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Hebatullah Samy Helmy,1 Ayman E El-Sahar,2 Rabab H Sayed,2 Rehab Nabil Shamma,3 Alaa Hamed Salama,4 Eman Maher Elbaz1 1Department of Biochemistry, 2Department of Pharmacology and Toxicology, 3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, 4Department of Pharmaceutical Technology, National Research Center, Cairo, Egypt Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease treated by nonsteroidal anti-inflammatory drugs (NSAIDs) including lornoxicam (LX). Nanocarriers have been used to increase the efficacy and reduce the side effects of various drugs. The objective of the present study was to compare the therapeutic efficacy of systemic administration of lornoxicam-loaded nanomicellar formula (LX-NM) with that of free LX.Materials and methods: The LX-loaded mixed polymeric nanomicellar formula was prepared by direct equilibrium technique. Two rat models were used in the study: carrageenan-induced acute edema and Freund’s complete adjuvant (FCA)-induced chronic arthritis.Results: The inhibitory effect of LX-NM on carrageenan-induced edema was higher than free LX for the same dose (1.3 mg/kg, i.p.). LX-NM (0.325 mg/kg, i.p.) produced effects comparable to that of diclofenac, which served as a standard. In the FCA model, daily treatment with LX-NM (0.325 mg/kg, i.p.) starting on day 14 significantly reduced the percentage of edema and increased weight growth. However, the same dose of LX failed to confer any significant change. Additionally, LX-NM significantly attenuated the rise of tumor necrosis factor-α (TNF-α), interleukin-1β, prostaglandin E2, nuclear factor-κβ, malondialdehyde and nitric oxide serum levels. In contrast, LX failed to show any significant reduction in elevated serum biomarkers except for TNF-α.Conclusion: LX-NM is an alternative delivery system that is simply prepared at low costs. It showed a superior therapeutic efficacy against RA compared to free LX. Thus, LX-NM can be considered as a promising candidate for treatment of RA and similar inflammatory disorders. Keywords: lornoxicam, polymeric micelles, nano-carriers, rheumatoid arthritis, inflammatory mediators

A mathematical analysis was conducted to predict the power requirements of the olive trunk shaker. The predicted required power of the olive trunk shaker is influenced by shaking displacement, fruit detachment force, fruit mass, stem length, damping ratio, unbalanced mass of the tree shaker, and exciting shaking frequency. The Olive trunk shaker was tested in the field at five attachment heights, 400, 500, 600, 700, and 800 mm, and six levels of olive trunk diameter: 78, 84, 101, 143, 158, and 186 mm. The results indicated that the theoretical shaking power was 12.8 kW while the actual required shaking power ranged from 7.1 to 17.8 kW, with an average of 12.6 kW due to variations in tree trunk diameters and different attachment heights. Multiple regression using the least squares method was employed to establish a statistical relation between the theoretical equation and the actual required power as a function of the clamp attachment height and trunk diameter. The regression coefficient of the predicted equation was 93.6% for attachment height values between 400 and 800 mm and tree trunk diameter values between 78 and 186 mm, with a mean absolute error of the prediction model was 0.5009 kW., (© 2024. The Author(s).)

Background: Chronic pancreatitis (CP) is a specific clinical disorder that develops from pancreatic fibrosis and immune cell dysregulation. It has been proposed that bone marrow dendritic cells (BMDCs) exosomes have significant effects on immune regulation. Thus, the current study acquainted the prophylactic and therapeutic effects of exosomes derived from BMDCs on a rat model of CP., Materials and Methods: BMDCs were prepared and identified, and then the exosomes were isolated by differential ultracentrifugation. Prophylactic and therapeutic effects of exosomes were investigated on L-arginine induced CP model., Results: Administration of two tail vein injections of exosomes (200 μg/kg/dose suspended in 0.2 ml PBS) markedly improved the pancreatic function and histology compared to CP group. Moreover, exosomes prominently mitigated the increase in amylase, lipase, tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β) and elevated antioxidant enzymes; catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx)., Conclusion: BMDCs exosomes can be considered as a promising candidate, with a high efficacy and stability compared with its parent cell, for management of CP and similar inflammatory diseases., (© 2024. The Author(s).)

