Enhancing collagen based nanoemulgel for effective topical delivery of Aceclofenac and Citronellol oil: Formulation, optimization, in-vitro evaluation, and in-vivo osteoarthritis study with a focus on HMGB-1/RAGE/NF-κB pathway, Klotho, and miR-499a.

The majority of conventional osteoarthritis (OA) treatments are based on molecular adjustment of certain signaling pathways associated with osteoarthritis (OA) pathogenesis, however there is a significant need to search for more effective and safe treatments. This study centers around formulating Aceclofenac (ACF) with high bioavailability in combination with Citronellol oil and collagen. The optimal concentrations of Citronellol oil/D-Limonene oil, Tween 80, and Transcutol HP were determined using a pseudoternary phase diagram. The formulated nanoemulsions were studied for thermophysical stability. Thermodynamically stable formula were analyzed for droplet size, zeta potential, and in-vitro permeation. Then, collagen based nanoemulsion were prepared to capitalize on its efficacy in reducing osteoarthritis side effects and characterized for nano size properties. Formulae F10 and F10C were chosen as optimum nanosize formula. Hense, they were prepared and characterized as nanoemulgel dosage form. The nanoemulgel formulae F10NEG1 and F10CNEG1 showed reasonable viscosity and spreadability, with complete drug release after 4 h. These formulae were chosen for further In vivo anti-OA study. Collagen based ACF/citronellol emugel were able to modulate HMGB-1/RAGE/NF-κB pathway, mitigating the production of inflammatory cytokine TNF-α. They were also able to modulate Klotho and miR-499, reducing serum CTXII and COMP, by reducing the cartilage destruction. Histological investigations validated the efficacy, safety, and superiority of Aceclofenac in combination with Citronellol oil and collagen (F10CNEG1) over solo the treated group (F10NEG1 and blank). Hence, the findings of the current work encourage the use of this promising combined formula in treatment of OA patients.

Aceclofenac/Citronellol Oil Nanoemulsion Repurposing Study: Formulation, In Vitro Characterization, and In Silico Evaluation of Their Antiproliferative and Pro-Apoptotic Activity against Melanoma Cell Line.

Aceclofenac (ACF) is a widely used non-steroidal anti-inflammatory drug (NSAID) known for its effectiveness in treating pain and inflammation. Recent studies have demonstrated that ACF possesses antiproliferative properties, inhibiting the growth of cancer cells in various cancer cell lines. Citronellol, a monoterpenoid alcohol found in essential oils, exhibits antioxidant properties and activities such as inhibiting cell growth and acetylcholinesterase inhibition. In this study, the objective was to formulate and evaluate an aceclofenac/citronellol oil nanoemulsion for its antiproliferative effects on melanoma. The optimal concentrations of citronellol oil, Tween 80, and Transcutol HP were determined using a pseudoternary phase diagram. The formulated nanoemulsions were characterized for droplet size, zeta potential, thermophysical stability, and in vitro release. The selected formula (F1) consisted of citronellol oil (1 gm%), Tween 80 (4 gm%), and Transcutol HP (1 gm%). F1 exhibited a spherical appearance with high drug content, small droplet size, and acceptable negative zeta potential. The amorphous state of the drug in the nanoemulsion was confirmed by Differential Scanning Calorimetry, while FTIR analysis indicated its homogenous solubility. The nanoemulsion showed significant antiproliferative activity, with a lower IC50 value compared to aceclofenac or citronellol alone. Flow cytometric analysis revealed cell cycle arrest and increased apoptosis induced by the nanoemulsion. In silico studies provided insights into the molecular mechanism underlying the observed antitumor activity. In conclusion, the developed aceclofenac/citronellol oil nanoemulsion exhibited potent cytotoxicity and pro-apoptotic effects, suggesting its potential as a repurposed antiproliferative agent for melanoma treatment. In a future plan, further animal model research for validation is suggested.

Propranolol-Loaded Trehalosome as Antiproliferative Agent for Treating Skin Cancer: Optimization, Cytotoxicity, and In Silico Studies.

