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Sarcopenia, the age-related decline in muscle mass and function, poses a significant health challenge as the global population ages. Mitochondrial dysfunction is a key factor in sarcopenia, as evidenced by the role of mitochondrial reactive oxygen species (mtROS) in mitochondrial biogenesis and dynamics, as well as mitophagy. Resistance exercise training (RET) is a well-established intervention for sarcopenia; however, its effects on the mitochondria in aging skeletal muscles remain unclear. This review aims to elucidate the relationship between mitochondrial dynamics and sarcopenia, with a specific focus on the implications of RET. Although aerobic exercise training (AET) has traditionally been viewed as more effective for mitochondrial enhancement, emerging evidence suggests that RET may also confer beneficial effects. Here, we highlight the potential of RET to modulate mtROS, drive mitochondrial biogenesis, optimize mitochondrial dynamics, and promote mitophagy in aging skeletal muscles. Understanding this interplay offers insights for combating sarcopenia and preserving skeletal muscle health in aging individuals. [ABSTRACT FROM AUTHOR]

Okadaic acid (OA) and its analogues cause diarrhetic shellfish poisoning (DSP) in humans, and risk assessments of these toxins require toxicity equivalency factors (TEFs), which represent the relative toxicities of analogues. However, no human death by DSP toxin has been reported, and its current TEF value is based on acute lethality. To properly reflect the symptoms of DSP, such as diarrhea without death, the chronic toxicity of DSP toxins at sublethal doses should be considered. In this study, we obtained acute oral LD50 values for OA and dinophysistoxin-1 (DTX-1) (1069 and 897 μg/kg, respectively) to set sublethal doses. Mice were treated with sublethal doses of OA and DTX-1 for 7 days. The mice lost body weight, and the disease activity index and intestinal crypt depths increased. Furthermore, these changes were more severe in OA-treated mice than in the DTX-1-treated mice. Strikingly, ascites was observed, and its severity was greater in mice treated with OA. Our findings suggest that OA is at least as toxic as DTX-1 after repeated oral administration at a low dose. This is the first study to compare repeated oral dosing of DSP toxins. Further sub-chronic and chronic studies are warranted to determine appropriate TEF values for DSP toxins. [ABSTRACT FROM AUTHOR]

Insulin resistance as a hallmark of type 2 DM (T2DM) plays a role in dementia by promoting pathological lesions or enhancing the vulnerability of the brain. Numerous studies related to insulin/insulin-like growth factor 1 (IGF-1) signaling are linked with various types of dementia. Brain insulin resistance in dementia is linked to disturbances in Aβ production and clearance, Tau hyperphosphorylation, microglial activation causing increased neuroinflammation, and the breakdown of tight junctions in the blood–brain barrier (BBB). These mechanisms have been studied primarily in Alzheimer's disease (AD), but research on other forms of dementia like vascular dementia (VaD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) has also explored overlapping mechanisms. Researchers are currently trying to repurpose anti-diabetic drugs to treat dementia, which are dominated by insulin sensitizers and insulin substrates. Although it seems promising and feasible, none of the trials have succeeded in ameliorating cognitive decline in late-onset dementia. We highlight the possibility of repositioning anti-diabetic drugs as a strategy for dementia therapy by reflecting on current and previous clinical trials. We also describe the molecular perspectives of various types of dementia through the insulin/IGF-1 signaling pathway. [ABSTRACT FROM AUTHOR]

