Endomysium determines active and passive force production in muscle fibers.

Connective tissues can be recognized as an important structural support element in muscles. Recent studies have also highlighted its importance in active force generation and transmission between muscles, particularly through the epimysium. In the present study, we aimed to investigate the impact of the endomysium, the connective tissue surrounding muscle fibers, on both passive and active force production. Pairs of skeletal muscle fibers were extracted from the extensor digitorum longus muscles of rats and, after chemical skinning, their passive and active force-length relationships were measured under two conditions: (i) with the endomysium between muscle fibers intact, and (ii) after its dissection. We found that the dissection of the endomysium caused force to significantly decrease in both active (by 22.2 % when normalized to the maximum isometric force; p < 0.001) and passive conditions (by 25.9 % when normalized to the maximum isometric force; p = 0.034). These findings indicate that the absence of endomysium compromises muscle fiber's not only passive but also active force production. This effect may be attributed to increased heterogeneity in sarcomere lengths, enhanced lattice spacing between myofilaments, or a diminished role of trans-sarcolemmal proteins due to dissecting the endomysium. Future investigations into the underlying mechanisms and their implications for various extracellular matrix-related diseases are warranted.

Role of parental smoking and environmental tobacco smoke exposure in childhood cancer: A study using hair cotinine analysis and questionnaires.

OBJECTIVES: In the etiology of childhood cancers, many genetic and environmental factors play a role. One of these factors could be cigarette smoking, and the main source of tobacco smoke exposure of children is parental smoking. However, establishing a causal relationship between parental smoking and childhood cancers has proven challenging due to difficulties in accurately detecting tobacco smoke exposure METHODS: To address this issue, we used hair cotinine analysis and a questionnaire to get information about tobacco smoke exposures of pediatric cancer patients and healthy children. A total of 104 pediatric cancer patients and 99 healthy children participated in our study. Parental smoking behaviors (pre-conceptional, during pregnancy, and current smoking) and environmental tobacco smoke (ETS) exposures of children are compared. RESULTS: We have found no differences between two groups by means of maternal smoking behaviors. However, the rates of paternal pre-conceptional smoking and smoking during pregnancy were significantly low in cancer patients (p < .05). These data suggest that social desirability bias among fathers of cancer patients may have contributed to this discrepancy. According to questionnaire, cancer patients had significantly lower ETS exposures than healthy children (p < .05). However, ETS exposure assessment through cotinine analysis demonstrated that cancer patients had higher exposure to ETS compared to healthy children (p < .001). CONCLUSION: Our findings provide evidence supporting the potential role of smoking as a risk factor for childhood cancers. This study also revealed that questionnaires could cause biases. We suggest that cotinine analysis along with validated questionnaires can be used to prevent biases in studies of tobacco smoke in the etiology of childhood cancers.

In silico approach reveals N-(5-phenoxythiophen-2-yl)-2-(arylthio)acetamides as promising selective SIRT2 inhibitors: the case of structural optimization of virtual screening-derived hits.

Epigenetic modifications play an essential role in tumor suppression and promotion. Among the diverse range of epigenetic regulators, SIRT2, a member of NAD+-dependent protein deacetylates, has emerged as a crucial regulator of cellular processes, including cell cycle progression, DNA repair, and metabolism, impacting tumor growth and survival. In the present work, a series of N-(5-phenoxythiophen-2-yl)-2-(arylthio)acetamide derivatives were identified following a structural optimization of previously reported virtual screening hits, accompanied by enhanced SIRT2 inhibitory potency. Among the compounds, ST44 and ST45 selectively inhibited SIRT2 with IC50 values of 6.50 and 7.24 µM, respectively. The predicted binding modes of the two compounds revealed the success of the optimization run. Moreover, ST44 displayed antiproliferative effects on the MCF-7 human breast cancer cell line. Further, the contribution of SIRT2 inhibition in this effect of ST44 was supported by western blotting, affording an increased α-tubulin acetylation. Furthermore, molecular dynamics (MD) simulations and binding free energy calculations using molecular mechanics/generalized born surface area (MM-GBSA) method evaluated the accuracy of predicted binding poses and ligand affinities. The results revealed that ST44 exhibited a remarkable level of stability, with minimal deviations from its initial docking conformation. These findings represented a significant improvement over the virtual screening hits and may contribute substantially to our knowledge for further selective SIRT2 drug discovery.Communicated by Ramaswamy H. Sarma.

