A novel treatment strategy targeting cellular pathways with natural products to alleviate sarcopenia.

Sarcopenia is a condition marked by a significant reduction in muscle mass and strength, primarily due to the aging process, which critically impacts muscle protein dynamics, metabolic functions, and overall physical functionality. This condition leads to increased body fat and reduced daily activity, contributing to severe health issues and a lower quality of life among the elderly. Recognized in the ICD-10-CM only in 2016, sarcopenia lacks definitive treatment options despite its growing prevalence and substantial social and economic implications. Given the aging global population, addressing sarcopenia has become increasingly relevant and necessary. The primary causes include aging, cachexia, diabetes, and nutritional deficiencies, leading to imbalances in protein synthesis and degradation, mitochondrial dysfunction, and hormonal changes. Exercise remains the most effective intervention, but it is often impractical for individuals with limited mobility, and pharmacological options such as anabolic steroids and myostatin inhibitors are not FDA-approved and are still under investigation. This review is crucial as it examines the potential of natural products as a novel treatment strategy for sarcopenia, targeting multiple mechanisms involved in its pathogenesis. By exploring natural products' multi-targeted effects, this study aims to provide innovative and practical solutions for sarcopenia management. Therefore, this review indicates significant improvements in muscle mass and function with the use of specific natural compounds, suggesting promising alternatives for those unable to engage in regular physical activity.

Inhibition of mTORC1 through ATF4-induced REDD1 and Sestrin2 expression by Metformin.

BACKGROUND: Although the major anticancer effect of metformin involves AMPK-dependent or AMPK-independent mTORC1 inhibition, the mechanisms of action are still not fully understood. METHODS: To investigate the molecular mechanisms underlying the effect of metformin on the mTORC1 inhibition, MTT assay, RT-PCR, and western blot analysis were performed. RESULTS: Metformin induced the expression of ATF4, REDD1, and Sestrin2 concomitant with its inhibition of mTORC1 activity. Treatment with REDD1 or Sestrin2 siRNA reversed the mTORC1 inhibition induced by metformin, indicating that REDD1 and Sestrin2 are important for the inhibition of mTORC1 triggered by metformin treatment. Moreover, REDD1- and Sestrin2-mediated mTORC1 inhibition in response to metformin was independent of AMPK activation. Additionally, lapatinib enhances cell sensitivity to metformin, and knockdown of REDD1 and Sestrin2 decreased cell sensitivity to metformin and lapatinib. CONCLUSIONS: ATF4-induced REDD1 and Sestrin2 expression in response to metformin plays an important role in mTORC1 inhibition independent of AMPK activation, and this signalling pathway could have therapeutic value.

Lysine is required for growth factor-induced mTORC1 activation.

Mechanistic target of rapamycincomplex 1 (mTORC1) integrates various environmental signals to regulate cell growth and metabolism. mTORC1 activity is sensitive to changes in amino acid levels. Here, we investigated the effect of lysine on mTORC1 activity in non-small cell lung cancer (NSCLC) cells. Lysine deprivation suppressed mTORC1 activity and lysine replenishment restored the decreased mTORC1 activity in lysine-deprived cells. Supplementing growth factors, such as insulin growth factor-1 or insulin restored the decreased mTORC1 activity in serum-deprived cells. However, in serum/lysine-deprived cells, supplementing growth factors was not sufficient to restore mTORC1 activity, suggesting thatgrowth factors could not activate mTORC1 efficiently in the absence of lysine. General control nonderepressible 2 and AMP-activated protein kinase were involved in lysine deprivation-mediated inhibition of mTORC1. Taken together, these results suggest that lysine might play role in the regulation of mTORC1 activation in NSCLC cells.

Flavanonol taxifolin attenuates proteasome inhibition-induced apoptosis in differentiated PC12 cells by suppressing cell death process.