Sarcopenic obesity (SO) is characterized by atrophic skeletal muscle impairment (sarcopenia) and obesity, which is associated with adverse outcomes of morbidity and mortality in elderly people. We investigated the effects of melatonin and exercise training on SO in 32-week-old senescence-accelerated mouse-prone-8 (SAMP8) mice fed a normal diet or a high-fat diet for 16 weeks. Melatonin, exercise, or melatonin and exercise for 8 weeks displayed reductions in the SO-induced impairment of skeletal muscle function and atrophy. Specifically, a decrease in mitochondrial calcium retention capacity in skeletal muscles observed in the HFD-con group was attenuated in melatonin and/or exercise intervention groups. More importantly, HFD-con mice displayed a lower number of Pax7+ satellite cells (SCs) and higher expression of p16ink than P8ND mice, which were attenuated by melatonin and/or exercise interventions. The cellular senescence in SC-derived primary myoblasts from HFD-con mice was significantly attenuated in myoblasts from the melatonin and/or exercise groups, which was reproduced in a senescence model of H2O2-treated C2C12 myoblasts. Our results suggest that melatonin and exercise training attenuate SO-induced skeletal muscle dysfunction, at least in part, through preserving the SC pool by inhibiting cellular senescence and attenuating mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Severe vascular and nerve damage from diabetes is a leading cause of erectile dysfunction (ED) and poor response to oral phosphodiesterase 5 inhibitors. Argonaute 2 (Ago2), a catalytic engine in mammalian RNA interference, is involved in neurovascular regeneration under inflammatory conditions. In the present study, we report that Ago2 administration can effectively improve penile erection by enhancing cavernous endothelial cell angiogenesis and survival under diabetic conditions. We found that although Ago2 is highly expressed around blood vessels and nerves, it is significantly reduced in the penis tissue of diabetic mice. Exogenous administration of the Ago2 protein restored erectile function in diabetic mice by reducing reactive oxygen species production-signaling pathways (inducing eNOS Ser1177/NF-κB Ser536 signaling) and improving cavernous endothelial angiogenesis, migration, and cell survival. Our study provides new evidence that Ago2 mediation may be a promising therapeutic strategy and a new approach for diabetic ED treatment. [ABSTRACT FROM AUTHOR]

In the 115 years since the discovery of Alzheimer's disease (AD), our knowledge, diagnosis, and therapeutics have significantly improved. Biomarkers are the primary tools for clinical research, diagnostics, and therapeutic monitoring in clinical trials. They provide much insightful information, and while they are not clinically used routinely, they help us to understand the mechanisms of this disease. This review charts the journey of AD biomarker discovery and development from cerebrospinal fluid (CSF) amyloid-beta 1-42 (Aβ42), total tau (T-tau), and phosphorylated tau (p-tau) biomarkers and imaging technologies to the next generation of biomarkers. We also discuss advanced high-sensitivity assay platforms for CSF Aβ42, T-tau, p-tau, and blood analysis. The recently proposed Aβ deposition/tau biomarker/neurodegeneration or neuronal injury (ATN) scheme might facilitate the definition of the biological status underpinning AD and offer a common language among researchers across biochemical biomarkers and imaging. Moreover, we highlight blood-based biomarkers for AD that offer a scalable alternative to CSF biomarkers through cost-saving and reduced invasiveness, and may provide an understanding of disease initiation and development. We discuss different groups of blood-based biomarker candidates, their advantages and limitations, and paths forward, from identification and analysis to clinical validation. The development of valid blood-based biomarkers may facilitate the implementation of future AD therapeutics and diagnostics. [ABSTRACT FROM AUTHOR]

Poly(ethylene glycol) diglycidyl ether (PEGDE) is widely used to cross-link polymers, particularly in the pharmaceutical and biomaterial sectors. However, the subcutaneous toxicity of PEGDE has not yet been assessed. PEGDE samples (500–40,000 μg/mouse) were subcutaneously injected into the paraspinal dorsum of BALB/c male mice. Cage-side observations were carried out with measurement of organ weight, body weight variation, and feed intake, as well as histopathological characterization on day 28 post-exposure. Mice that received 40,000 μg of PEGDE showed severe toxic response and had to be euthanized. Subcutaneous injection of PEGDE did not alter feed intake and organ weight; however, the body weight variation of mice injected with 20,000 μg of PEGDE was significantly lower than that of the other groups. Exposure to 10,000 and 20,000 μg of PEGDE induced epidermal ulcer formation and hair loss. The histology of skin tissue in mice administered with 20,000 μg of PEGDE showed re-epithelialized or unhealed wounds. However, the liver, spleen, and kidneys were histologically normal. Collectively, PEGDE, particularly above 10,000 μg/mouse, caused subcutaneous toxicity with ulceration, but no toxicity in the other organs. These results may indicate the optimal concentration of subcutaneously injected PEGDE. [ABSTRACT FROM AUTHOR]

