The synergistic effect of nanocurcumin and donepezil on Alzheimer's via PI3K/AKT/GSK-3ß pathway modulating.

Alzheimer's disease (AD) hallmarks include amyloid-ßeta (Aß) and tau proteins aggregates, neurite degeneration, microglial activation with cognitive impairment. Phosphatidylinositol-3-kinase/protein kinase B/Glycogen synthase kinase-3-beta (PI3K/AKT/GSK-3) pathway is essential for neuroprotection, cell survival and proliferation by blocking apoptosis. This study aimed to assess protective role of nanocurcumin (NCMN) as strong antioxidant and anti-inflammatory agent with elucidating its synergistic effects with Donepezil as acetylcholinesterase inhibitor on AD in rats via modulating PI3K/AKT/GSK-3ß pathway. The experiment was performed on 70 male Wistar albino rats divided into seven groups (control, NCMN, Donepezil, AD-model, Donepezil co-treatment, NCMN only co-treatment, and NCMN+Donepezil combined treatment). Behavioral and biochemical investigations as cholinesterase activity, oxidative stress (malondialdehyde, reduced glutathione, nitric oxide, superoxidedismutase, and catalase), tumor necrosis factor-alpha, Tau, ß-site amyloid precursor protein cleaving enzyme-1 (BACE-1), Phosphatase and tensin homolog (Pten), mitogen-activated protein kinase-1 (MAPK-1), Glycogen synthase kinase-3-beta (GSK-3ß) and toll-like receptor-4 were evaluated. Treatment with NCMN improved memory, locomotion, neuronal differentiation by activating PI3K/AKT/GSK-3ß pathway. These results were confirmed by histological studies in hippocampus.

Childhood and Adolescent Relapsed/Refractory Aggressive B-Cell Lymphomas With t(8;14) and BCL2 Expression, Burkitt Lymphoma Versus Diffuse Large B-Cell Lymphoma: A Diagnostic Challenge.

We present 2 diagnostically challenging cases of pediatric/adolescent relapsed/refractory aggressive mature B-cell non-Hodgkin lymphoma (B-NHL) within the spectrum of Burkitt lymphoma and diffuse large B-cell lymphoma and illustrate the different therapeutic regimens that are employed for pediatric and adult cancer centers. Both cases displayed varying-sized lymphoma cells with occasional single prominent nucleoli and heterogeneous BCL2 expression. Cytogenetics revealed complex karyotypes with t(8:14)(q24.2;q32) and IGH::MYC rearrangement by FISH. Next generation sequencing revealed deleterious TP53 and MYC mutations. We concluded that both could be diagnosed as "DLBCL-NOS with MYC rearrangement" using the current pathologic classifications, 2022 International Consensus Classification (ICC) and World Health Organization Classifications of Haematolymphoid Tumors (WHO-HAEM5). This report illustrates diagnostic challenges and treatment dilemmas that may be encountered, particularly for adolescent and young adults (AYA).

Mechanistic role of quercetin as inhibitor for adenosine deaminase enzyme in rheumatoid arthritis: systematic review.

Rheumatoid arthritis (RA) is an autoimmune disease involving T and B lymphocytes. Autoantibodies contribute to joint deterioration and worsening symptoms. Adenosine deaminase (ADA), an enzyme in purine metabolism, influences adenosine levels and joint inflammation. Inhibiting ADA could impact RA progression. Intracellular ATP breakdown generates adenosine, which increases in hypoxic and inflammatory conditions. Lymphocytes with ADA play a role in RA. Inhibiting lymphocytic ADA activity has an immune-regulatory effect. Synovial fluid levels of ADA are closely associated with the disease's systemic activity, making it a useful parameter for evaluating joint inflammation. Flavonoids, such as quercetin (QUE), are natural substances that can inhibit ADA activity. QUE demonstrates immune-regulatory effects and restores T-cell homeostasis, making it a promising candidate for RA therapy. In this review, we will explore the impact of QUE in suppressing ADA and reducing produced the inflammation in RA, including preclinical investigations and clinical trials.

