterol (LC), 0.3% (w/w) cholesterol alone (HC) or treated with 3 mg/kg/day atorvastatin or 0.3 mg/kg/day ezetimibe. One group remained on chow (control). After 39 weeks, OA grades of the knees and the extent of ATH were determined. Plasma cholesterol levels were measured throughout the study. Results LC and HC groups developed significantly more OA at the medial side than the control group in a dose-dependent manner. Atorvastatin but not ezetimibe treatment significantly suppressed OA development. As expected, features of ATH were significantly increased in the LC and HC groups compared with the control group and suppressed by atorvastatin (48%) and ezetimibe (55%) treatment. There were significant correlations between the development of OA on the medial side of the joint and cholesterol exposure (r=0.4) or ATH features (r=0.3). Conclusions Dietary cholesterol and accordingly increased plasma levels play a role in the development of OA. The correlation found between OA, cholesterol and ATH demonstrates that these variables are connected, but indicates the contribution of other ongoing processes in the development of OA. The suppressive effect on OA development of atorvastatin but not of ezetimibe, which had similar cholesterol exposure levels, corroborates these findings.