The proteasomal dysfunction and mitochondrial impairment has been implicated in neuronal degeneration. Taxifolin has antioxidant and anti-inflammatory effects. However, the effect of taxifolin on the neuronal cell death induced by proteasome inhibition has not been studied. Therefore, in the respect of cell death process, we assessed the effect of taxifolin on the proteasome inhibition-induced apoptosis in neuronal cell injury using differentiated PC12 cells. The proteasome inhibitors MG132 and MG115 induced a decrease in Bid, Bcl-2, and survivin protein levels, an increase in Bax, loss of the mitochondrial transmembrane potential, cytochrome c release, activation of caspases(-8, -9 and -3), an increase in the tumor suppressor p53 levels and cleavage of PARP-1. The addition of taxifolin attenuated the proteasome inhibitor-induced changes in the apoptosis-related protein levels, formation of reactive oxygen species, depletion and oxidation of GSH, formations of malondialdehyde and carbonyls, and cell death. The results show that taxifolin may attenuate the proteasome inhibitor-induced apoptosis in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The preventive effect of taxifolin appears to be attributed to its inhibitory effect on the formation of reactive oxygen species, and depletion and oxidation of GSH.

3,4,5-Tricaffeoylquinic Acid Attenuates TRAIL-induced Apoptosis in Human Keratinocytes by Suppressing Apoptosis-related Protein Activation.

Caffeoyl derivatives exhibit antiinflammatory and antioxidant effects. However, the effect of 3,4,5-tricaffeoylquinic acid on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in keratinocytes that may be involved in skin diseases has not been studied. In this respect, we investigated the effect of 3,4,5-tricaffeoylquinic acid on TRAIL-induced apoptosis in human keratinocytes. 3,4,5-Tricaffeoylquinic acid and oxidant scavengers attenuated the decrease in the cytosolic levels of Bid, Bcl-2, and survivin proteins; the increase in the levels of cytosolic Bax, p53, and phosphorylated p53; the increase in the levels of phosphorylated p38; the increase in the mitochondrial levels of the voltage-dependent anion channel; loss of the mitochondrial transmembrane potential; the release of cytochrome c; activation of caspases (8, 9, and 3); cleavage of poly [ADP-ribose] polymerase-1; production of reactive oxygen species; the depletion of glutathione (GSH); nuclear damage; and cell death in keratinocytes treated with TRAIL. These results suggest that 3,4,5-tricaffeoylquinic acid may reduce TRAIL-induced apoptosis in human keratinocytes by suppressing the activation of the caspase-8 and Bid pathways and the mitochondria-mediated cell death pathway. The effect appears to be associated with the inhibitory effect on the production of reactive oxygen species and depletion of GSH. 3,4,5-Tricaffeoylquinic acid appears to be effective in the prevention of TRAIL-induced apoptosis-mediated skin diseases.

3,4,5-tricaffeoylquinic acid attenuates proteasome inhibition-mediated programmed cell death in differentiated PC12 cells.

The dysfunction of the proteasome system is suggested to be implicated in neuronal degeneration. Caffeoylquinic acid derivatives have demonstrated anti-oxidant and anti-inflammatory effects. However, the effect of 3,4,5-tricaffeoylquinic acid on the neuronal cell death induced by proteasome inhibition has not been studied. Therefore, in the respect of cell death process, we assessed the effect of 3,4,5-tricaffeoylquinic acid on the proteasome inhibition-induced programmed cell death using differentiated PC12 cells. The proteasome inhibitors MG132 and MG115 induced a decrease in Bid, Bcl-2, and survivin protein levels, an increase in Bax, loss of the mitochondrial transmembrane potential, cytochrome c release, activation of caspases (-8, -9 and -3), and an increase in the tumor suppressor p53 levels. Treatment with 3,4,5-tricaffeoylquinic acid attenuated the proteasome inhibitor-induced changes in the programmed cell death-related protein levels, formation of reactive oxygen species, GSH depletion and cell death. The results show that 3,4,5-tricaffeoylquinic acid may attenuate the proteasome inhibitor-induced programmed cell death in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The preventive effect of 3,4,5-tricaffeoylquinic acid appears to be attributed to its inhibitory effect on the formation of reactive oxygen species and depletion of GSH.

Adverse health correlates of intimate partner violence against older women: Mining electronic health records.