Studying the viability and growth kinetics of vancomycin-resistant Enterococcus faecalis V583 following femtosecond laser irradiation (420-465 nm).

Enterococcus faecalis is among the most resistant bacteria found in infected root canals. The demand for cutting-edge disinfection methods has rekindled research on photoinactivation with visible light. This study investigated the bactericidal activity of femtosecond laser irradiation against vancomycin-resistant Enterococcus faecalis V583 (VRE). The effect of parameters such as wavelength and energy density on the viability and growth kinetics of VRE was studied to design an optimized laser-based antimicrobial photoinactivation approach without any prior addition of exogenous photosensitizers. The most effective wavelengths were 430 nm and 435 nm at a fluence of 1000 J/cm2, causing a nearly 2-log reduction (98.6% and 98.3% inhibition, respectively) in viable bacterial counts. The colony-forming units and growth rate of the laser-treated cultures were progressively decreased as energy density or light dose increased at 445 nm but reached a limit at 1250 J/cm2. At a higher fluence of 2000 J/cm2, the efficacy was reduced due to a photobleaching phenomenon. Our results highlight the importance of optimizing laser exposure parameters, such as wavelength and fluence, in bacterial photoinactivation experiments. To our knowledge, this is the first study to report an optimized wavelength for the inactivation of VRE using visible femtosecond laser light.

Feedback control in hemodialysis.

A number of systems of feedback control during dialysis have been developed, which have the shared characteristic of prospectively measuring physiological parameters and then automatically altering dialysis parameters in real time according to a pre-specified dialysis prescription. These include feedback systems aimed at reducing intradialytic hypotension based on relative blood volume monitoring linked to adjustments in ultrafiltration and dialysate conductivity, and blood temperature monitoring linked to alterations in dialysate temperature. Feedback systems also exist that manipulate sodium balance during dialysis by assessing and adjusting dialysate conductivity. In this review article, we discuss the rationale for automated feedback systems during dialysis, describe how the different feedback systems work, and provide a review of the current evidence on their clinical effectiveness.

The effect of accelerated pulsed high-fluence corneal cross-linking on corneal endothelium; a prospective specular microscopy study.

BACKGROUND: Corneal collagen cross-linking (CXL) is a procedure utilized for halting keratoconus progression with different approved protocols. The current study aimed to assess the corneal endothelial changes following the relatively new accelerated pulsed high-fluence protocol of epithelium-off corneal cross-linking for the treatment of mild to moderate keratoconus. METHODS: This prospective case series study enrolled 45 eyes of 27 patients with mild to moderate progressive keratoconus who underwent accelerated pulsed high-fluence CXL (pl-ACXL, 30 mW/ cm2 UVA at 365 nm wavelength, 8 min pulsed mode 1 s on / 1 s off with a total energy of 7.2 J/ cm2). The main outcome measures were corneal endothelial changes assessed by specular microscopy at 3 and 6 months postoperatively including endothelial cell density (ECD), coefficient of variation, percentage of hexagonal cells, average, minimum and maximum endothelial cell sizes. Demarcation line depth was assessed 1 month following surgery. RESULTS: The mean age of the studied sample was 24.89 ± 7.21. The mean preoperative ECD (2944.6 ± 247.41 cell/mm2) showed non-significant reduction at 3 and 6 months postoperatively (2931.03 ± 253.82 and 2924.7 ± 224.88 cell/mm2, respectively, P-value = 0.361). There were no significant changes in the mean coefficient of variation, percentage of hexagonal cells, average, minimum and maximum endothelial cell sizes at 3 and 6 months following pl-ACXL (P-value > 0.05). The mean demarcation line depth 1 month after pl-ACXL was 214 ± 17.43 µm. CONCLUSIONS: Corneal endothelial changes following accelerated pulsed high-fluence CXL were minimal with stability of endothelial cell count and non-significant morphological changes. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04160338 (13/11/2019).