Benign prostatic hyperplasia (BPH) is a nonmalignant enlargement of the prostate common in older men. Diallyl sulfide (DAS), a major component of garlic, has been reported to possess antioxidant, anti-inflammatory, and antiproliferative effects. However, the underlying protective immunomodulatory mechanism of DAS on BPH remains vague. Herein, experimental BPH was induced in rats by daily subcutaneous injection of testosterone propionate (TP) (3 mg/kg, s.c.) for 4 weeks. In parallel, finasteride (Fin) (5 mg/kg, p.o) or DAS (50 mg/kg, p.o.) was administered orally during BPH induction. TP-induced histological alterations and the immune-inflammatory cascade. On the other hand, DAS or Fin administration alleviated all abnormalities induced testosterone. Fin and DAS administration markedly reduced prostate weight by 53% with Fin, and by 60% with DAS. Moreover, serum testosterone and DHT were reduced by 55% and 52%, respectively, with Fin and by 68% and 75%, respectively, with DAS, in concordance with decreased protein expression of androgen receptor (AR), and prostate-specific antigen (PSA). Furthermore, both regime lessen immune-inflammatory milieu, as evidenced by decrease CD4+ T-cells protein expression and associated inflammatory cytokines. Concomitantly, Fin and DAS exhibited marked mitigation in insulin-like growth factor-1 (IGF-1), transforming growth factor-beta1 (TGF-β1), and phosphorylated extracellular signal-regulated kinase (ERK1/2) signaling. Besides alleviating oxidative stress by 53% and 68% in prostatic MDA and by 27% and 7% in prostatic iNOS with Fin and DAS, respectively. In conclusion, this work highlighted a potential therapeutic approach of DAS as a dietary preventive agent against BPH via its anti-inflammatory and immunomodulatory effect along with suppression of the ERK pathway.

Recently, oxidative stress was implicated in the environmental contaminant Di-(2-ethylhexyl) phthalate (DEHP)-induced testicular toxicity, however the mechanism is unclear. We investigated the role of oxidative stress-responsive microRNAs in DEHP-induced aberrations and the protective effect of the citrus flavonoid, hesperidin (HSP). Male Wistar rats were randomly allocated into four groups as vehicle-treated control, DEHP-alone group (500 mg/kg/day) for 30 days, and HSP (25 or 50 mg/kg) for 60 days; testicular damage was triggered by oral administration of DEHP (500 mg/kg/day) after thirty days of oral administration of HSP (25 or 50 mg/kg). DEHP administration reduced testis weight coefficient, serum testosterone, testicular 3β-hydroxysteroid dehydrogenase and antioxidant enzyme activities, and elevated serum fatty acid-binding protein-9, testicular malondialdehyde, and Bax/Bcl2 ratio. Aberrant testicular miR-126-3p and miR-181a expression was observed, along with decreased expression of sirtuin1 (SIRT1) and its targets; nuclear factor-erythroid 2-related factor2, haeme oxygenase-1, and superoxide dismutase2. HSP administration significantly ameliorated these changes and restored testicular function in a dose-dependent manner. We highlight a novel role of oxidative stress-miR-126/miR-181a-SIRT1 network in mediating DEHP-induced changes which were reversed by the antioxidant HSP., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Inflammatory bowel disease (IBD) is a debilitating condition characterized by chronic inflammation of the colon which can increase the risk of colon cancer. Celecoxib (CXB), a cyclooxygenase-2 inhibitor, showed potential for the prophylaxis against IBD. However, it suffers from poor aqueous solubility and cardiovascular toxicity on prolonged use. Here, CXB solubility was enhanced using nanomixed micelles (NMMs) and then colon targeted in a pulsatile system to minimize systemic side effects. Pluronic P123 NMMs with bile salts or hydrophilic Pluronics were prepared using the thin film hydration technique. NMMs were characterized for particle size, size distribution and zeta potential before and after freeze drying and for solubility enhancement. The freeze dried NMMs were then loaded in pulsatile systems with varying tablet plugs containing time-dependent polymers at different concentrations. The optimum NMM consisted of Pluronic P123 and sodium taurocholate (1:1) and CXB:surfactant mixture ratio of 1:30. The pulsatile capsules, containing a tablet plug made of 75% Carbopol®, achieved the target release profile with 88.35% of the dose released after an 8 hrs lag period. Finally, the optimum NMM/pulsatile system showed protective effect against experimentally-induced colitis compared to conventional capsules and pulsatile capsules filled with pure CXB., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