Intimate partner violence (IPV) is often studied as a problem that predominantly affects younger women. However, studies show that older women are also frequently victims of abuse even though the physical effects of abuse are harder to detect. In this study, we mined the electronic health records (EHR) available through IBM Explorys to identify health correlates of IPV that are specific to older women. Our analyses suggested that diagnostic terms that are co-morbid with IPV in older women are dominated by substance abuse and associated toxicities. When we considered differential co-morbidity, i.e., terms that are significantly more associated with IPV in older women compared to younger women, we identified terms spanning mental health issues, musculoskeletal issues, neoplasms, and disorders of various organ systems including skin, ears, nose and throat. Our findings provide pointers for further investigation in understanding the health effects of IPV among older women, as well as potential markers that can be used for screening IPV.

Collagen Peptide Exerts an Anti-Obesity Effect by Influencing the Firmicutes/Bacteroidetes Ratio in the Gut.

Alterations in the intestinal microbial flora are known to cause various diseases, and many people routinely consume probiotics or prebiotics to balance intestinal microorganisms and the growth of beneficial bacteria. In this study, we selected a peptide from fish (tilapia) skin that induces significant changes in the intestinal microflora of mice and reduces the Firmicutes/Bacteroidetes ratio, which is linked to obesity. We attempted to verify the anti-obesity effect of selected fish collagen peptides in a high-fat-diet-based obese mouse model. As anticipated, the collagen peptide co-administered with a high-fat diet significantly inhibited the increase in the Firmicutes/Bacteroidetes ratio. It increased specific bacterial taxa, including Clostridium_sensu_stricto_1, Faecalibaculum, Bacteroides, and Streptococcus, known for their anti-obesity effects. Consequently, alterations in the gut microbiota resulted in the activation of metabolic pathways, such as polysaccharide degradation and essential amino acid synthesis, which are associated with obesity inhibition. In addition, collagen peptide also effectively reduced all obesity signs caused by a high-fat diet, such as abdominal fat accumulation, high blood glucose levels, and weight gain. Ingestion of collagen peptides derived from fish skin induced significant changes in the intestinal microflora and is a potential auxiliary therapeutic agent to suppress the onset of obesity.

Inhibition of AKT Enhances the Sensitivity of NSCLC Cells to Metformin.

BACKGROUND/AIM: Metformin is an antidiabetic drug that has been reported to have antitumor activity in many cancer types. This study investigated the molecular mechanisms underlying the antitumor effect of metformin. MATERIALS AND METHODS: We investigated the molecular mechanism of the antitumor effect of metformin alone and in combination with AKT serine/threonine kinase (AKT) inhibition via cell viability and western blot analyses. RESULTS: Notably, metformin increased the phosphorylation of AKT at serine 473 using protein array screening. Metformin-induced AKT activation was markedly suppressed by siRNA targeting activating transcription factor 4 (ATF4) but not AMP-activated protein kinase α. These results indicate that AKT activation by metformin was induced in an ATF4-dependent and AMPKα-independent manner. Treatment using metformin combined with MK-2206, an AKT inhibitor, or a siRNA for AKT markedly reduced the viability of cells compared with those cells treated with these agents alone. In addition, MK-2206 increased cell sensitivity to the combination of metformin with ionizing radiation or cisplatin. CONCLUSION: Inhibition of AKT can enhance the antitumor effect of metformin and would be a promising strategy to sensitize non-small-cell lung cancer to a combination of metformin with radiation or cisplatin.

Increased O-GlcNAcylation of c-Myc Promotes Pre-B Cell Proliferation.

O-linked ß-N-acetylglucosamine (O-GlcNAc) modification regulates the activity of hundreds of nucleocytoplasmic proteins involved in a wide variety of cellular processes, such as gene expression, signaling, and cell growth; however, the mechanism underlying the regulation of B cell development and function by O-GlcNAcylation remains largely unknown. Here, we demonstrate that changes in cellular O-GlcNAc levels significantly affected the growth of pre-B cells, which rapidly proliferate to allow expansion of functional clones that express successfully rearranged heavy chains at the pro-B stage during early B cell development. In our study, the overall O-GlcNAc levels in these proliferative pre-B cells, which are linked to the glucose uptake rate, were highly induced when compared with those in pro-B cells. Thus, pharmacologically, genetically, or nutritionally, inhibition of O-GlcNAcylation in pre-B cells markedly downregulated c-Myc expression, resulting in cell cycle arrest via blockade of cyclin expression. Importantly, the population of B cells after the pro-B cell stage in mouse bone marrow was severely impaired by the administration of an O-GlcNAc inhibitor. These results strongly suggest that O-GlcNAcylation-dependent expression of c-Myc represents a new regulatory component of pre-B cell proliferation, as well as a potential therapeutic target for the treatment of pre-B cell-derived leukemia.