This study aims at preparing propranolol-loaded trehalosomes (a trehalose-coated liposome) to be used as an antiproliferative agent for treating skin cancer. A factorial design was used to select the optimum formula, where trehalose, lecithin, and Tween 80 levels were studied. A total of 24 runs were prepared and characterized according to size, charge, entrapment efficiency, and release after 3 h to select the optimum formula. The optimized formula was investigated using TEM, DSC, and FTIR. Cell studies were carried out against the human melanoma cell line to measure cytotoxicity, apoptosis/necrosis, and cell cycle arrest. In silico studies were conducted to understand the interaction between propranolol and the influential receptors in melanoma. The results showed the selected formula consisted of trehalose (175 mg), lecithin (164 mg), and Tween 80 (200 mg) with a size of 245 nm, a charge of -9 mV, an EE% of 68%, and a Q3 of 62%. Moreover, the selected formula has good cytotoxicity compared to the free drug due to the synergistic effect of the drug and the designed carrier. IC50 of free propranolol and the encapsulation of propranolol were 17.48 µg/mL and 7.26 µg/mL, respectively. Also, propranolol and the encapsulation of propranolol were found to significantly increase early and late apoptosis, in addition to inducing G1 phase cell cycle arrest. An in silico virtual study demonstrated that the highest influential receptors in melanoma were the vitamin D receptor, CRH-R1, VEGFR 1, and c-Kit, which matches the results of experimental apoptotic and cell cycle analysis. In conclusion, the selected formula has good cytotoxicity compared to the free drug due to the synergistic effect of the drug and the designed carrier, which make it a good candidate as an antiproliferative agent for treating skin cancer.

Enhanced bioavailability and pharmacokinetics parameters of Enalapril solid self nanoemulsifying oral dispersible tablet: formulation, in vitro and in vivo evaluation.

Enalapril (EN) is an antihypertensive drug that is sparingly soluble in water with limited oral bioavailability. Successfully prepared self-nanoemulsifying systems (SNES) loaded with EN were developed. The solubility of EN in different oils, surfactants, and cosurfactants was tested. Pseudoternary phase diagrams were developed, and various SNES formulations were prepared and evaluated regarding content uniformity, emulsification time, droplet size (DS), and zeta potential (ZP). The selected system was examined using transmission electron microscopy. Solid Self-Nanoemulsifying Systems (SSNES) were formulated using Avicel® PH101 carrier and Aerosil® 200 adsorbent to form a free-flowing powder. The powder was formulated as an oral disintegrating tablet (ODT) using superdisintegrants and tested for physicochemical properties and stability. Finally, an in vivo pharmacokinetic study in healthy human volunteers was carried out. The composition of the selected SNES was 10% Labrafil®, 60% Tween 80, and 30% Transcutol® HP. It developed with an emulsification time of 21 sec, DP range of 60.16 nm, ZP of 1.17 mV, and spherical-shaped globules. The accelerated stability testing proved that there was no significant difference in physical properties after storage for 3 months. The percentage of relative bioavailability for formula F2 was 112.04%. The results of this study proved that the prepared EN-SSNES ODT represents a novel formulation alternative to the currently marketed tablet.

Impacts of synthetic androgen and estrogenic antagonist administration on growth performance, sex steroids hormones, and immune markers of male and female broilers.

The influence of synthetic androgen and estrogenic antagonists (Tamoxifen) on body characteristics and immune response of male and female broilers and the correlation between sex hormone levels were estimated in our experiment. One day old chicks were sexed, and chicks of each sex were randomly distributed on three experimental treatments; the first treatment group (TAM20) chicks were supplied with estrogenic antagonist tamoxifen citrate 20 mg/kg body weight through oral administration for four times every other day from third until ninth d; Androgen treatment chicks were injected intramuscular with veterinary androgen AD GAN@ (Boldenone Undecylenate 50 mg) 1 cm/10 kg body weight at fifth and ninth day, and the third treatment was control. Androgen treatment reported the highest feed intake with the lowest for TAM20 treatment. Concerning carcass characteristics, early androgen injection increased breast percentage significantly compared to TAM20 treatment. Androgen supplementation increased significantly comb the percentage. However, TAM20 decreased it particularly compared to control. Moreover, the percentage of comb and shanks was substantially higher for males than females. Concerning the effects of both treatments on sex hormones, androgen showed favorable effects on testosterone and estrogen compared to Tamoxifen 20 treatment. On the other hand, the administration of TAM 20 improves phagocytic activity compared to androgen administration.

Impacts of sex steroids and aromatase inhibitor on performances, carcass characteristics and gonadal histology of broiler chickens slaughtered at different ages.