Using Femtosecond Laser Light-Activated Materials: The Biomimetic Dentin Remineralization Was Monitored by Laser-Induced Breakdown Spectroscopy.

Introduction: The purpose of this study is to investigate and compare the effects of the antimicrobial agents Moringa oleifera and bioactive glass nanoparticles activated by femtosecond laser light on the biomimetic dentin remineralization using teeth having carious dentin ICDAS code 3. Methods and Materials: A total of 27 dentin surface samples were divided into three groups: the first group was treated with a Moringa oleifera extract, while the second group was treated with bioactive glass nanoparticles, and as for the control group, the third group received no additional agent. All groups were subjected to femtosecond laser light at three different wavelengths: 390 nm, 445 nm, and 780 nm. The photoactivation of each sample was achieved using the femtosecond laser light for 5 min with an average power rating of 300 mW, a pulse duration of 100 fs, and a pulse repetition rate of 80 Hz. The mineral content of the samples was obtained and analyzed using the laser-induced breakdown spectroscopy (LIBS). The LIBS analysis was conducted with the following laser light parameters: average power of ~215 mW, wavelength of 532 nm, pulse duration of 10 ns, and a pulse repetition rate of 10 Hz. Results: Most studied samples exhibited a relative increase in the mineral content that may enhance biomimetic remineralization. Moringa oleifera photoactivated by femtosecond laser light at 445 nm achieved a significant increase in mineral content. Conclusion: Using the femtosecond laser light to activate the relatively cheap and commercially available antimicrobial agent Moringa oleifera supports the strategy of minimal invasive approaches for the treatment and biomimetic remineralization of carious dentin ICDAS code 3.

Quercetin mitigates rheumatoid arthritis by inhibiting adenosine deaminase in rats.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by synovial proliferation and bone destruction. Adenosine deaminase (ADA) is a key inflammatory enzyme that increases joint stiffness and pain in RA. In this study, we evaluated the in-silico, and in vivo inhibitory effect of quercetin isolated from Egyptian Fenugreek on ADA enzyme activity. We also determined the combinatorial effect of quercetin on methotrexate mediated anti-inflammatory efficacy and toxicity. In-silico molecular docking was conducted and confirmed in an in vivo RA rat model. The results showed that the inhibition constant of quercetin on joint ADA by docking and in-vitro was 61.9 and 55.5 mM, respectively. Therefore, quercetin exhibits anti-inflammatory effect in a rat RA model as evidenced by reducing the specific activity of ADA in joint tissues, lower jaw volume, enhance body weight, downregulate ADA gene expression, reduce levels of RA cytokines interleukin-1ß, interleukin-6, tumor necrosis factor-α, also, rheumatoid factor, C-reactive protein, and anti-cyclic citrullinated peptide RA biomarker levels. These findings demonstrate that the purified quercetin has a promising anti-inflammatory effect against RA disease through its inhibitory effects on the ADA enzyme. Furthermore, isolated quercetin improved the anti-inflammatory efficacy of methotrexate, reduced its toxic effects by increasing antioxidant enzymes and reducing oxidative stress.

Frailty, multimorbidity and sarcopaenia in haemodialysis patients.