How mechanics of individual muscle-tendon units define knee and ankle joint function in health and cerebral palsy-a narrative review.

This study reviews the relationship between muscle-tendon biomechanics and joint function, with a particular focus on how cerebral palsy (CP) affects this relationship. In healthy individuals, muscle size is a critical determinant of strength, with muscle volume, cross-sectional area, and moment arm correlating with knee and ankle joint torque for different isometric/isokinetic contractions. However, in CP, impaired muscle growth contributes to joint pathophysiology even though only a limited number of studies have investigated the impact of deficits in muscle size on pathological joint function. As muscles are the primary factors determining joint torque, in this review two main approaches used for muscle force quantification are discussed. The direct quantification of individual muscle forces from their relevant tendons through intraoperative approaches holds a high potential for characterizing healthy and diseased muscles but poses challenges due to the invasive nature of the technique. On the other hand, musculoskeletal models, using an inverse dynamic approach, can predict muscle forces, but rely on several assumptions and have inherent limitations. Neither technique has become established in routine clinical practice. Nevertheless, identifying the relative contribution of each muscle to the overall joint moment would be key for diagnosis and formulating efficient treatment strategies for patients with CP. This review emphasizes the necessity of implementing the intraoperative approach into general surgical practice, particularly for joint correction operations in diverse patient groups. Obtaining in vivo data directly would enhance musculoskeletal models, providing more accurate force estimations. This integrated approach can improve the clinicians' decision-making process and advance treatment strategies by predicting changes at the muscle and joint levels before interventions, thus, holding the potential to significantly enhance clinical outcomes.

Detecting age-related changes in skeletal muscle mechanics using ultrasound shear wave elastography.

Aging leads to a decline in muscle mass and force-generating capacity. Ultrasound shear wave elastography (SWE) is a non-invasive method to capture age-related muscular adaptation. This study assessed biceps brachii muscle (BB) mechanics, hypothesizing that shear elastic modulus reflects (i) passive muscle force increase imposed by length change, (ii) activation-dependent mechanical changes, and (iii) differences between older and younger individuals. Fourteen healthy volunteers aged 60-80 participated. Shear elastic modulus, surface electromyography, and elbow torque were measured at five elbow positions in passive and active states. Data collected from young adults aged 20-40 were compared. The BB passive shear elastic modulus increased from flexion to extension, with the older group exhibiting up to 52.58% higher values. Maximum elbow flexion torque decreased in extended positions, with the older group 23.67% weaker. Significant effects of elbow angle, activity level, and age on total and active shear elastic modulus were found during submaximal contractions. The older group had 20.25% lower active shear elastic modulus at 25% maximum voluntary contraction. SWE effectively quantified passive and activation-dependent BB mechanics, detecting age-related alterations at rest and during low-level activities. These findings suggest shear elastic modulus as a promising biomarker for identifying altered muscle mechanics in aging.

Effects of pyrrolopyrimidine derivatives on cancer cells cultured in vitro and potential mechanism.

In this study, the anticancer activities of some pyrrolopyrimidine derivatives were evaluated. Compound 3 is the most cytotoxic compound on MCF-7 cancer cells with an IC50 value of 23.42 µM. Also, compound 3 induced apoptosis and the ROS(+) cell population in MCF-7 cells. Moreover, it significantly reduced MMP-9 activity, having 42.16 ± 5.10% and 58.28 ± 1.96% inhibitory activities at 10 µM and 50 µM concentrations, respectively. Molecular docking results supported the activity, showing key hydrogen bonds with the binding site of MMP-9. Therefore, compound 3 might be a lead compound for the development of potent MMP-9 inhibitors.

Cuproptosis as the new kryptonite of cancer: a copper-dependent novel cell death mechanism with promising implications for the treatment of hepatocellular carcinoma.