3-Nitropropionic acid (3-NP) induces a spectrum of Huntington's disease (HD)-like neuropathologies in the rat striatum. The present study aimed to demonstrate the neuroprotective effect of lercanidipine (LER) in rats with 3-NP-induced neurotoxicity, address the possible additional protective effect of combined treatment with bone marrow-derived mesenchymal stem cells (BM-MSCs) and LER, and investigate the possible involvement of the Ca 2+ /calcineurin (CaN)/nuclear factor of activated T cells c4 (NFATc4) and Wnt/β-catenin signalling pathways. Rats were injected with 3-NP (10 mg/kg/day, i.p.) for two weeks and were divided into four subgroups; the first served as the control HD group, the second received a daily dose of LER (0.5 mg/kg, i.p.), the third received a single injection of BM-MSCs (1 x 106/rat, i.v.) and the last received a combination of both BM-MSCs and LER. The combined therapy improved motor and behaviour performance. Meanwhile, this treatment led to a marked reduction in striatal cytosolic Ca 2+, CaN, tumour necrosis factor-alpha, and NFATc4 expression and the Bax/Bcl2 ratio. Combined therapy also increased striatal brain-derived neurotrophic factor, FOXP3, Wnt, and β-catenin protein expression. Furthermore, haematoxylin-eosin and Nissl staining revealed an amelioration of striatum tissue injury with the combined treatment. In conclusion, the current study provides evidence for a neuroprotective effect of LER and/or BM-MSCs in 3-NP-induced neurotoxicity in rats. Interestingly, combined LER/BM-MSC therapy was superior to cell therapy alone in inhibiting 3-NP-induced neurological insults via modulation of the Ca 2+ /CaN/NFATc4 and Wnt/β-catenin signalling pathways. LER/BM-MSC combined therapy may represent a feasible approach for improving the beneficial effects of stem cell therapy in HD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Single nucleotide polymorphisms (SNPs) in microRNA-target sites influence an individual's risk and prognosis for autoimmune diseases. Myotubularin-related protein 3 (MTMR3), an autophagy-related gene, is a direct target of miR-181a. We investigated whether MTMR3 SNP rs12537 in the miR-181a-binding site is associated with the susceptibility and progression of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Overall, 94 patients with RA, 80 patients with SLE, and 104 healthy volunteers were recruited. Genotyping and expression analysis of circulating MTMR3 and miR-181a were performed by qPCR. The autophagic marker MAP1LC3B was measured by ELISA. The rs12537 minor homozygote (TT) genotype was a candidate risk factor of both RA and SLE. rs12537TT was associated with lower serum MTMR3 expression and higher LC3B levels than other genotypes in patients with both diseases. Serum miR-181a expression was higher in rs12537TT carriers than in other genotypes among SLE patients. Serum miR-181a and MTMR3 levels were inversely correlated in SLE but not in RA patients. rs12537TT and serum miR-181a were positively associated with disease severity in both diseases. Our results identify a novel role of rs12537 in the susceptibility and progression of RA and SLE, possibly through impacting the interaction between miR-181a and MTMR3 leading to increased autophagy.

Reduced estradiol levels are associated with depression in women during the transition to and after menopause. A considerable number of studies focusing on the theme of treating depression through the activation of erythropoietin (EPO)-induced signaling pathways have been published. Venlafaxine is an approved antidepressant drug that inhibits both serotonin and norepinephrine transporters. The aim of the present study was to investigate the effects of venlafaxine on the depressive-like behaviors and serum estradiol levels in female rats following ovariectomy (OVX) and the possible roles of EPO-induced signaling pathways. Venlafaxine (10 mg/kg/day) was orally administered to OVX rats over a period of 4 weeks using two different treatment regimens: either starting 24 h or 2 weeks after OVX. Venlafaxine showed a superior efficacy in inducing antidepressant-like effects after an acute treatment (24 h post-OVX) than after the delayed treatment (2 weeks post-OVX) and was characterized by a decreased immobility time in the forced swimming test. In parallel, venlafaxine induced EPO and EPO receptor mRNA expression and increased levels of phospho-Janus kinase 2 (p-JAK2), phospho-signal transducer and activator of transcription 5, and phospho-extracellular signal-regulated kinase 1/2 in the hippocampus of OVX rats. Meanwhile, rats exhibited a marked reduction in the hippocampal Bax/Bcl2 ratio, caspase-3 activity, and tumor necrosis factor alpha levels after venlafaxine treatment. Venlafaxine also increased the hippocampal brain-derived neurotrophic factor and serum estradiol levels. Based on these findings, venlafaxine exerts a neuroprotective effect on OVX rats that is at least partially attributed to the activation of EPO/EPOR/JAK2 signaling pathways, anti-apoptotic activities, anti-inflammatory activities, and neurotrophic activities, as well as an increase in serum estradiol level. Graphical Abstract ᅟ.

