Correction: Eid et al. Interference with TGFß1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome. Molecules 2021, 26, 866.

The authors wish to make the following changes to the paper [...].

Effectiveness of high intensity laser therapy on pain, grip strength and median nerve conductivity in pregnant women with carpal tunnel syndrome: A randomized controlled trial.

STUDY DESIGN: Single-blind randomized controlled trial. INTRODUCTION: High-intensity laser therapy (HILT) was recently introduced to the physiotherapy field as a treatment option for patients with carpal tunnel syndrome (CTS). However, evidence about its effectiveness on pregnant women with CTS is sparse. PURPOSE OF STUDY: To test the effectiveness of HILT combined with a conventional physical therapy program to reduce pain intensity, sensory and motor nerve distal latency, and increase grip strength in pregnant women with CTS compared with the physical therapy alone. METHODS: Fifty-four pregnant women with mild to moderate CTS were randomized and further allocated into two groups. The HILT group (n = 27) received both HILT and conventional physical therapy, and the control group (n = 27) received only physical therapy, including nerve and tendon gliding exercises and the use of an orthotic device. Participants received the interventions at the University Hospital (omitted for review) three times per week for 5 weeks. An 11-points numerical pain rating scale, electromyography, and a handheld dynamometer were used for data collection before and after the treatment. RESULTS: Participants from both groups presented significant improvement in the median nerve motor nerve distal latency (MNDL), sensory nerve distal latency, numerical pain rating scale, and handgrip strength after the intervention. The between-group difference showed more improvements in participants of the HILT group on reducing pain intensity, mean difference (MD) = -3.11 (-4.1 to 2.1), and sensory nerve distal latency, MD = -0.3 (-0.5 to -0.1) compared with the control group. DISCUSSION: HILT produced greater improvement in outcomes of pregnant women with mild to moderate CTS whichsuggests that adding HILT to traditional CTS physical therapy protocol is beneficial and safe. CONCLUSIONS: High-intensity laser therapy combined with a standard physical therapy program for CTS in pregnant women is better than the physical therapy program alone to improve pain intensity and median nerve sensory distal latency.

Interference with TGFß1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome.

The role of cannabinoid receptors in nephropathy is gaining much attention. This study investigated the effects of two neutral CB1 receptor antagonists, AM6545 and AM4113, on nephropathy associated with metabolic syndrome (MetS). MetS was induced in rats by high-fructose high-salt feeding for 12 weeks. AM6545, the peripheral silent antagonist and AM4113, the central neutral antagonist were administered in the last 4 weeks. At the end of study, blood and urine samples were collected for biochemical analyses while the kidneys were excised for histopathological investigation and transforming growth factor beta 1 (TGFß1) measurement. MetS was associated with deteriorated kidney function as indicated by the elevated proteinuria and albumin excretion rate. Both compounds equally inhibited the elevated proteinuria and albumin excretion rate while having no effect on creatinine clearance and blood pressure. In addition, AM6545 and AM4113 alleviated the observed swelling and inflammatory cells infiltration in different kidney structures. Moreover, AM6545 and AM4113 alleviated the observed histopathological alterations in kidney structure of MetS rats. MetS was associated with a ten-fold increase in urine uric acid while both compounds blocked this increase. Furthermore, AM6545 and AM4113 completely prevented the collagen deposition and the elevated expression of the TGFß1 seen in MetS animals. In conclusion, AM6545 and AM4113, possess reno-protective effects by interfering with TGFß1-mediated renal inflammation and fibrosis, via peripheral action.

Effects of the CB1 Receptor Antagonists AM6545 and AM4113 on Insulin Resistance in a High-Fructose High-Salt Rat Model of Metabolic Syndrome.