Copper is an essential element for critical cellular functions such as mitochondrial respiration, cholesterol biosynthesis and immune response. Altered copper homeostasis has been associated with various disorders, including cancer. The copper overload is known to contribute to tumorigenesis, angiogenesis and metastasis, and recently it has been suggested that the elevated level of this element may also create vulnerability to a novel cell death mechanism, named cuproptosis. Excessive amount of copper in mitochondria binds to lipoylated enzymes of the TCA cycle and forms insoluble oligomers. The aggregation of these oligomers and subsequent iron-sulfur cluster protein loss results in proteotoxic stress and eventual cell death. Hepatocellular carcinoma is a common malignancy with a low survival rate, despite the available treatment options. The discovery of cuproptosis led many researchers to explore its potential use in hepatocellular cancer therapy due to the rich mitochondria content of hepatic cells. In this regard, a number of genomic studies were conducted to discover several cuproptosis-related genes and explored their association with prognosis, survival and immunotherapy response. This review brings together the available data on the relationship between cuproptosis and hepatocellular cancer for the first time, and highlights some of the potential biomarkers or target molecules that may be useful in the treatment.

Alpha-lipoic acid induced apoptosis of PC3 prostate cancer cells through an alteration on mitochondrial membrane depolarization and MMP-9 mRNA expression.

Cancer has become an important cause of mortality and morbidity in the world. Over the past decades, biomedical research revealed insights into the molecular events and signaling pathways involved in carcinogenesis and cancer progression. Matrix metalloproteinases (MMPs) are a diverse family of enzymes that can degrade various components of the extracellular matrix and are considered as potential diagnostic and prognostic biomarkers for many cancer types and cancer stages. Recently, studies on the role of natural-origin active substances in the prevention of cancer development gained importance. Among them, the α-lipoic acid, which is commonly found in plants, displayed potent anti-proliferative effects on cancer cell lines. However, the effect of the compound on the induction of apoptosis and mRNA expression of MMPs in human prostate cancer cells remains unclear. The present study aimed to evaluate the anti-proliferative and apoptotic activity of α-lipoic acid in human PC3 prostate carcinoma cells considering different concentrations and exposure durations. The findings showed that, α-lipoic acid significantly decreased PC3 cell viability with an IC50 value of 1.71 mM at 48 h (p < 0.05). Additionally, the compound significantly increased Annexin-V binding in cells compared to control and induced a significant alteration in mitochondrial membrane potential and caspase levels (p < 0.05). Furhermore, the RT-PCR analyses have revealed that α-lipoic acid reduced MMP-9 mRNA expression in PC3 cells compared to the control (p < 0.05). In conclusion, this study highlights that α-lipoic acid induced apoptosis in human PC3 prostate cancer cells and inhibited the MMP-9 gene at the mRNA level, which is known to play a role in metastasis development.

The five Ferulago species inhibited cell proliferation and induced apoptosis of A549, MCF-7, PC3 and SW480 cancer cells in vitro.

In this study, it was aimed to evaluate the cytotoxic and apoptotic activities of ethanolic extracts prepared from the roots of 5 Ferulago species [F. humilis Boiss., F. macrosciadia Boiss. & Balansa, F. sandrasica Pesmen & Quézel, F. silaifolia (Boiss.) Boiss., F. trojana Akalin & Pimenov] on various human cancer cell lines. The cytotoxicity analyses against human lung (A549), breast (MCF-7), prostate (PC3) and colon (SW480) cancer cell lines were determined by MTT test; while the apoptotic effect was evaluated by Annexin V binding assay. All studied extracts showed concentration-dependent cytotoxic activity with an IC50 value ranging from 0.416 to 5.336 mg/mL. The studied Ferulago species significantly induced apoptosis of cancer cells, while F. macrosciadia had the highest apoptotic activity on MCF-7 cells with 21.79 ± 1.63% apoptotic cell population (p < 0.0001). In addition, felamedin and prantschimgin content of the extracts, which are common coumarins in Ferulago species, were evaluated by HPLC. According to HPLC analysis, the highest amount of felamedin content was found in F. trojana, while the highest content of prantschimgin was found in F. sandrasica among the studied Ferulago species. This preliminary research has revealed that the studied Ferulago species have promising effects on various cancer cell lines. Further studies are planned to determine the compounds responsible for the effect and underlying mechanism.