Synthesis of monodisperse starch microparticles through molecular rearrangement of short-chain glucans from natural waxy maize starch.

Here, we report a sustainable approach for the synthesis of starch-based microparticles with well-defined shape and size through molecular self-assembly of short-chain glucan (SCG) obtained enzymatically from waxy maize starch. We employed chitosan as a steric stabilizer to modulate the nucleation process, which significantly reduced undesirable aggregations during the nucleation and growth phases, resulting in the production of highly monodisperse microparticles. The size of chitosan-assisted starch microparticles (CS-SMPs) was effectively controlled by the concentration of debranching enzyme as well as by debranching time, of which the factors influencing the final size were investigated. By modulating the rate and time of debranching reaction in combination with the steric stabilizing effect of chitosan, we were able to prepare highly monodisperse CS-SMPs from 200 nm to 5 µm with a production yield of over 70% from natural starch. Furthermore, the potential of CS-SMPs as a carrier system for oral delivery of bioactive compounds were demonstrated using model guest molecules.

Self-assembly kinetics of debranched short-chain glucans from waxy maize starch to form spherical microparticles and its applications.

Starch microparticles (SMPs) of well-defined size and morphology were synthesized through pullulanase-mediated debranching of waxy maize starch followed by spontaneous re-assembly of the resulting short-chain glucan molecules in aqueous solution. Enzymatic debranching of amylopectins from native starch generated two major fractions corresponding to a smaller glucan and partially digested larger amylopectin molecules. The ratio of short-chain glucan (SCG) over partially digested amylopectin (PDAp) turned out to be the deterministic factors for the size and crystallinity of SMPs, of which the ratio could be controlled by the concentration of debranching enzyme. The PDAp fraction was closely associated with the creation of nuclei, determining the growth kinetics of SMPs which led to the formation of SMPs with a diameter ranging from 0.52.5 µm. In addition, we demonstrated that iron oxide nanoparticles (IONPs) were successfully incorporated into the starch microstructure by introducing them during the self-assembly reaction, conferring desired functionality onto the final SMPs. The incorporated IONPs rendered the SMPs an excellent magnetic sensitivity, which were successfully applied for the separation and concentration of target bacteria upon conjugation of specific antibody on the surface of SMPs. The simple processes and biocompatible nature of starch would make this approach attractive for many applications in the area of food, medicine and other related materials sciences.

Molecular Rearrangement of Glucans from Natural Starch To Form Size-Controlled Functional Magnetic Polymer Beads.

Herein, we report a fairly simple and environmentally friendly approach for the fabrication of starch-based magnetic polymer beads (SMPBs) with uniform shape and size through spontaneous rearrangement of short-chain glucan (SCG) produced by enzymatic debranching of waxy maize starch. The paramagnetic materials, dextran-coated iron oxide nanoparticles (Dex@IONPs), were readily incorporated into the starch microstructure and rendered a superparamagnetic property to the SMPBs. The morphology and size of resulting SMPBs turned out to be modulated by Dex@IONPs in a concentration-dependent manner, of which Dex@IONPs was assumed to be acting as a seed inducing the epitaxial crystallization of SCG and further transforming it into homogeneous microparticles. The surface of SMPBs was readily functionalized with an antibody through a one-step reaction using a linker protein. The immuno-SMPBs showed great capture efficiency (>90%) for target bacteria. The colloidal stability and favorable surface environment for biomolecules are believed to be responsible for the high capture efficiency and specificity of the SMPBs. Furthermore, the captured bacteria along with antibody and linker protein were effectively eluted from the surface of SMPBs by adding free maltose, making this new material suitable for various chromatographic applications.