Background and Objectives: Insulin resistance (IR) is a serious condition leading to development of diabetes and cardiovascular complications. Hyper-activation of cannabinoid receptors-1 (CB1) has been linked to the development of metabolic disorders such as IR. Therefore, the effect of blocking CB1 on the development of IR was investigated in the present study. Materials and Methods: A 12-week high-fructose/high-salt feeding model of metabolic syndrome was used to induce IR in male Wistar rats. For this purpose, two different CB1-antagonists were synthesized and administered to the rats during the final four weeks of the study, AM6545, the peripheral neutral antagonist and AM4113, the central neutral antagonist. Results: High-fructose/salt feeding for 12 weeks led to development of IR while both AM6545 and AM4113, administered in the last 4 weeks, significantly inhibited IR. This was correlated with increased animal body weight wherein both AM6545 and AM4113 decreased body weight in IR animals but with loss of IR/body weight correlation. While IR animals showed significant elevations in serum cholesterol and triglycerides with no direct correlation with IR, both AM6545 and AM4113 inhibited these elevations, with direct IR/cholesterol correlation in case of AM6545. IR animals had elevated serum uric acid, which was reduced by both AM6545 and AM4113. In addition, IR animals had decreased adiponectin levels and elevated liver TNFα content with strong IR/adiponectin and IR/TNFα correlations. AM6545 inhibited the decreased adiponectin and the increased TNFα levels and retained the strong IR/adiponectin correlation. However, AM4113 inhibited the decreased adiponectin and the increased TNFα levels, but with loss of IR/adiponectin and IR/TNFα correlations. Conclusions: Both CB1 neutral antagonists alleviated IR peripherally, and exerted similar effects on rats with metabolic syndrome. They also displayed anti-dyslipidemic, anti-hyperurecemic and anti-inflammatory effects. Overall, these results should assist in the development of CB1 neutral antagonists with improved safety profiles for managing metabolic disorders.

The Impact of Tennis and Golfer's Elbow on Shoulder External Rotators and Abductors' Peak Torque.

CONTEXT: Upper limb activities require a repetitive movement of the shoulder external rotator and abductor muscles. The malfunction of the proximal part of the upper limb kinetic chain tends to change the mechanics of the distal part and increase the risk of injuries. OBJECTIVES: To compare the normalized eccentric peak torque (NEPT) of the shoulder external rotator and abductor muscles among healthy athletes and those with tennis elbow and golfer's elbow. DESIGN: An experimental cross-sectional study. SETTING: Isokinetic laboratory, Faculty of Physical Therapy, Cairo University. PARTICIPANTS: A total of 30 male athletes participated voluntarily in this study. INTERVENTION: Participants were distributed into 3 groups: healthy group, tennis elbow group, and golfer's elbow group. MAIN OUTCOME MEASURES: NEPT of shoulder abductors and external rotators. The Biodex Isokinetic Dynamometer was used to measure the variables of interest. RESULTS: There was a significant increase in the NEPT of shoulder abductors and external rotators in healthy control group compared with both tennis elbow and golfer's elbow groups at an angular velocity of 60°/s (P < .05). Moreover, there was a significant increase in the NEPT of shoulder external rotators and abductors at an angular velocity of 120°/s in healthy control group compared with tennis elbow group and in golfer's elbow group compared with tennis elbow group (P < .05). CONCLUSION: Tennis elbow and golfer's elbow are associated with decreased NEPT of shoulder external rotators and abductors compared with those of healthy athletes. This tends to decrease the external stability of the shoulder joint and put high stress on the distal joints of the upper kinetic chain.

Antihyperglycemic activities of extracts of the mistletoes Plicosepalus acaciae and P. curviflorus in comparison to their solid lipid nanoparticle suspension formulations.

The antihyperglycemic activity of the extracts and preparations of solid lipid nanoparticle suspensions of two mistletoes growing in Saudi Arabia, Plicosepalus acaciae and P. curviflorus, as well as their possible antioxidant effect were investigated in a type 2 diabetic animal model. Type 2 diabetes was induced in adult male Wistar rats by a high-fat diet followed by injection of streptozotocin (STZ). The diabetic rats were treated in parallel with pioglitazone hydrochloride (PIO), non-toxic extracts of P. acaciae and P. curviflorus, as well as three different solid lipid nanoparticle (SLN) suspension formulations prepared from each of the two extracts. Blood glucose level, insulin resistance, oxidative stress parameters, and antioxidant markers were determined. The total extracts of P. acaciae and P. curviflorus as well as the SLN formulations exhibited a significant blood glucose-lowering effect associated with antioxidant effects in the diabetic rats. The SLN preparation with the highest lipid content gave the best result. Reduction of hyperglycemia and insulin resistance in the diabetic rats was, at least partly, due to the antioxidant activities of the extracts and their SLN formulations.

Sulfadiazine Exerts Potential Anticancer Effect in HepG2 and MCF7 Cells by Inhibiting TNFα, IL1b, COX-1, COX-2, 5-LOX Gene Expression: Evidence from In Vitro and Computational Studies.