Leaky gut is a condition of increased paracellular permeability of the intestine due to compromised tight junction barriers. In recent years, this affliction has drawn the attention of scientists from different fields, as a myriad of studies prosecuted it to be the silent culprit of various immune diseases. Due to various controversies surrounding its culpability in the clinic, approaches to leaky gut are restricted in maintaining a healthy lifestyle, avoiding irritating factors, and practicing alternative medicine, including the consumption of supplements. In the current study, we investigate the tight junction-modulating effects of processed Aloe vera gel (PAG), comprising 5–400-kD polysaccharides as the main components. Our results show that oral treatment of 143 mg/kg PAG daily for 10 days improves the age-related leaky gut condition in old mice, by reducing their individual urinal lactulose/mannitol (L/M) ratio. In concordance with in vivo experiments, PAG treatment at dose 400 μg/mL accelerated the polarization process of Caco-2 monolayers. The underlying mechanism was attributed to enhancement in the expression of intestinal tight junction-associated scaffold protein zonula occludens (ZO)-1 at the translation level. This was induced by activation of the MAPK/ERK signaling pathway, which inhibits the translation repressor 4E-BP1. In conclusion, we propose that consuming PAG as a complementary food has the potential to benefit high-risk patients. [ABSTRACT FROM AUTHOR]

Sweet potato (Ipomoea batata) is considered a superfood among vegetables and has been consumed for centuries. Traditionally, sweet potato is used to treat several illnesses, including diarrhea and stomach disorders. This study aimed to explore the protective effect of sweet potato on intestinal barrier function, and to identify the active compounds of sweet potato and their underlying mechanism of action. To this purpose, bioactivity-guided isolation, Western blotting, and immunostaining assays were applied. Interestingly, our bioactivity-guided approach enabled the first isolation and identification of trifostigmanoside I (TS I) from sweet potato. TS I induced mucin production and promoted the phosphorylation of PKCα/β in LS174T human colon cancer cells. In addition, it protected the function of tight junctions in the Caco-2 cell line. These findings suggest that TS I rescued the impaired abilities of MUC2, and protected the tight junctions through PKCα/β, to maintain intestinal barrier function. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) is one of the most frequently prescribed analgesic and anti-pyretic drugs. However, APAP-induced hepatotoxicity is a major cause of acute liver failure globally. While the therapeutic dose is safe, an overdose of APAP produces an excess of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), subsequently resulting in hepatotoxicity. Allyl isothiocyanate (AITC), a bioactive molecule in cruciferous plants, is reported to exert various biological effects, including anti-inflammatory, anti-cancer, and anti-microbial effects. Notably, AITC is known for activating nuclear factor erythroid 2-related factor 2 (NRF2), but there is limited evidence supporting the beneficial effects on hepatocytes and liver, where AITC is mainly metabolized. We applied a mouse model in the current study to investigate whether AITC protects the liver against APAP-induced injury, wherein we observed the protective effects of AITC. Furthermore, NRF2 nuclear translocation and the increase of target genes by AITC treatment were confirmed by in vitro experiments. APAP-induced cell damage was attenuated by AITC via an NRF2-dependent manner, and rapid NRF2 activation by AITC was attributed to the elevation of NRF2 stability by decreasing its spontaneous degradation. Moreover, liver tissues from our mouse experiment revealed that AITC increases the expression of heme oxygenase-1 (HO-1), an NRF2 target gene, confirming the potential of AITC as a hepatoprotective agent that induces NRF2 activation. Taken together, our results indicate the potential of AITC as a natural-product-derived NRF2 activator targeting the liver. [ABSTRACT FROM AUTHOR]