PURPOSE OF REVIEW: It is well recognised that haemodialysis patients have higher levels of multimorbidity, frailty and sarcopaenia. This review examines the current understanding of the three concepts in relation to the general population and haemodialysis patients, and the methods used to quantify them. It also looks at the interaction between multimorbidity, frailty and sarcopaenia in this patient group and proposes a new model that utilises muscle mass index and fat mass index as a surrogate representation of the three concepts. RECENT FINDINGS: Multimorbidity in on the rise in the general population and this is one of the contributing factors to higher rates of chronic kidney disease, progression to end-stage renal disease and multimorbidity in haemodialysis patients. Malnutrition and haemodialysis induced end organ damage further contributes to muscle loss and frailty in this patient group. There is a significant overlap and interaction between multimorbidity, frailty and sarcopaenia in haemodialysis and their presence carries a significant impact on quality of life and survival. There are multiple scores for measuring multimorbidity, frailty and sarcopenia and there is no consensus on their utilisation in haemodialysis patients. We propose the use of fat mass index and muscle mass index model as a surrogate method for clinically quantifying multimorbidity, frailty and sarcopaenia. SUMMARY: Effective public health policies are likely to have an impact on reducing the prevalence of multimorbidity and the development of end stage renal disease. Future research is required to develop interventions that are targeted at maintaining muscle mass and function in haemodialysis patients.

Viral hepatitis in pregnancy.

Viral hepatitis is caused by a heterogenous group of viral agents representing a wide range of phylogenetic groups. Many viruses can involve the liver and cause liver injury but only a subset are delineated as 'hepatitis viruses' based upon their primary site of replication and tropism for hepatocytes which make up the bulk of the liver cell population. Since their discovery, beginning with the agent that caused serum hepatitis in the 1960s, the alphabetic designations have been utilized. To date, we have five hepatitis viruses, A through E, though it is postulated that others may exist. This chapter will focus on those viruses. Note that hepatitis D is included as a subset of hepatitis B, as it cannot exist without concurrent hepatitis B infection. Pregnancy has the potential to affect all aspects of these viral agents due to the unique immunologic and physiologic changes that occur during and after the gestational period. In this review, we will discuss the most common viral hepatitis and their effects during pregnancy.

The synthetic opioid fentanyl increases HIV replication and chemokine co-receptor expression in vitro.

The US is experiencing a major public health crisis that is fueled by the illicit use of synthetic opioids including fentanyl. While several drugs of abuse can enhance viral replication and/or antagonize immune responses, the impact of specific synthetic opioids on HIV pathogenesis is poorly understood. Thus, we evaluated the effects of fentanyl on HIV replication in vitro. HIV-susceptible or HIV-expressing cell lines were incubated with fentanyl. HIV p24 synthesis and chemokine receptor levels were quantified by ELISA in culture supernatants and cell lysates, respectively. Addition of fentanyl resulted in a dose-dependent increase in HIV replication. Fentanyl enhanced expression of the HIV chemokine co-receptors CXCR4 and CCR5 and caused a dose-dependent decrease in cell viability. The opioid antagonist naltrexone blocked the effect of fentanyl on HIV replication and CCR5 receptor levels but not CXCR4 receptor levels. TLR9 expression was induced by HIV; however, fentanyl inhibited TLR9 expression in a dose-dependent manner. These data demonstrate that the synthetic opioid fentanyl can promote HIV replication in vitro. As increased HIV levels are associated with accelerated disease progression and higher likelihood of transmission, additional research is required to enhance the understanding of opioid-virus interactions and to develop new and/or optimized treatment strategies for persons with HIV and opioid use disorder.

Anticancer Effects of Combination of Indole-3-Carbinol and Hydroxychloroquine on Ehrlich Ascites Carcinoma via Targeting Autophagy and Apoptosis.

Indole-3-carbinol (I3C) is an active component of cruciferous vegetables which is considered a promising antineoplastic agent. This study aimed to assess I3C antineoplastic activity alone and with hydroxychloroquine (HCQ) on Ehrlich ascites carcinoma (EAC) model. Eighty female mice were divided into six groups wherein all groups except groups I and II received EAC cells (106 cells/mouse i.p.). Group I, served as control; group II served as I3C; group III served as EAC; groups IV and V received I3C (250 mg/kg body weight oral), and HCQ (60 mg/kg body weight i.p.) respectively; GVI received both I3C and HCQ. Antitumor response markers, serum, hepatic and renal biochemical parameters, histopathological changes, as well as autophagy and apoptosis markers in EAC cells were analyzed. The combination of I3C and HCQ showed the best antitumor responses with increased survival time and ameliorated biochemical parameters. Moreover, I3C upregulated LC3B and downregulated p62 gene expression in EAC cells. Furthermore, I3C combined with HCQ induced apoptosis by highly upregulating cleaved caspase-3 and Bax while downregulating Bcl-2 proteins expression in EAC cells in comparison with each drug alone. In conclusion, I3C combined with HCQ exhibited better antitumor activities than each drug alone via targeting autophagy and apoptosis.