Drug repurposing is a promising approach that has the potential to revolutionize the drug discovery and development process. By leveraging existing drugs, we can bring new treatments to patients more quickly and affordably. Anti-inflammatory drugs have been shown to target multiple pathways involved in cancer development and progression. This suggests that they may be more effective in treating cancer than drugs that target a single pathway. Cell viability was measured using the MTT assay. The expression of genes related to inflammation (TNFa, IL1b, COX-1, COX-2, and 5-LOX) was measured in HepG2, MCF7, and THLE-2 cells using qPCR. The levels of TNFα, IL1b, COX-1, COX-2, and 5-LOX were also measured in these cells using an ELISA kit. An enzyme binding assay revealed that sulfadiazine expressed weaker inhibitory activity against COX-2 (IC50 = 5.27 µM) in comparison with the COX-2 selective reference inhibitor celecoxib (COX-2 IC50 = 1.94 µM). However, a more balanced inhibitory effect was revealed for sulfadiazine against the COX/LOX pathway with greater affinity towards 5-LOX (IC50 = 19.1 µM) versus COX-1 (IC50 = 18.4 µM) as compared to celecoxib (5-LOX IC50 = 16.7 µM, and COX-1 IC50 = 5.9 µM). MTT assays revealed the IC50 values of 245.69 ± 4.1 µM and 215.68 ± 3.8 µM on HepG2 and MCF7 cell lines, respectively, compared to the standard drug cisplatin (66.92 ± 1.8 µM and 46.83 ± 1.3 µM, respectively). The anti-inflammatory effect of sulfadiazine was also depicted through its effect on the levels of inflammatory markers and inflammation-related genes (TNFα, IL1b, COX-1, COX-2, 5-LOX). Molecular simulation studies revealed key binding interactions that explain the difference in the activity profiles of sulfadiazine compared to celecoxib. The results suggest that sulfadiazine exhibited balanced inhibitory activity against the 5-LOX/COX-1 enzymes compared to the selective COX-2 inhibitor, celecoxib. These findings highlight the potential of sulfadiazine as a potential anticancer agent through balanced inhibitory activity against the COX/LOX pathway and reduction in the expression of inflammatory genes.

Clinical Efficacy of High-Intensity Laser Therapy on Lateral Epicondylitis Patients: A Systematic Review and Meta-analysis.

OBJECTIVES: Recently, high-intensity laser therapy has been used in the therapeutic protocols for pain management. We aimed to evaluate the clinical efficacy of high-intensity laser therapy versus other different modalities for improving lateral epicondylitis symptoms. METHODOLOGY: We conducted a systematic review and meta-analysis on prospective randomized controlled trials from PubMed, Embase, Scopus, Web of Science, and Science Direct until June 2021 using relevant key words. We analyzed the data using Review Manager software (RevMan 5.4). RESULTS: Six randomized controlled trials with 344 patients were included. There is low-quality evidence that high-intensity laser therapy generates a small reduction on pain intensity compared with a control group either during activity (mean difference = -0.98, 95% confidence interval = -1.6 to -0.35, P = 0.002) or during rest (mean difference = -0.98, 95% confidence interval = -1.68 to -0.09, P = 0.03). In addition, there is low-quality evidence that high-intensity laser therapy provides small improvements in quality of life (physical component) compared with control (mean difference = 9.76, 95% confidence interval = 2.69 to 16.83, P < 0.0001). CONCLUSIONS: High-intensity laser therapy is an effective therapeutic modality to reduce pain and improve quality of life (36-item short form health survey physical component) in patients experiencing persistent symptoms of lateral epicondylitis. However, grip strength, hand function, and quality of life (36-item short form health survey) did not show significant differences between high-intensity laser therapy and other therapies.

Effects of the CB1 receptor antagonists AM6545 and AM4113 on metabolic syndrome-induced prostatic hyperplasia in rats.

Metabolic syndrome (MetS) is a combination of metabolic disorders that can predispose individuals to benign prostatic hyperplasia (BPH). The inhibition of the cannabinoid 1 (CB1) receptor has been used to treat metabolic disorders in animal models. This study reports the use of a peripherally restricted CB1 antagonist (AM6545) and a neutral CB1 antagonist (AM4113) to improve MetS-related BPH in rats. Animals were divided into three control groups to receive either a normal rodent diet, AM6545, or AM4113. MetS was induced in the fourth, fifth, and sixth groups using a concentrated fructose solution and high-salt diet delivered as food pellets for eight weeks. The fifth and sixth groups were further given AM6545 or AM4113 for additional four weeks. Body and prostate weights were measured and prostate sections were stained with hematoxylin eosin. Cyclin D1, markers of oxidative stress and inflammation, and levels of the endocannabinoids were recorded. BPH in rats with MetS was confirmed through increased prostate weight and index, as well as histopathology. Treatment with either AM6545 or AM4113 significantly decreased prostate weight, improved prostate histology, and reduced cyclin D1 expression compared with the MetS group. Groups treated with CB1 antagonists experienced reduced lipid peroxidation, recovered glutathione depletion, restored catalase activity, and had lower inflammatory markers interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α). MetS rats treated with either AM6545 or AM4113 showed reduced concentrations of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the prostate compared with the MetS group. In conclusion, the CB1 antagonists AM6545 and AM4113 protect against MetS-induced BPH through their anti-proliferative, antioxidant, and anti-inflammatory effects.