Sarcopenia, a syndrome commonly seen in elderly populations, is often characterized by a gradual loss of skeletal muscle, leading to the decline of muscle strength and physical performance. Growing evidence suggests that the prevalence of sarcopenia increases in patients with heart failure (HF), which is a dominant pathogenesis in the aging heart. HF causes diverse metabolic complications that may result in sarcopenia. Therefore, sarcopenia may act as a strong predictor of frailty, disability, and mortality associated with HF. Currently, standard treatments for slowing muscle loss in patients with HF are not available. Therefore, here, we review the pathophysiological mechanisms underlying sarcopenia in HF as well as current knowledge regarding the beneficial effects of exercise on sarcopenia in HF and related mechanisms, including hormonal changes, myostatin, oxidative stress, inflammation, apoptosis, autophagy, the ubiquitin-proteasome system, and insulin resistance. [ABSTRACT FROM AUTHOR]

Aging represents a major risk for developing cardiac disease, including heart failure. The gradual deterioration of cell quality control with aging leads to cell death, a phenomenon associated with mitochondrial dysfunction in the heart. Apoptosis is an important quality control process and a necessary phenomenon for maintaining homeostasis and normal function of the heart. However, the mechanism of mitochondria-mediated apoptosis in aged hearts remains poorly understood. Here, we used male Fischer 344 rats of various ages, representing very young (1 month), young (4 months), middle-aged (12 months), and old (20 months) rats, to determine whether mitochondria-mediated apoptotic signals and apoptosis in the left ventricle of the heart are altered notably with aging. As the rats aged, the extramyocyte space and myocyte cross-sectional area in their left ventricle muscle increased, while the number of myocytes decreased. Additionally, mitochondrion-mediated apoptotic signals and apoptosis increased remarkably during aging. Therefore, our results demonstrate that aging promotes remarkable morphological changes and increases the degree of mitochondrion-mediated apoptosis in the left ventricle of rat hearts. [ABSTRACT FROM AUTHOR]

Although Alzheimer's disease (AD)-like pathology is frequently found in patients with post-stroke dementia, little is known about the effects of aerobic exercise on the modifications of tau and related proteins. Therefore, we evaluated the effects of aerobic exercise on the phosphorylation and acetylation of tau and the expressions of tau-related proteins, after middle cerebral artery occlusion (MCAO) stroke. Twenty-four Sprague–Dawley rats with MCAO infarction were used in this study. The rehabilitation group (RG) received treadmill training 40 min/day for 12 weeks, whereas the sedentary group (SG) did not receive any type of training. Functional tests, such as the single pellet reaching task, rotarod, and radial arm maze tests, were performed monthly for 3 months. In ipsilateral cortices in the RG and SG groups, level of Ac-tau was lower in the RG, whereas levels of p-tauS396, p-tauS262, and p-tauS202/T205 were not significantly lower in the RG. Level of phosphorylated glycogen synthase kinase 3-beta Tyr 216 (p-GSK3βY216) was lower in the RG, but levels of p-AMPK and phosphorylated glycogen synthase kinase 3-beta Ser 9 (p-GSK3βS9) were not significantly lower. Levels of COX-2 and BDNF were not significantly different between the two groups, while SIRT1 significantly decreased in ipsilateral cortices in RG. In addition, aerobic training also improved motor, balance, and memory functions. Rehabilitation with aerobic exercise inhibited tau modification, especially tau acetylation, following infarction in the rat MCAO model, which was accompanied with the improvement of motor and cognitive functions. [ABSTRACT FROM AUTHOR]