This experiment was established to evaluate the influence of synthetic steroid hormone and aromatase inhibitor on performance, carcass characteristics, hormonal profile and gonadal structure of broiler chickens slaughtered at two different ages. A total of 360 Cobb Avian48 chicks were sexed and distributed randomly into three groups: Tam10 group; birds received Tamoxifen10mg (Tamfen 10 mg@ ) orally at a level of 10 mg/kg body weight daily from the 3rd till the 9th day of age; BOL group: birds injected intramuscularly with Boldenone undecylenate (BOLD-GAN@ 0.1 mg/kg) at the 5th and the 9th day of age; and Control group. BOL injection or Tam supplementation improved performance traits compared with the control group. Although Tam positive effect appeared early before the 5th week of age, the BOL effect was delayed to the 6th week. BOL injection improved carcass characteristics of both sexes at both 5 and 6 weeks slaughtering ages. Regardless of treatment effect, the mortality% was higher in the late weeks of age than in the early weeks. Moreover, BOL treatment increased comb% compared with control and Tam treatments. Generally, males had significantly higher testosterone levels and lower oestrogen levels than females. Males treated with Boldenone had the highest testosterone level, although testosterone levels did not differ considerably among females of the various groups. BOL treatment females had the lowest oestrogen level. Both Tam10 and Boldenone had adverse effects on testicular and ovarian histology, affecting the typical structures. Finally, we concluded that the anabolic effect of Tam10 may be achieved in griller broilers production without changing the sex hormones assay. Although Boldenone achieved an anabolic effect without changing blood sex hormone levels, this effect is induced early with females and delayed with males, which prolongs the marketing period. The goal is to shorten this period. Therefore, this material can only be used with the possibility of separating females from males to be used with females only.

Improved Wear-Resistant Performance of Epoxy Resin Composites Using Ceramic Particles.

This work investigated the effects of using a new fabrication technique to prepare polymer composite on the wear-resistant performance of epoxy resin composites under dry friction conditions. Polymer composite samples with different weight contents of silicon carbide (SiC) particles were manufactured. This paper addresses the wear behavior of the obtained samples. With the suggested technique, the samples were prepared from epoxy/silicon carbide particles using a layer of thin kraft paper to prevent the sedimentation of the ceramic particles and to control the weight content of ceramic in the polymer. Kraft paper was used as a layer in the polymer composite. The hardness, wear resistance, and water absorption capacity of the produced epoxy composite samples prepared using the kraft paper technique were evaluated. The morphology of epoxy composite samples showed a significant improvement in the ceramic distribution and enhancement of interface bonding between ceramic and the polymer. The hardness values of the developed polymer composites were enhanced by up to 42.8%, which was obtained at 18 wt.% SiC particles. Increasing the ceramic content in the epoxy also led to the enhancement of wear resistance compared with pure epoxy. The results of the microstructure study also showed that the kraft paper layers helped in maintaining the distribution of the ceramic particles according to the previously specified content in each layer in the sample. Wear tests showed that the wear rate of the polymer composite decreased with the increase in the ceramic content. This study provides a new recycling method for using old kraft paper in polymer composite manufacturing to improve the distribution of ceramic particles in the polymer matrix.

Effects of Heat-Treatment on Tensile Behavior and Dimension Stability of 3D Printed Carbon Fiber Reinforced Composites.

This work investigated the effects of heat treatment on the tensile behavior of 3D-printed high modules carbon fiber-reinforced composites. The manufacturing of samples with different material combinations using polylactic acid (PLA) reinforced with 9% carbon fiber (PLACF), acrylonitrile butadiene styrene (ABS) reinforced with 9% carbon fiber (ABSCF) were made. This paper addresses the tensile behavior of different structured arrangements at different% of densities between two kinds of filaments. The comparison of the tensile behavior between heat treated and untreated samples. The results showed that heat treatment improves the tensile properties of samples by enhancing the bonding of filament layers and by reducing the porosity content. At all structure specifications, the rectilinear pattern gives higher strength of up to 33% compared with the Archimedean chords pattern. Moreover, there is a limited improvement in the tensile strength and modulus of elasticity values for the samples treated at low heat-treatment temperature. The suggested methodology to evaluate the tensile behavior of the pairs of materials selected is innovative and could be used to examine sandwich designs as an alternative to producing multi-material components using inexpensive materials.

Impacts of tea tree or lemongrass essential oils supplementation on growth, immunity, carcass traits, and blood biochemical parameters of broilers reared under different stocking densities.