Quantifying the effects of achilles tendon lengthening surgery: An intraoperative approach.

Achilles tendon lengthening (ATL) is frequently used in the treatment of foot deformities. However, there is currently no objective method to determine the optimal muscle length during surgery. We developed an intraoperative approach to evaluate the passive and active forces of the triceps surae muscle group before and after ATL and aimed to test the following hypotheses: 1) the ankle passive range of motion (ROM) increases, 2) passive muscle forces decrease post-ATL, and 3) forces measured from patients with non-neurological and neurological conditions demonstrate different characteristics. Passive forces at various ankle joint positions were measured in ten patients (11.3 ± 3.0 years old) pre- and post-ATL using a force transducer attached to the Achilles tendon. In six patients, active isometric forces were measured by stimulating the triceps surae supramaximally. Passive forces decreased by 94.3% (p < 0.0001), and ROM increased by 89.4% (p < 0.0001) post-ATL. The pre-ATL passive forces were 70.8% ± 15.1% lower in patients with idiopathic foot deformities than in patients with neurological conditions (p < 0.001). The peak active force of 209.8 ± 114.3 N was achieved at an ankle angle of 38.3° ± 16.0°, where the passive force was 6.3 ± 6.7 N. The inter-individual variability was substantial in both groups. In conclusion, the hypotheses posed were supported. The present findings suggest that muscle passive and active force production as well as the inter-individual variability should be considered when planning further treatment.

Mitochondrial transplantation: Effects on chemotherapy in prostate and ovarian cancer cells in vitro and in vivo.

Prostate and ovarian cancers affect the male and female reproductive organs and are among the most common cancers in developing countries. Previous studies have demonstrated that cancer cells have a high rate of aerobic glycolysis that is present in nearly all invasive human cancers and persists even under normoxic conditions. Aerobic glycolysis has been correlated with chemotherapeutic resistance and tumor aggressiveness. These data suggest that mitochondrial dysfunction may confer a significant proliferative advantage during the somatic evolution of cancer. In this study we investigated the effect of direct mitochondria transplantation on cancer cell proliferation and chemotherapeutic sensitivity in prostate and ovarian cancer models, both in vitro and in vivo. Our results show that the transplantation of viable, respiration competent mitochondria has no effect on cancer cell proliferation but significantly decreases migration and alters cell cycle checkpoints. Our results further demonstrate that mitochondrial transplantation significantly increases chemotherapeutic sensitivity, providing similar apoptotic levels with low-dose chemotherapy as that achieved with high-dose chemotherapy. These results suggest that mitochondria transplantation provides a novel approach for early prostate and ovarian cancer therapy, significantly increasing chemotherapeutic sensitivity in in vitro and in vivo murine models.

Characterization of Muscle Weakness Due to Myasthenia Gravis Using Shear Wave Elastography.

Myasthenia gravis (MG) is often accompanied with muscle weakness; however, little is known about mechanical adaptions of the affected muscles. As the latter can be assessed using ultrasound shear wave elastography (SWE), this study characterizes the biceps brachii muscle of 11 patients with MG and compares them with that of 14 healthy volunteers. Simultaneous SWE, elbow torque and surface electromyography measurements were performed during rest, maximal voluntary contraction (MVC) and submaximal isometric contractions (up to 25%, 50% and 75% MVC) at different elbow angles from flexion to extension. We found that, with increasing elbow angle, maximum elbow torque decreased (p < 0.001), whereas muscle stiffness increased during rest (p = 0.001), MVC (p = 0.004) and submaximal contractions (p < 0.001). Muscle stiffness increased with increasing contraction intensities during submaximal contractions (p < 0.001). In comparison to the healthy cohort, muscle stiffness of MG patients was 2.1 times higher at rest (p < 0.001) but 8.93% lower in active state (75% MVC, p = 0.044). We conclude that (i) increased muscle stiffness shown by SWE during rest might be an indicator of MG, (ii) SWE reflects muscle weakness and (iii) SWE can be used to characterize MG muscle.