Statins are used to prevent and treat atherosclerotic cardiovascular disease, but they also induce myopathy and mitochondrial dysfunction. Here, we investigated whether exercise training prevents glucose intolerance, muscle impairment, and mitochondrial dysfunction in the skeletal muscles of Wistar rats treated with atorvastatin (5 mg kg−1 day−1) for 12 weeks. The rats were assigned to the following three groups: the control (CON), atorvastatin-treated (ATO), and ATO plus aerobic exercise training groups (ATO+EXE). The ATO+EXE group exhibited higher glucose tolerance and forelimb strength and lower creatine kinase levels than the other groups. Mitochondrial respiratory and Ca2+ retention capacity was significantly lower in the ATO group than in the other groups, but exercise training protected against atorvastatin-induced impairment in both the soleus and white gastrocnemius muscles. The mitochondrial H2O2 emission rate was relatively higher in the ATO group and lower in the ATO+EXE group, in both the soleus and white gastrocnemius muscles, than in the CON group. In the soleus muscle, the Bcl-2, SOD1, SOD2, Akt, and AMPK phosphorylation levels were significantly higher in the ATO+EXE group than in the ATO group. In the white gastrocnemius muscle, the SOD2, Akt, and AMPK phosphorylation levels were significantly higher in the ATO+EXE group than in the ATO group. Therefore, exercise training might regulate atorvastatin-induced muscle damage, muscle fatigue, and mitochondrial dysfunction in the skeletal muscles. [ABSTRACT FROM AUTHOR]

Sarcopenia has been defined as a progressive decline of skeletal muscle mass, strength, and functions in elderly people. It is accompanied by physical frailty, functional disability, falls, hospitalization, and mortality, and is becoming a major geriatric disorder owing to the increasing life expectancy and growing older population worldwide. Experimental models are critical to understand the pathophysiology of sarcopenia and develop therapeutic strategies. Although its etiologies remain to be further elucidated, several mechanisms of sarcopenia have been identified, including cellular senescence, proteostasis imbalance, oxidative stress, and "inflammaging." In this article, we address three main aspects. First, we describe the fundamental aging mechanisms. Next, we discuss both in vitro and in vivo experimental models based on molecular mechanisms that have the potential to elucidate the biochemical processes integral to sarcopenia. The use of appropriate models to reflect sarcopenia and/or its underlying pathways will enable researchers to understand sarcopenia and develop novel therapeutic strategies for sarcopenia. Lastly, we discuss the possible molecular targets and the current status of drug candidates for sarcopenia treatment. In conclusion, the development of experimental models for sarcopenia is essential to discover molecular targets that are valuable as biochemical biomarkers and/or therapeutic targets for sarcopenia. [ABSTRACT FROM AUTHOR]

Cells have developed elaborate quality-control mechanisms for proteins and organelles to maintain cellular homeostasis. Such quality-control mechanisms are maintained by conformational folding via molecular chaperones and by degradation through the ubiquitin-proteasome or autophagy-lysosome system. Accumulating evidence suggests that impaired autophagy contributes to the accumulation of intracellular inclusion bodies consisting of misfolded proteins, which is a hallmark of most neurodegenerative diseases. In addition, genetic mutations in core autophagy-related genes have been reported to be linked to neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Conversely, the pathogenic proteins, such as amyloid β and α-synuclein, are detrimental to the autophagy pathway. Here, we review the recent advances in understanding the relationship between autophagic defects and the pathogenesis of neurodegenerative diseases and suggest autophagy induction as a promising strategy for the treatment of these conditions. [ABSTRACT FROM AUTHOR]