The effects of tea tree essential oil (TTEO) and lemongrass essential oil (LGEO) with different stocking densities on the growth performance, biochemical markers, antioxidants, and immunity state of broiler chickens were studied.  Birds were housed at stocking densities of 25, 30, 35, and 40 kg/m2. The treatments were, basal diet without any supplementation, the second and third groups were supplemented with 300 mg TTEO/kg feed, and 300 mg LGEO/kg feed, respectively. Results revealed that increasing stocking density from 25 to 40 kg/m2 significantly reduced body weight and daily weight gain at different ages. The phagocytic index and activity were significantly higher under the lower stocking density (25 kg/m2). Serum amyloid A (SAA), serum or liver transferrin (TRF), or C-reactive protein (CRP) were significant decreased when decreasing stocking density. Increasing stocking density from 25 to 40 kg/m2 resulted in a significant increase in the serum urea, creatinine, uric acid, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), and catalase (CAT) levels. However, there was a significant reduction in antioxidant enzyme activity, including glutathione peroxidase (GPx) and superoxide dismutase (SOD), as stocking density increased. The supplementation of TTEO produced significantly higher body weight and daily weight gain followed by LGEO. Additionally, the mortality rates were reduced in TTEO (27.4%) and LGEO (25%) groups. TTEO or LGEO supplementation significantly improved meat constituents and cellular immunity and reduced serum total lipids, serum and meat cholesterol, and triglycerides, SAA, TRF, and CRP. For all these measured parameters, superior results were obtained when TTEO was used compared to LGEO. TTEO or LGEO supplementation also significantly reduced serum urea, creatinine, uric acid, and the enzymatic activities of LDH, ALT, AST, MDA, and CAT (but not GPx and SOD) in comparison to the control treatment. Overall, our results showed the superiority of TTEO over LGEO as a feed supplement in broiler diets. In conclusion, TTEO treatment offers a better solution for raising broiler chickens in high stocking density.

Tenoxicam loaded hyalcubosomes for osteoarthritis.

The main aim is to develop transcutaneous tenoxicam (TNX) loaded vesicles to control osteoarthritis (OA) without common side effects. Different vesicles were prepared by the emulsification technique, where poloxamer and glyceryl monooleate used for cubosomes. Then, hyalcubosomes were prepared by adding sodium hyaluronate to cubosomes components. Different characterization techniques were used. The selected formulations were tested using an ex-vivo permeation study to evaluate the ability to penetrate and retained in skin layers. Also, in-vitro cell studies using human skin fibroblasts were evaluated the safety of the formulation. The anti-inflammatory efficiency was tested using an in-vivo carrageenan-induced rat paw edema model. Finally, the efficiency to control OA symptoms was tested on three patients with a medical history of knee OA. Results confirmed the successful development of spherical cubosomes with particle size <250 nm, -14.5 mV, high entrapment efficiency percentage (>90%). Moreover, the addition of sodium hyaluronate to selected cubosomes improved viscosity and spreadability. Permeation study confirmed drug penetration and deposition. Cell studies proved the safety of the selected formulation. The animal model showed high anti-inflammatory activity. Finally, the preliminary clinical study demonstrates the potential efficacy and safety of the formulation in controlling OA symptoms over 8 weeks of therapy.

Impact of Oral Supplementation of Different Levels of Tamoxifen on Productive and Reproductive Efficiencies and Carcass Traits of Avian48 and Arbor Acres Broilers.

This research was aimed at estimating the effect of oral supplementation of Tamoxifen on productive efficiency, carcass characteristics, hormonal profile and gonadal structure of two broiler breeds. One hundred and eighty chicks of each breed of Avian48 and Arbor Acres were divided into three groups: control group; TAM10 group, supplied with 10 mg Tamoxifen/kg of body weight at 3, 5, 7 and 9 days of life; and TAM20 group, supplied at the same intervals with 20 mg Tamoxifen/kg of body weight. Both levels of Tamoxifen improved productive performance at early ages, but Arbor Acres produced better results with TAM20 levels than TAM10, while Avian48 breeds reacted adversely. On the contrary, Tamoxifen supplementation significantly decreased feed intake and feed conversion (after the first two weeks of life) compared to control with a higher level of decrease reported for TAM20 treatments than TAM10 and for Arbor Acres compared to Avian48 breed. Carcass traits were not affected significantly with Tamoxifen supplementation compared to control although Arbor Acres responded better to TAM20 and Avian48 for TAM10. With regard to the effect of Tamoxifen (TAM) on sex hormones, it could be concluded that TAM10 treatments showed a stimulating effect on the level of such hormones as compared with the TAM20 group with the most favourable results being clearly detectable in 42-day-old birds although both concentrations of Tamoxifen did not differ significantly from control. However, treatment of broiler chickens with Tamoxifen in different doses caused a gradual decrease in follicle production rate and eventually led to an increase of the atretic follicles in different stages of atresia. Finally, we can conclude that Tamoxifen supplementation can improve performance and carcass efficiency of broilers without changing the hormonal profile, however much research is required to estimate the best concentration required for each breed.