Etoposide in combination with erastin synergistically altered iron homeostasis and induced ferroptotic cell death through regulating IREB2/FPN1 expression in estrogen receptor positive-breast cancer cells.

AIM: Ferroptosis is an iron-dependent cell death mechanism that substantially differs from apoptosis. Since its mechanism involves increased oxidative stress and rich iron content, cancer cells are particularly vulnerable to ferroptotic death compared to healthy tissues. In the present study, the effect of etoposide in combination with a ferroptotic agent, erastin, was investigated in breast cancer. MAIN METHODS: Cell viability was assessed by the MTT assay. Oxidative stress, lipid peroxidation and glutathione peroxidase activity were detected using the relevant kits. Intracellular iron levels were measured by HPLC. Ferroptosis markers were explored by western blotting. KEY FINDINGS: Results demonstrated that although etoposide didn't induce a significant cell death up to 50 µM in MCF-7 cells, with the addition of erastin, a significant synergistic activity was achieved at a dose as low as 1 µM (p < 0.05), contrary to normal breast epithelial cells. This cytotoxic effect was blocked by ferrostatin-1, which is a specific inhibitor of ferroptosis. The combined treatment of etoposide and erastin synergistically induced oxidative stress and lipid peroxidation, while suppressing glutathione peroxidase activity. More importantly, the combination treatment synergistically increased iron accumulation, which was associated with altered expression of IREB2/FPN1. Additionally, ferroptosis-regulating proteins ACSF2 and GPX4 were altered more potently by the combination treatment, compared to untreated cells and erastin treatment alone (p < 0.05). SIGNIFICANCE: In conclusion, this is the first study that reports enhanced cytotoxicity of etoposide, in combination with erastin, in ER-positive breast cancer cells via activation of ferroptotic pathways, and offers a new perspective for future regimens.

Shear wave elastography characterizes passive and active mechanical properties of biceps brachii muscle in vivo.

Mechanical characterization of individual muscles in their in vivo environment is not well studied. Shear wave elastography (SWE) as a non-invasive technique was shown to be promising in quantifying the local mechanical properties of skeletal muscles. This study aimed to investigate the mechanics of the biceps brachii muscle (BB) derived from SWE in relation to elbow joint position and contraction intensity during isometric contraction. 14 healthy, young subjects participated in the study and five different joint positions (60°-180° elbow angle) were investigated. Shear elastic modulus and surface electromyography (sEMG) of the BB and elbow torque were measured simultaneously, both in passive (i.e., resting) and active states during slow, sub-maximal isometric ramp contractions up to 25%, 50%, and 75% of the maximum voluntary contraction. At passive state, the shear elastic modulus of the BB increased with increasing elbow angle (p < 0.001). Maximum elbow flexion torque was produced at 60° and it decreased with increasing elbow angle (p = 0.001). During sub-maximal contractions, both elbow angle (p < 0.001) and contraction intensity (p < 0.001) had significant effects on the shear elastic modulus but only contraction intensity (p < 0.001) affected sEMG amplitude of the BB. Although torque was decreased at extended elbow positions (150°, 180°), higher active shear elastic modulus of BB muscle was found compared to flexed positions (60°, 90°). Linear regression of the BB sEMG amplitude over elbow torque showed good agreement for all joint positions (R2 between 0.69 and 0.89) while the linear agreement between shear elastic modulus of BB and elbow torque differed between flexed (R2 = 0.70 at 60° and R2 = 0.79 at 90°) and extended positions (with the lowest R2 = 0.57 at 150°). We conclude that using SWE, we can detect length-dependent mechanical changes of BB both in passive and active states. More importantly, SWE can be used to characterize active muscle properties in vivo. The present findings have critical importance for developing muscle stiffness as a measure of individual muscle force to validate muscle models and using SWE in clinical diagnostics.