Radiation is a widely used treatment for cancer patients, with over half the cancer patients receiving radiation therapy during their course of treatment. Considerable evidence from both preclinical and clinical studies show that tumor recurrence gets restored following radiotherapy, due to the influx of circulating cells consisting primarily of monocytes. The attachment of monocyte to endothelial cell is the first step of the extravasation process. However, the exact molecules that direct the transmigration of monocyte from the blood vessels to the tumors remain largely unknown. The nerve injury-induced protein 1 (Ninjurin1 or Ninj1) gene, which encodes a homophilic adhesion molecule and cell surface protein, was found to be upregulated in inflammatory lesions, particularly in macrophages/monocytes, neutrophils, and endothelial cells. More recently Ninj1 was reported to be regulated following p53 activation. Considering p53 has been known to be activated by radiation, we wondered whether Ninj1 could be increased in the endothelial cells by radiation and it might contribute to the recruiting of monocytes in the tumor. Here we demonstrate that radiation-mediated up-regulation of Ninj1 in endothelial cell lines such as human umbilical vein endothelial cells (HUVECs), EA.hy926, and immortalized HUVECs. Consistent with this, we found over-expressed Ninj1 in irradiated xenograft tumors, and increased monocyte infiltration into tumors. Radiation-induced Ninj1 was transcriptionally regulated by p53, as confirmed by transfection of p53 siRNA. In addition, Ninj1 over-expression in endothelial cells accelerated monocyte adhesion. Irradiation-induced endothelial cells and monocyte interaction was inhibited by knock-down of Ninj1. Furthermore, over-expressed Ninj1 stimulated MMP-2 and MMP-9 expression in monocyte cell lines, whereas the MMP-2 and MMP-9 expression were attenuated by Ninj1 knock-down in monocytes. Taken together, we provide evidence that Ninj1 is a key molecule that generates an interaction between endothelial cells and monocytes. This result suggests that radiation-mediated Ninj1 expression in endothelial cells could be involved in the post-radiotherapy recurrence mechanism. [ABSTRACT FROM AUTHOR]

The potential inhibitory effect of quercetin, a major plant flavonol, on breast cancer resistance protein (BCRP) activity was investigated in this study. The presence of quercetin significantly increased the cellular accumulation and associated cytotoxicity of the BCRP substrate mitoxantrone in human cervical cancer cells (HeLa cells) in a concentration-dependent manner. The transcellular efflux of prazosin, a stereotypical BCRP substrate, was also significantly reduced in the presence of quercetin in a bidirectional transport assay using human BCRP-overexpressing cells; further kinetic analysis revealed IC50 and Ki values of 4.22 and 3.91 μM, respectively. Moreover, pretreatment with 10 mg/kg quercetin in rats led to a 1.8-fold and 1.5-fold increase in the AUC8h (i.e., 44.5 ± 11.8 min∙μg/mL vs. 25.7 ± 9.98 min∙μg/mL, p < 0.05) and Cmax (i.e., 179 ± 23.0 ng/mL vs. 122 ± 23.2 ng/mL, p < 0.05) of orally administered sulfasalazine, respectively. Collectively, these results provide evidence that quercetin acts as an in vivo as well as in vitro inhibitor of BCRP. Considering the high dietary intake of quercetin as well as its consumption as a dietary supplement, issuing a caution regarding its food–drug interactions should be considered. [ABSTRACT FROM AUTHOR]

Sarcopenia is defined as the involuntary loss of skeletal muscle mass and function with aging and is associated with several adverse health outcomes. Recently, the disruption of regular circadian rhythms, due to shift work or nocturnal lifestyle, is emerging as a novel deleterious factor for the development of sarcopenia. The underlying mechanisms responsible for circadian disruption-induced sarcopenia include molecular circadian clock and mitochondrial function associated with the regulation of circadian rhythms. Exercise is a potent modulator of skeletal muscle metabolism and is considered to be a crucial preventative and therapeutic intervention strategy for sarcopenia. Moreover, emerging evidence shows that exercise, acting as a zeitgeber (time cue) of the skeletal muscle clock, can be an efficacious tool for re-setting the clock in sarcopenia. In this review, we provide the evidence of the impact of circadian disruption on skeletal muscle loss resulting in sarcopenia. Furthermore, we highlight the importance of exercise timing (i.e., scheduled physical activity) as a novel therapeutic strategy to target circadian disruption in skeletal muscle. [ABSTRACT FROM AUTHOR]