Background: The bone represents one of the most common sites of metastases in breast cancer. The aim of the current study was to evaluate the diagnostic potential of several circulating markers to detect metastasis to bones in patients with breast cancer., Patients and Methods: Receptor activator of Nuclear Factor-kappa β (NF-Kβ) ligand (RANKL), osteoprotegrin (OPG), vitamin D (VIT D), Chitinase-3-like protein 1; also known as YKL-40, topoisomerase IIα (TOPO2a), and human epidermal growth factor receptor 2 (HER2) were measured in blood samples obtained from 122 patients with breast cancer and 25 healthy controls., Results: All biomarkers were significantly elevated in patients with breast cancer with bone metastasis compared with nonmetastatic patients except YKL-40. RANKL had the highest diagnostic performance for bone metastasis detection with an area under the curve of 97.3, a sensitivity of 85%, and a specificity of 98.6%. Furthermore, logistic regression analysis resulted in a model of RANKL combined with HER2 that had even higher discriminatory power of metastasis to bones than that of RANKL alone. Overall correct classification of the model was 98.9%., Conclusion: We recommend that measuring RANKL together with HER2 can be routinely applied to allow early detection of bone metastases in patients with breast cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) possess tumor-initiating, metastatic, and drug resistance properties. This study was conducted to evaluate the effects of PEGylated interferon-α2a (PEG-IFN-α2a) and 5-fluorouracil (5-FU) on the expression of CSC markers and on specific pathways that contribute to the propagation of CSCs in HCC. HCC was initiated in rats using a single intraperitoneal dose of diethylnitrosamine (DENA) (200 mg/kg) and promoted by weekly subcutaneous injections of carbon tetrachloride (CCl4) for 6 weeks. After the appearance of dysplastic nodules, the animals received PEG-IFN-α2a or 5-FU for 8 weeks. CSC markers (OV6, CD90) and molecules related to transforming growth factor β (TGF-β) and other signaling pathways were assessed in hepatic tissues. The PEG-IFN-α2a treatment effectively suppressed the hepatic expression of OV6 and CD90, ameliorated the diminished hepatic expression of TGF-β receptor II (TGF-βRII) and β2-spectrin (β2SP), and significantly reduced the elevated hepatic expression of TGF-β1, interleukin6 (IL6), signal transducer and activator of transcription3 (STAT3), and vascular endothelial growth factor (VEGF). In contrast, the 5-FU treatment failed to reduce the overexpression of CSC markers and barely affected the disrupted TGF-β signaling. Furthermore, it had no effect on angiogenesis or nitrosative stress. PEG-IFN-α2a, but not 5-FU, could reduce the propagation of CSCs during the progression of HCC by upregulating the disrupted TGF-β signaling, suppressing the IL6/STAT3 pathway and reducing angiogenesis.

Over 100 patients with lepromatous leprosy were treated with rifampicin in a series of pilot, uncontrolled, and controlled trials in 1968-77. The rapid bactericidal effect of rifampicin on Mycobacterium leprae was confirmed. Clinical improvement became apparent sometimes as early as 14 days after the start of treatment. Nevertheless, a few persisting viable M leprae were detected as long as five years after the start of treatment with rifampicin either by itself or in combination with the bacteriostatic drug thiambutosine. Treatment with rifampicin and dapsone for six months reduced the number of persisting leprosy bacteria more than treatment with dapsone alone. Although rifampicin proved more effective than dapsone, it is unlikely that used by itself if can significantly shorten the length of treatment in lepromatous leprosy. Therefore initial intensive combined treatment with two or more bactericidal drugs (including rifampicin) warrants further investigation in both untreated leprosy and lepromatous leprosy resistant to dapsone.