Cross-education effect of balance training program in patients with chronic ankle instability: A randomized controlled trial.

Chronic ankle instability (CAI) is frequently developed due to failure of the functional rehabilitation after acute ankle sprain. So, there is a need for an alternative way by which we can begin neuro-muscular control retraining sooner. PURPOSE: This study was conducted to examine the effect of 6-week Single-limb Balance Training Program of the non-affected side on the Overall Stability Index (OASI), Antero-Posterior Stability Index (APSI), and the Medio-Lateral Stability Index (MLSI) of the affected side in females with unilateral CAI. METHODS: Thirty-two female patients with CAI with mean age 20.96 ± 1.69 years participated in this study. They were randomly assigned into three groups: experimental group A (Cross-Education) (n = 11) performed the exercises for the non-affected side, experimental group B (Traditional Training) (n = 11) performed the exercises for the affected side, and Control group C (n = 10) did not perform any exercises. The randomization was done using statistical random tables. Data were collected using the Biodex Balance system before and after training. RESULTS: Two-way mixed design MANOVA revealed that there were significant improvements in the mean values of the OASI, APSI and MLSI after training (p < .05) in both the Cross-Education group (A) and Traditional Training group (B) with no significant difference in-between for the OASI, MLSI and APSI after training. There was no significant difference (p > .05) between the pre and post-training mean values of the OASI, MLSI and APSI in the Control group (C). CONCLUSION: Single-limb balance training for the non-affected side is effective in improving the postural control of the affected side in patients with CAI.

A Validated HPLC Method for the Determination of Linagliptin in Rat Plasma. Application to a Pharmacokinetic Study.

A sensitive and reproducible HPLC method for the determination of linagliptin (LNG) in rat plasma was developed and validated using pindolol (PIN) as the internal standard. Both LNG and PIN were separated on a Zorbax Eclipse XDB C18 column kept at ambient temperature using as mobile phase a combination of 75% methanol: 25% formic acid 0.1% pH 4.1 at a flow rate of 1.0 mL min-1. UV detection was performed at 254 nm. The method was validated in compliance with ICH guidelines and found to be linear in the range of 5-1,000 ng mL-1. The limit of quantification (LOQ) was found to be 5 ng mL-1 based on 100 µL of plasma. The variations for intra- and inter-assay precision were <10%, and the accuracy values were ranged between 93.3 and 102.5%. The extraction recovery (R%) was >83%. The assay was successfully applied to an in vivo pharmacokinetic study of LNG in rats that were administered a single oral dose of 10 mg kg-1 LNG. The maximum concentration (Cmax) and the area under the plasma concentration-time curve (AUC0-72) were 927.5 ± 23.9 and 18,285.02 ± 605.76 ng mL-1, respectively.

Evaluation of Hepatoprotective Activity of Adansonia digitata Extract on Acetaminophen-Induced Hepatotoxicity in Rats.

The methanol extract of the fruit pulp of Adansonia digitata L. (Malvaceae) was examined for its hepatoprotective activity against liver damage induced by acetaminophen in rats. The principle depends on the fact that administration of acetaminophen will be associated with development of oxidative stress. In addition, hepatospecific serum markers will be disturbed. Treatment of the rats with the methanol extract of the fruit pulp of Adansonia digitata L. prior to administration of acetaminophen significantly reduced the disturbance in liver function. Liver functions were measured by assessment of total protein, total bilirubin, ALP, ALT, and AST. Oxidative stress parameter and antioxidant markers were also evaluated. Moreover, histopathological evaluation was performed in order to assess liver case regarding inflammatory infiltration or necrosis. Animals were observed for any symptoms of toxicity after administration of extract of the fruit pulp of Adansonia digitata L. to ensure safety of the fruit extract.

Anti-hyperglycaemic effect of Phragmenthera austroarabica A.G.Mill. & J.A.Nyberg extract in streptozotocin-induced diabetes in rats.