Exosome-like extracellular vesicles (ELVs) contain biomolecules that have potential as diagnostic biomarkers, such as proteins, micro-RNAs (miRNAs), and lipids. However, it is difficult to enrich ELVs consistently with high yield and purity from clinical samples, which hampers the development of ELV biomarkers. This is particularly true for miRNAs in protein-rich plasma. Hence, we modified ELV isolation protocols of three commercially available polymer-precipitation-based kits using proteinase K (PK) treatment to quantify ELV-associated miRNAs in human plasma. We compared the yield, purity, and characteristics of enriched plasma ELVs, and measured the relative quantity of three selected miRNAs (miR-30c, miR-126, and miR-192) in ELVs using six human plasma samples. Compared with the original protocols, we demonstrated that ELVs can be isolated with PK treatment with high purity (i.e., lack of non-exosomal proteins and homogeneous size of vesicles) and yield (i.e., abundancy of exosomal markers), which were dependent on kits. Using the kit with the highest purity and yield with PK treatment, we successfully quantified ELV miRNAs (levels of 45%–65% in total plasma) with acceptable variability. Collectively, ELV enrichment using the modified easy-to-use method appears suitable for the analysis of miRNAs, although its clinical applicability needs to be confirmed in larger clinical studies. [ABSTRACT FROM AUTHOR]

AMP-activated protein kinase (AMPK) has been implicated in contractility changes in bladders with partial bladder outlet obstruction (PBOO), but the role of AMPK in the contractile response of normal bladder remains unclear. We investigated the phosphorylation of AMPKα and expression of the involved upstream AMPK kinases (AMPKKs) in a model of bladders with PBOO and sought to determine whether the pharmacological inhibition of these two factors affected detrusor contractility in normal bladders, using female Sprague–Dawley rats. Cystometry and Western blot analysis were performed in rats that were subjected to PBOO induction or a sham operation. Cystometry was performed in normal rats that received selective inhibitors of AMPKα and Ca2+/calmodulin-dependent protein kinase kinase (CaMKKβ) (compound C and STO-609, respectively) at doses determined in the experiments. In the PBOO bladders, bladder weight and micturition pressure (MP) were higher and AMPKα phosphorylation (T172) and CaMKKβ expression was significantly reduced. Compound C and STO-609 increased MP. The increased contractile response in bladders with PBOO-induced hypertrophy was related to decreased CaMKKβ/AMPK signaling activity, and the pharmacological inhibition of this pathway in normal bladders increased detrusor contractility, implying a role of CaMKKβ/AMPK signaling in the bladder in the regulation of detrusor contractility. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease characterized by memory decline and cognitive dysfunction. Although the primary causes of AD are not clear, it is widely accepted that the accumulation of amyloid beta (Aβ) and consecutive hyper-phosphorylation of tau, synaptic loss, oxidative stress and neuronal death might play a vital role in AD pathogenesis. Recently, it has been widely suggested that extracellular vesicles (EVs), which are released from virtually all cell types, are a mediator in regulating AD pathogenesis. Clinical evidence for the diagnostic performance of EV-associated biomarkers, particularly exosome biomarkers in the blood, is also emerging. In this review, we briefly introduce the biological function of EVs in the central nervous system and discuss the roles of EVs in AD pathogenesis. In particular, the roles of EVs associated with autophagy and lysosomal degradation systems in AD proteinopathy and in disease propagation are discussed. Next, we summarize candidates for biochemical AD biomarkers in EVs, including proteins and miRNAs. The accumulating data brings hope that the application of EVs will be helpful for early diagnostics and the identification of new therapeutic targets for AD. However, at the same time, there are several challenges in developing valid EV biomarkers. We highlight considerations for the development of AD biomarkers from circulating EVs, which includes the standardization of pre-analytical sources of variability, yield and purity of isolated EVs and quantification of EV biomarkers. The development of valid EV AD biomarkers may be facilitated by collaboration between investigators and the industry. [ABSTRACT FROM AUTHOR]