The effect of varied dietary grains on plasma lipid profiles, gut transit time, and aorta histopathology in experimental rats.

This study was designed to investigate the influence of natural brown and black rice consumption on plasma lipid parameters, transit time, and thickness of the aortic wall in rats fed different combinations of grains. Fifty male rats were divided into five groups and raised for eight weeks with diets containing white rice (WR), white rice and brown rice (WRBR), white rice and black rice (WRBL), brown rice and black rice (BRBL), or wheat flour (WH). Gut transit time was the shortest in the BRBL group, and was longer in the order of WRBL, WRBR, WR, and WH group. Plasma lipid profiles differed significantly according to the grain combination. The BRBL group had the lowest levels of triglyceride (TG), total cholesterol (T-C), and low-density lipoprotein cholesterol (LDL-C), and the highest plasma high-density lipoprotein cholesterol (HDL-C) concentration among all groups. The aortic wall thickness hatro for body weight was lower in rats in order of BRBL, WRBR, WH, WRBL, and WR group. In conclusion, black rice and brown rice have anti-atherogenic effects by decreasing plasma lipide profiles and attenuating the thickness of the aortic wall.

Analysis of National Pharmacovigilance Data Associated with Statin Use in Korea.

The aim of this study was to evaluate clinical manifestations, age distribution and risk factors of adverse drug reactions (ADRs) of statins. Korean Adverse Event Reporting System (KAERS) database records (July 2009-June 2014) on statin-treated adults were used. ADRs classified as 'certain', 'probable' and 'possible' based on the WHO-Uppsala Monitoring Centre criteria were analysed. The frequency of ADRs was compared between adults (18-64 years) and older people (age ≥65 years) groups. In total, 2161 ADRs from 1690 patients (579, 34.3% older people) were included for analysis. Mean patient age and ADRs per patient were 60.46 ± 12.72 years and 1.28, respectively. ADRs were reported with atorvastatin (48.4%), rosuvastatin (23.0%), pitavastatin (10.4%) and simvastatin (9.1%). The frequent ADRs were gastrointestinal (421 events, 19.5%), musculoskeletal (331, 15.3%), skin (312, 14.4%) and hepatobiliary disorders (286, 13.2%). Skin disorders were significantly more frequent in adults compared to those in older patients (16.3% versus 12.4%, p = 0.021). Common clinical symptoms were myalgia (263 events, 12.2%), dyspepsia (133, 6.2%) and pruritus (103, 4.8%). Myalgia was more frequently reported in adults (12.7% versus 9.5%, p = 0.039) and dizziness was more frequent in older people (3.4% versus 5.8%, p = 0.015). According to KAERS data, leading statin ADRs were gastrointestinal and musculoskeletal disorders. Myalgia and dyspepsia were the common clinical symptoms.

Thermoelectric Properties of Bi2Te3: CuI and the Effect of Its Doping with Pb Atoms.

In order to understand the effect of Pb-CuI co-doping on the thermoelectric performance of Bi2Te3, n-type Bi2Te3 co-doped with x at % CuI and 1/2x at % Pb (x = 0, 0.01, 0.03, 0.05, 0.07, and 0.10) were prepared via high temperature solid state reaction and consolidated using spark plasma sintering. Electron and thermal transport properties, i.e., electrical conductivity, carrier concentration, Hall mobility, Seebeck coefficient, and thermal conductivity, of CuI-Pb co-doped Bi2Te3 were measured in the temperature range from 300 K to 523 K, and compared to corresponding x% of CuI-doped Bi2Te3 and undoped Bi2Te3. The addition of a small amount of Pb significantly decreased the carrier concentration, which could be attributed to the holes from Pb atoms, thus the CuI-Pb co-doped samples show a lower electrical conductivity and a higher Seebeck coefficient when compared to CuI-doped samples with similar x values. The incorporation of Pb into CuI-doped Bi2Te3 rarely changed the power factor because of the trade-off relationship between the electrical conductivity and the Seebeck coefficient. The total thermal conductivity(κtot) of co-doped samples (κtot ~ 1.4 W/m∙K at 300 K) is slightly lower than that of 1% CuI-doped Bi2Te3 (κtot ~ 1.5 W/m∙K at 300 K) and undoped Bi2Te3 (κtot ~ 1.6 W/m∙K at 300 K) due to the alloy scattering. The 1% CuI-Pb co-doped Bi2Te3 sample shows the highest ZT value of 0.96 at 370 K. All data on electrical and thermal transport properties suggest that the thermoelectric properties of Bi2Te3 and its operating temperature can be controlled by co-doping.