Investigation on formulation parameters of donepezil HCl loaded solid lipid nanoparticles

Abstract Donepezil-HCl is a member of the acetylcholinesterase inhibitors that is indicated for the symptomatic treatment of Alzheimer's disease (AD) and has many side effects. In this study, to reduce the side effects of Donepezil-HCl and increase the penetration of the drug through the blood-brain barrier, we aimed to design a solid lipid nanoparticle (SLN) formulation. The effects of the different formulation parameters, such as homogenization speed, sonication time, lipid and drug concentration, surfactant type and concentration, and volume of the aqueous phase, were assessed for optimization. The particle size and PDI increased with increasing lipid concentration but decreased with increasing amounts of surfactant (Tween 80) and co-surfactant (lecithin). When the homogenization rate and sonication time increased, the particle size decreased and the encapsulation efficiency increased. The optimized formulation exhibited particle size, PDI, encapsulation efficiency, and zeta potential of 87.2±0.11 nm; 0.22±0.02; 93.84±0.01 %; -17.0±0.12 mV respectively. The in vitro release investigation revealed that approximately 70% of Donepezil-HCl was cumulatively released after 24 hours. TEM analysis proved that spherical and smooth particles were obtained and formulations had no toxic effect on cells. The final optimized formulation could be a candidate for Donepezil-HCl application in Alzheimer's treatment with reduced side effects and doses for patients

Atorvastatin induces downregulation of matrix metalloproteinase-2/9 in MDA-MB-231 triple negative breast cancer cells.

Matrix metalloproteinases (MMPs) are a family of endopeptidases, mainly responsible of extracellular tissue remodeling. Abundant expression of MMPs leads to a number of tumorigenic processes including proliferation, angiogenesis, metastasis and invasion. Therefore, suppressing MMP expression is particularly important in cancer. Atorvastatin is a member of statin family, with cholesterol-lowering properties. Recently, it has emerged as a potential anticancer agent. Multiple researchers have reported promising results of atorvastatin use in cancer therapies. However, its effect on the expression of matrix metalloproteinases in breast cancer is unknown. In the present study, we have confirmed the apoptotic activity of atorvastatin on highly metastatic MDA-MB-231 triple negative breast cancer cells and investigated the gene expression of MMP-2/9. In this regard, MTT analysis was performed to evaluate cytotoxicity. Apoptotic activity was assessed by Annexin V binding and multicaspase assays. Western blot analysis was used to detect the apoptosis-related proteins. RT-PCR analysis was performed to evaluate the mRNA expression levels of MMP-2/9. Results indicated that atorvastatin reduces cell viability significantly at 5 µM after 48 h of treatment (p < 0.0001). It also induces caspase-dependent apoptosis, alters the expression of Bax and Bcl-2 in favour of apoptosis and stimulates cell cycle arrest at S phase (p < 0.05). Moreover, atorvastatin downregulates the mRNA expression of MMP-2 and MMP-9 significantly (p < 0.05). In conclusion, these results demonstrate for the first time that atorvastatin inhibits MMP-2 and MMP-9 gene expression in MDA-MB-231 cells, in addition to inducing caspase-dependent apoptosis.

Botulinum Toxin Intervention in Cerebral Palsy-Induced Spasticity Management: Projected and Contradictory Effects on Skeletal Muscles.

Spasticity, following the neurological disorder of cerebral palsy (CP), describes a pathological condition, the central feature of which is involuntary and prolonged muscle contraction. The persistent resistance of spastic muscles to stretching is often followed by structural and mechanical changes in musculature. This leads to functional limitations at the respective joint. Focal injection of botulinum toxin type-A (BTX-A) is effectively used to manage spasticity and improve the quality of life of the patients. By blocking acetylcholine release at the neuromuscular junction and causing temporary muscle paralysis, BTX-A aims to reduce spasticity and hereby improve joint function. However, recent studies have indicated some contradictory effects such as increased muscle stiffness or a narrower range of active force production. The potential of these toxin- and atrophy-related alterations in worsening the condition of spastic muscles that are already subjected to changes should be further investigated and quantified. By focusing on the effects of BTX-A on muscle biomechanics and overall function in children with CP, this review deals with which of these goals have been achieved and to what extent, and what can await us in the future.

Box-Behnken design optimization and in vitro cell based evaluation of piroxicam loaded core-shell type hybrid nanocarriers for prostate cancer.