We aimed to present the study design of an independent validation cohort from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (AD) (KBASE-V) and to investigate the baseline characteristics of the participants according to the AD clinical spectrum. We recruited 71 cognitively normal (CN) participants, 96 with subjective cognitive decline (SCD), 72 with mild cognitive impairment (MCI), and 56 with AD dementia (ADD). The participants are followed for three years. The Consortium to Establish a Registry for AD scores was significantly different between all of the groups. The logical memory delayed recall scores were significantly different between all groups, except between the MCI and ADD groups. The Mini-Mental State Examination score, hippocampal volume, and cerebrospinal fluid (CSF) amyloid-β42 level were significant difference among the SCD, MCI, and ADD groups. The frequencies of participants with amyloid pathology according to PET or CSF studies were 8.9%, 25.6%, 48.3%, and 90.0% in the CN, SCD, MCI, and ADD groups, respectively. According to ATN classification, A+/T+/N+ or A+/T+/N− was observed in 0%, 15.5%, 31.0%, and 78.3% in the CN, SCD, MCI, and ADD groups, respectively. The KBASE-V showed a clear difference according to the AD clinical spectrum in neuropsychological tests and AD biomarkers. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is characterized by chronic or recurrent inflammation of the gastrointestinal tract. Even though the current strategies to treat IBD include anti-inflammatory drugs and immune modulators, these treatments have side-effects. New strategies are, therefore, required to overcome the limitations of the therapies. In this study, we investigated the anti-colitic effects of allyl isothiocyanate (AITC), which is an active ingredient present in Wasabia japonica. The DSS-induced colitis model in the mouse was used to mimic human IBD and we observed that AITC treatment ameliorated the severity of colitis. We further studied the mechanism involved to ameliorate the colitis. To investigate the involvement of AITC on the intestinal barrier function, the effect on the intercellular tight junction was evaluated in the Caco-2 cell line while mucin expression was assessed in the LS174T cell line. AITC positively regulated tight junction proteins and mucin 2 (MUC2) against DSS-induced damage or depletion. Our data of in vivo studies were also consistent with the in vitro results. Furthermore, we observed that MUC2 increased by AITC is dependent on ERK signaling. In conclusion, we propose that AITC can be considered as a new strategy for treating IBD by modulating tight junction proteins and mucin. [ABSTRACT FROM AUTHOR]

Sweet potato ( Ipomoea batata ) is considered a superfood among vegetables and has been consumed for centuries. Traditionally, sweet potato is used to treat several illnesses, including diarrhea and stomach disorders. This study aimed to explore the protective effect of sweet potato on intestinal barrier function, and to identify the active compounds of sweet potato and their underlying mechanism of action. To this purpose, bioactivity-guided isolation, Western blotting, and immunostaining assays were applied. Interestingly, our bioactivity-guided approach enabled the first isolation and identification of trifostigmanoside I (TS I) from sweet potato. TS I induced mucin production and promoted the phosphorylation of PKCα/β in LS174T human colon cancer cells. In addition, it protected the function of tight junctions in the Caco-2 cell line. These findings suggest that TS I rescued the impaired abilities of MUC2, and protected the tight junctions through PKCα/β, to maintain intestinal barrier function.

Nerve injury-induced protein 1 (Ninjurin1, Ninj1) is a cell-surface adhesion molecule that regulates cell migration and attachment. This study demonstrates the increase in Ninj1 protein expression during development of intestinal inflammation. Ninj1-deficient mice exhibited significantly attenuated bodyweight loss, shortening of colon length, intestinal inflammation, and lesser pathological lesions than wild-type mice. Although more severe inflammation and serious lesions are observed in wild-type mice than Ninj1-deficient mice, there were no changes in the numbers of infiltrating macrophages in the inflamed tissues obtained from WT and Ninj1-deficient mice. Ninj1 expression results in activation of macrophages, and these activated macrophages secrete more cytokines and chemokines than Ninj1-deficient macrophages. Moreover, mice with conditional deletion of Ninj1 in myeloid cells (Ninj1 fl/fl ; Lyz-Cre+) alleviated experimental colitis compared with wild-type mice. In summary, we propose that the Ninj1 in myeloid cells play a pivotal function in intestinal inflammatory conditions.