Antiviral treatment for treatment-naïve chronic hepatitis B: systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Chronic hepatitis B (CHB) infection poses a significant burden to public health worldwide. Most cases are clinically silent until late in the disease course. The main goal of current therapy is to improve survival and quality of life by preventing disease progression to cirrhosis and liver failure, and consequently hepatocellular carcinoma development. The objective of this review is to provide a contemporary and comprehensive evaluation of the effectiveness of treatment options. METHODS: We performed a systematic review of peer-reviewed literature for randomized controlled trials involving treatment-naïve CHB adult population who received antiviral therapy. The endpoints were virologic response (VR), normalization of alanine aminotransferase (ALT norm), HBeAg loss, HBeAg seroconversion, and HBsAg loss for the HBeAg-positive population; and VR and ALT norm for the HBeAg-negative population. Network meta-analysis (NMA) was performed to synthesize evidence on the efficacy of treatment. RESULTS: Forty-two publications were selected. Twenty-three evaluated HBeAg-positive population, 13 evaluated HBeAg-negative population, and six evaluated both. We applied NMA to the efficacy outcomes of the two populations separately. Treatment strategies were ranked by the probability of achieving outcomes, and pairwise comparisons calculated from NMA were reported in odds ratios (OR). For HBeAg-positive population, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) were the best for VR; OR vs adefovir = 14.29, 95% CI 7.69-25 and 12.5, 95% CI 4.35-33.33 respectively. TAF was the best for achieving ALT norm (OR vs placebo = 12.5, 95% CI 4.55-33.33), HBeAg loss, and seroconversion (OR vs entecavir/TDF combination = 3.03, 95% CI 1.04-8.84 and 3.33, 95% CI 1.16-10 respectively). In the HBeAg-negative population, TDF and TAF were the best for VR (OR vs adefovir = 9.79, 95% CI 2.38-42.7 and 11.71, 95% CI 1.03-150.48 respectively). Telbivudine and TAF were the best for ALT norm. Certain nucleos(t)ide combinations also had high probability of achieving positive outcomes. CONCLUSIONS: Our results are consonant with current clinical guidelines and other evidence reviews. For both HBeAg-positive and HBeAg-negative populations, TDF and TAF are the most effective agents for virologic suppression, and TAF is effective across all outcomes.

Formulation and characterization of chlorhexidine HCl nanoemulsion as a promising antibacterial root canal irrigant: in-vitro and ex-vivo studies.

Introduction and aim: Chlorhexidine Hydrochloride [Chx.HCl] has a broad-spectrum antibacterial effect, sustained action and low toxicity so it has been recommended as a potential root canal irrigant. The aim of this study was to improve the penetration ability, cleansing and antibacterial effect of Chx.HCl using a newly formulated Chx.HCl nanoemulsion and use it as root canal irrigant. Methods: Chx.HCl nanoemulsions were prepared using two different oils; Oleic acid and Labrafil M1944CS, two surfactants; Tween 20 and Tween 80 and co-surfactant; Propylene Glycol. Pseudoternary phase diagrams were constructed to designate the optimum systems. The prepared nanoemulsion formulae were evaluated for their drug content, emulsification time, dispersibility, droplet size, in-vitro drug release, thermodynamic stability, In-vitro antibacterial activity and ex-vivo study for the selected formula. Comparisons were made of Chx.HCl nanoemulsion with two different concentrations 0.75% and 1.6% vs Chx.HCl normal particle size as root canal irrigant for their penetration ability, cleansing effect and antibacterial effect. Results: The selected formula was F6 with composition of 2% Labrafil, 12% Tween 80 and 6% Propylene glycol. It has small particle size (12.18 nm), short emulsification time (1.67 seconds), and fast dissolution rate after 2 minutes. It was found to be a thermodynamically/physically stable system. The higher concentration of Chx.HClnanoemulsion1.6% shows the best penetration ability compared to Chx.HCl normal particle size due to the smaller particle size. Chx.HCl nanoemulsion 1.6% has the lowest mean value of the remaining debris surface area (2001.47 µm2) when compared to normal particle size material (2609.56 µm2). Conclusion: Chx.HCl nanoemulsion preparation has better cleansing ability and antibacterial effect with high efficacy on Enterococcus faecalis, where high reduction rate or complete eradication of bacterial cells has been achieved.