This study was undertaken to investigate the hypoglycaemic activity of Phragmenthera austroarabica A.G.Mill. & J.A.Nyberg extract and evaluate its possible antioxidant and anti-hyperlipidaemic effect in type 2 diabetic animal model. Type 2 diabetes was induced by a high-fat diet followed by injection with streptozotocin. Diabetic adult male Wistar rats were allocated into three groups and treated with pioglitazone HCl (PIO) or the extract of P. austroarabica A.G.Mill. & J.A.Nyberg (250 or 500 mg/kg b.wt.). In addition, a normal control group and a diabetic control group were used for comparison. Blood glucose, insulin resistance, oxidative stress parameter, antioxidant markers and serum lipids were evaluated. The extract of P. austroarabica A.G.Mill. & J.A.Nyberg exhibited a significant hypoglycaemia associated with antioxidant and anti-hyperlipidaemic effects in diabetic rats. The antioxidant activities are responsible, at least partly, for the improvements that have been noticed in hyperglycaemia and insulin resistance of diabetic rats. The extract revealed no symptoms of toxicity. It is concluded that this plant might be considered as an excellent candidate for future study on diabetes mellitus.

Circadian variations in exsorptive transport: in situ intestinal perfusion data and in vivo relevance.

The circadian timing system (CTS) governs the 24-h rhythm of the organism and, hence, also main pathways responsible for drug pharmacokinetics. P-glycoprotein (P-gp) is a drug transporter that plays a pivotal role in drug absorption, distribution, and elimination, and temporal changes in its activity may affect input, output, activity, and toxicity profile of drugs. In the current study, the influence of different circadian stages on the overall intestinal permeability (P(eff)) of the P-gp substrates talinolol and losartan was evaluated in in situ intestinal perfusion studies in rats. Additionally, in vivo studies in rats were performed by employing the P-gp probe talinolol during the day (nonactive) and night (active) period in rats. Effective intestinal permeabilities of talinolol and losartan were smaller in studies performed during the night (p < .05), indicating that P-gp-dependent intestinal secretion is greater during the nighttime activity span than daytime rest span of the animals. P-gp modulators vinblastine and PSC833 led to a significant decrease of talinolol and losartan exsorption in the intestinal segments as compared with control groups. Strikingly, the permeability-enhancing effect of vinblastine and PSC833 was higher with night perfusions, for both talinolol and losartan. In vivo studies performed with talinolol revealed-consistent with the in situ studies (P(eff) day > night)-a day vs. night difference in the oral availability of talinolol in the group of male rats in terms of the area under the curve (AUC) data (AUC(day) > AUC(night)). The P-gp modulator vinblastine significantly increased talinolol AUC(day) (p < .05), whereas only a weak vinblastine effect was seen in night. According to the in situ data, the functional activity of P-gp was regulated by the CTS in jejunum and ileum, which are major intestinal segments for energy-dependent efflux. In conclusion, circadian rhythms may affect carrier-mediated active efflux and play a role in the absorption process. In addition to daily rhythms in P-gp activity in rat intestine, the in vivo studies indicate that absorption-, distribution-, metabolism-, and elimination-relevant rhythms may be involved in the circadian kinetics of the drug, besides transporter-dependent efflux, such well-known aspects as metabolic or renal clearance or motility. Since this also holds true for a potentially interacting second compound (modulator), modulator effects should be evaluated carefully in transporter related drug-drug interactions.

Control of the myiasis-producing fly, Lucilia sericata, with Egyptian essential oils.

BACKGROUND: Myiasis caused by Lucilia sericata (Diptera: Calliphoridae) is widely distributed throughout the world and affects both humans and animals. In addition, L. sericata larvae and adults may play a role in spreading causal agents of mycobacterial infections. Therefore, it is important to establish new and safe alternative methods of controlling this blowfly. METHODS: The insecticidal effectiveness of four commercially available essential oils [lettuce (Lactuca sativa), chamomile (Matricaria chamomilla), anise (Pimpinella anisum), rosemary (Rosmarinus officinalis)] against third larval instars of L. sericata was evaluated. The effects of sublethal concentrations of these oils on pupation rates, adult emergences, sex ratios, and morphological anomalies were also determined. RESULTS: The oils were highly toxic to L. sericata larvae, with median lethal concentrations (LC(50) ) of 0.57%, 0.85%, 2.74%, and 6.77% for lettuce, chamomile, anise, and rosemary oils, respectively. Pupation rates were markedly decreased after treatment with 8% lettuce oil, and adult emergence was suppressed by 2% lettuce and chamomile oils. Morphological abnormalities were recorded after treatment with all tested oils, and lettuce was the major cause of deformation. There was a predominance of males over females (4 : 1) after treatment with lower concentrations of chamomile and rosemary; such a skew toward males would lead to a population decline. CONCLUSIONS: The four tested oils are inexpensive and may represent new botanical insecticides for controlling blowflies.