Flavonoid myricetin inhibits TNF-α-stimulated production of inflammatory mediators by suppressing the Akt, mTOR and NF-κB pathways in human keratinocytes.

Flavonoid myricetin has been shown to exhibit anti-inflammatory and anti-oxidant effects. Nevertheless, the effect of myricetin on the TNF-α-stimulated production of inflammatory mediators in keratinocytes has not been studied. Using human keratinocytes, we examined the effect of myricetin on the TNF-α-stimulated production of inflammatory mediators in relation to the Akt, mTOR and NF-κB pathways, which regulate the transcription genes involved in immune and inflammatory responses. TNF-α stimulated production of the inflammatory mediators and reactive oxygen species in keratinocytes, and activation of the Akt, mTOR and NF-κB pathways in HaCaT cells and primary keratinocytes. Myricetin, Akt inhibitor, Bay 11-7085 (an inhibitor of NF-κB activation), rapamycin (mTOR inhibitor) and N-acetylcysteine attenuated TNF-α-induced activation of Akt, mTOR and NF-κB. Myricetin and N-acetylcysteine attenuated the TNF-α-stimulated production of cytokines and chemokines, and production of reactive oxygen species in keratinocytes. The results show that myricetin may reduce TNF-α-stimulated inflammatory mediator production in keratinocytes by suppressing the activation of the Akt, mTOR and NF-κB pathways. The effect of myricetin appears to be associated with inhibition of the production of reactive oxygen species. Further, myricetin appears to attenuate the proinflammatory mediator-induced inflammatory skin diseases.

Mechanically Robust and Healable Transparent Electrode Fabricated via Vapor-Assisted Solution Process.

A mechanically robust, transparent, and healable electrode was successfully developed by embedding Ag nanowires (AgNWs) on the surface of polydimethylsiloxane-based polyurethane (PDMS-CPU) cross-linked by Diels-Alder (DA) adducts. The reversibility of the DA reaction enabled the heated dimethylformamide (DMF) vapor to induce de-cross-linking of the PDMS-CPU preformed as a substrate. A combination of the retro-DA reaction and the plasticizer effect softened the polymer surface, embedding the coated AgNWs on the surface of the polymer. With this simple postprocessing, the surface roughness and mechanical stability of the electrode were largely enhanced. Even with a 55 µm bending radius, which corresponds to a strain of 90%, the resistance of the electrode after 10 min of vapor treatment increased by 2.1% for inward bending and 5.3% for outward bending. This result shows a great potential of the proposed method, as it can also be used to fabricate various mechanically deformable transparent electrode. Furthermore, swelling of the PDMS-CPU film owing to the DMF vapor facilitated the healing properties of the scratched electrodes.

Critical Role of Diels-Adler Adducts to Realise Stretchable Transparent Electrodes Based on Silver Nanowires and Silicone Elastomer.

This paper presents the successful fabrication of a transparent electrode comprising a sandwich structure of silicone/Ag nanowires (AgNWs)/silicone equipped with Diels-Alder (DA) adducts as crosslinkers to realise highly stable stretchability. Because of the reversible DA reaction, the crosslinked silicone successfully bonds with the silicone overcoat, which should completely seal the electrode. Thus, any surrounding liquid cannot leak through the interfaces among the constituents. Furthermore, the nanowires are protected by the silicone cover when they are stressed by mechanical loads such as bending, folding, and stretching. After delicate optimisation of the layered silicone/AgNW/silicone sandwich structure, a stretchable transparent electrode which can withstand 1000 cycles of 50% stretching-releasing with an exceptionally high stability and reversibility was fabricated. This structure can be used as a transparent strain sensor; it possesses a strong piezoresistivity with a gauge factor greater than 11.