Establishing 3D Printing at the Point of Care: Basic Principles and Tools for Success.

As the medical applications of three-dimensional (3D) printing increase, so does the number of health care organizations in which adoption or expansion of 3D printing facilities is under consideration. With recent advancements in 3D printing technology, medical practitioners have embraced this powerful tool to help them to deliver high-quality patient care, with a focus on sustainability. The use of 3D printing in the hospital or clinic at the point of care (POC) has profound potential, but its adoption is not without unanticipated challenges and considerations. The authors provide the basic principles and considerations for building the infrastructure to support 3D printing inside the hospital. This process includes building a business case; determining the requirements for facilities, space, and staff; designing a digital workflow; and considering how electronic health records may have a role in the future. The authors also discuss the supported applications and benefits of medical 3D printing and briefly highlight quality and regulatory considerations. The information presented is meant to be a practical guide to assist radiology departments in exploring the possibilities of POC 3D printing and expanding it from a niche application to a fixture of clinical care. An invited commentary by Ballard is available online. ©RSNA, 2022.

Enhanced and tunable femtosecond nonlinear optical properties of pure and nickel-doped zinc oxide films.

The nonlinear optical properties of pure ZnO and Ni-doped ZnO thin films are explored using the Z-scan technique at different input laser intensities and an excitation wavelength of 750 nm by 100 fs laser pulses. The pure ZnO and Ni-doped ZnO thin films were prepared by radio frequency magnetron sputtering at room temperature. A scanning electron microscope equipped with energy-dispersive x-ray spectroscopy was used to measure the thickness and composition of the thin films, while a UV-visible spectrophotometer was used to measure the linear optical properties. The structure of the thin films was measured using x-ray diffraction. Saturable absorption (SA) was observed in the pure ZnO thin film, while Ni-doped ZnO illustrated a combination of SA and reverse SA (RSA). The nonlinear absorption coefficient (ß) and nonlinear refractive index (n2) of both pure ZnO and Ni-doped ZnO thin films were found to be input laser intensity dependent. As the input laser intensity increased, the nonlinear absorption coefficient and the nonlinear refractive index of both samples increased. An enhancement of two times in the nonlinear refractive index was observed for the Ni-doped ZnO thin film compared to the pure ZnO thin film. The optical limiting behavior of pure ZnO and Ni-doped ZnO thin films was investigated, and the data demonstrated that Ni-doped ZnO thin film is a good candidate for optical limiter applications due to the presence of strong RSA.

A Finite Element-Based Analysis of a Hemodynamics Efficient Flow Stent Suitable for Different Abdominal Aneurysm Shapes.

This research aimed to examine the impact of a proposed flow stent (PFS) on different abdominal artery shapes. For that purpose, a finite element-based model using the computational fluid dynamics (CFD) method is developed. The effect of PFS intervention on the hemodynamic efficiency is estimated by all of the significant criteria used for the evaluation of aneurysm occlusion and possible rupture; the flow velocity, pressure, wall shear stress (WSS), and WSS-related indices. Results showed that PFS intervention preserves the effects of high flowrate and decreases irregular flow recirculation in the sac of the aneurysm. The flow velocity reduction inside the aneurysm sac is in the range of 55% to 80% and the time-averaged wall shear stress (TAWSS) reduction is in the range of 42% to 53% by PFS deployment. The simulation results implies that PFS could heal an aneurysm efficiently with a mechanism that causes the development of thrombus and ultimately leads to aneurysm resorption.