In the present research, piroxicam entrapped core-shell lipid-polymer hybrid nanocarriers were developed and also evaluated in terms of nanoparticle features and cell-based in vitro efficacy on prostate cancer cells. Box-Behnken optimization approach was implemented to evaluate the impact of the input variables, namely phospholipid/PLGA ratio, total lipids/lecithin molar ratio, and piroxicam concentration, on two output variables: particle size and entrapment efficiency. Surface charge, size distribution, morphological structure of particles, drug release profiles, presence of outer lipid shell, thermal profile and possible interactions and storage stability of core-shell nanocarriers of piroxicam were studied as particle features. Cell viability, apoptosis and cell cycle arrest studies were utilized for in vitro cell-based evaluation of the core-shell nanosystems. The hybrid nanocarrier formulation with a particle size of 119.2 nm and an entrapment efficiency of 91.7% at the center point of the design was selected as the optimized formulation according to the desired function (d) method applied within the scope of the Box-Behnken design approach and RSM strategy. The cell viability and apoptosis experiments were performed on the optimized nanocarrier. In conclusion, this study demonstrates that the optimized core-shell nanoformulation of piroxicam is a more promising strategy in the treatment of prostate cancer compared to the pure molecule.

Procedures for obtaining muscle physiology parameters during a gracilis free-functioning muscle transfer in adult patients with brachial plexus injury.

A complete understanding of muscle mechanics allows for the creation of models that closely mimic human muscle function so they can be used to study human locomotion and evaluate surgical intervention. This includes knowledge of muscle-tendon parameters required for accurate prediction of muscle forces. However, few studies report experimental data obtained directly from whole human muscle due to the invasive nature of these experiments. This article presents an intraoperative, in vivo measurement protocol for whole muscle-tendon parameters that include muscle-tendon unit length, sarcomere length, passive tension, and active tension in response to external stimulation. The advantage of this protocol is the ability to obtain these rare experimental data in situ in addition to muscle volume and weight since the gracilis is also completely removed from the leg. The entire protocol including the surgical steps for gracilis harvest takes ~ 3 h. Actual testing of the gracilis where experimental data is measured takes place within a 30-min window during surgery.

Hit evaluation results in 5-benzyl-1,3,4-thiadiazole-2-carboxamide based SIRT2-selective inhibitor with improved affinity and selectivity.

Sirtuin 2 (SIRT2), member of sirtuin family, belongs to class III histone deacetylases (HDACs) and is majorly cytosolic with occasional nuclear translocation. The enzymatic activity of SIRT2 is dependent on nicotinamide adenine dinucleotide (NAD+) and SIRT2 regulates post-translational modifications that are responsible for deacetylation of lysine residues in histone and non-histone substrates. SIRT2, thus affects most likely multiple cellular processes, such as signaling, gene expression, aging, autophagy, and has been identified as potential drug target in relation to inflammation, neurodegenerative diseases and cancer. Therefore, probing potential selective inhibitors is essential for the accurate understanding of enzyme functions. Here, we report a series of heteroaryl-2-carboxamide hybrids bearing substituted benzyl or substituted phenoxy group at the 5-position of the central heterocyclic ring. The synthesized compounds were screened against SIRT1-3 and MCF-7 human breast cancer cell line to evaluate their biological activity. The best SIRT2 inhibition profiles were displayed by ST29 (SIRT2 IC50 = 38.69 µM) and ST30 (SIRT2 IC50 = 43.29 µM) with excellent selectivity against SIRT2 over SIRT1 and SIRT3. Molecular docking study of the synthesized compounds into SIRT2 active site was performed to rationalize the remarkable SIRT2 inhibitory activity. Furthermore, we performed all-atom, explicit-solvent molecular dynamics (MD) simulations and end-point binding free energy calculations using molecular mechanics/generalized Born surface area (MM/GBSA) method to evaluate whether this design strategy was successfully deployed. The results implied that the binding poses and ligand affinities were predicted without significant loss of accuracy. Conclusively, the developed chemotypes were advocated as promising leads for SIRT2 inhibition and required further investigation for SIRT2-targeted drug discovery and development.