Comparison and Effect of Common Beverages on Color Stability of Different Esthetic Restorative Materials: An In Vitro Study.

AIM: The aim of this in vitro study is to assess the color stability of different esthetic veneer restorative materials (feldspathic ceramic, hybrid ceramic, zirconia-reinforced lithium silicate glass ceramic, and composite resin) after being exposed to commonly consumed beverages that have staining potential. MATERIALS AND METHODS: Sixty specimens were prepared into rectangular blocks with fixed dimensions of 10 × 12 × 2.5 mm. Machinable feldspathic ceramic (FC), zirconia-reinforced lithium silicate glass ceramic (LS), and a hybrid ceramic (HC) were milled using CAD/CAM (n = 15), and specimens of microparticle composite resin (MPC) were manually prepared by with the same dimensions (n = 15). All specimens were randomly divided into three subgroups (= 5) according to immersing solutions used (coffee, black tea, and red wine). All specimens were immersed for a period of 72 hours. A colorimetric evaluation was done for each specimen before and after immersion using a spectrophotometer and the difference in color was calculated according to the CIE-Lab system. To analyze the data, two-way ANOVA and one-way ANOVA tests of significance were used to compare between the different study groups, followed by pairwise comparisons using post hoc test (Tukey). RESULTS: Different restorative materials showed statistical significance regarding color change after staining (p < 0.001); however, no statistical significance in color change (p > 0.05) was found between the different beverages used. CONCLUSION: All tested ceramic materials had better color stability compared with composite resin. All the staining beverages used in the current study might cause a significant color change in the tested restorative materials. CLINICAL SIGNIFICANCE: The color stability of esthetic restorative materials affects their clinical performance in the oral cavity, where the restorative materials are usually exposed to staining beverages that are frequently consumed by patients. Therefore, it is important to understand the staining effect of the different beverages on esthetic restorative materials.

Alzheimer's disease improved through the activity of mitochondrial chain complexes and their gene expression in rats by boswellic acid.

The foremost neurodegenerative disease is Alzheimer's (AD), which is characterized as a gradual decrease in memory, cognitive function, and also personal changes occurred. This study aims to assess the role of boswellic bioactive component in control Alzheimer's disease through enhancing mitochondrial electron transport chain complexes in the rat model. Rats were divided into five equal groups: the control group (G1), boswellic acid control group (G2), AD disease group (G3), boswellic acid -pre-treated group (G4) and boswellic acid-treated group (G5). At the end of the experiment, blood glucose level, tau protein, different neurochemicals parameters (dopamine, acetylcholine), L-malondialdehyde (MDA) levels, and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities was determined. Also, GLUT2 and mitochondrial electron transport chain complexes were evaluated. As a result, an increase in hippocampus glucose, tau protein expression, MDA and GLUT2 in the AD group (G3) compared to control groups (G1 and G2) has been recorded. These parameters were declined after pre (G4) and treated (G5) by boswellic acid. The neurochemicals, antioxidants parameters, four mitochondrial chain complexes activities and their gene expression in the hippocampus of the AD group were decreased compared to the control groups (G1 and G2). In contrast, pre and treated groups by boswellic acid (G4 and G5, respectively) have shown an increase in antioxidants parameters, and the activities of four mitochondrial complexes, with the best improvement in the pre-treated group (G4), then treated group (G5). In conclusion; the boswellic acid improved the antioxidant and mitochondrial complexes in Alzheimer's disease.

The bactericidal efficacy of femtosecond laser-based therapy on the most common infectious bacterial pathogens in chronic wounds: an in vitro study.

We investigated the influence of femtosecond laser irradiation on the growth of the two most common infectious bacterial pathogens in wounds; Staphylococcus aureus and Pseudomonas aeruginosa as an attempt to validate optimum parameters for a laser-based bactericidal modality to be used clinically. Bacterial cultures were exposed to femtosecond laser irradiation at different wavelengths, exposure times, and laser powers. The source of femtosecond laser was INSPIRE HF100 laser system, Spectra-Physics, which is pumped by a mode-locked femtosecond Ti: sapphire laser MAI TAI HP, Spectra-Physics. After irradiation, bacterial cells' survival was monitored by observing the clear zones of inhibition in cultured agar plates. Results for all strains indicated that the exposure to femtosecond laser irradiation with a wavelength ranging from ultraviolet (λ > 350 nm) to blue laser light (λ < 480 nm), for a period above 20 min and with a power density of ≈ 0.063 W/cm2, was enough to inhibit both bacterial pathogens with the results maintained for 1 week following irradiation.

Propolis Potentiates Methotrexate Anticancer Mechanism and Reduces its Toxic Effects.

Egyptian propolis is a powerful antioxidant and free radical scavenger produced by bees. The current study was designed to characterize Egyptian propolis, investigate its anticancer effect in vitro and its protective role against methotrexate (MTX) toxicity in Ehrlich ascites carcinoma (EAC) experimental model. Our results revealed a high content of total phenolics, flavonoids and dihydroflavonols in propolis ethanolic extract (PEE). PEE prompted cytotoxic effects in cancer cell lines and antitumor effects against EAC mice model by reducing tumor volume, count of viable tumor cells with a significant elevation in the life span as well as the mean survival time of mice. The hepatic and renal biochemical and toxicity parameters of EAC-bearing mice treated with MTX were improved by PEE. Also, it elevates the expression of Bax, caspase-3 and cytochrome-C and reduces the Bcl2 expression in EAC cells. Moreover, PEE with MTX induced cell cycle arrest at the G0/G1 phase. Interestingly, the combination of PEE with MTX showed potent apoptosis as shown by DNA fragmentation gel, comet assay and dihydrofolate reductase level (DHFR). These findings demonstrate that Egyptian propolis extract had high chemical diversity and different antioxidant effects. Also, it optimizes the antitumor potential of MTX and declined its toxic effects.

Improvement in Hepatic Fibrosis Biomarkers Associated With Chemokine Receptor Inactivation Through Mutation or Therapeutic Blockade.

BACKGROUND: The C-C chemokine receptor Type 5 (CCR5) is a key receptor for human immunodeficiency virus type 1 (HIV-1) entry into T-cells and a variant allele, CCR5 delta-32, is associated with decreased viral replication and disease progression. Active HIV-1 replication is highly associated with accelerated rates of hepatic fibrosis. We postulated that CCR5 plays a role in the development of hepatic fibrosis and evaluated the longitudinal effect of natural or drug-induced CCR5 mutation and blockade on biomarkers of liver fibrosis in HIV-1 patients. METHODS: To accomplish this goal, we examined 2 distinct cohorts. First, we evaluated fibrosis markers in the Multicenter Hemophilia Cohort Studies (MHCS), which included subjects with HIV and hepatitis C virus (HCV) coinfection with the CCR5 delta-32 allele. We also evaluated an HIV-1 infected cohort that was treated with a dual CCR5/CCR2 antagonist, cenicriviroc. The enhanced liver fibrosis (ELF) index was validated against liver histology obtained from HCV/HIV and HCV patients and demonstrated strong correlation with fibrosis stage. RESULTS: In both the MHCS patients and patients treated with cenicriviroc, CCR5 mutation or blockade was associated with a significant decrease in the ELF index. Among the patients with the delta-32 allele, the ELF index rate significantly decreased in sequential samples as compared to CCR5 wild-type patients (P = .043). This was not observed in control subjects treated with efavirenz nor with a lower dose of 100 mg cenicriviroc. CONCLUSION: These findings suggest that hepatic fibrosis in HIV-1 infected patients can be modulated by the mutation of CCR5 and/or use of CCR5/CCR2 blockade agents. CLINICAL TRIALS REGISTRATION: NCT01338883.