A preclinical screen to evaluate pharmacotherapies for the treatment of agitation in dementia.

Agitation associated with dementia is frequently reported clinically but has received little attention in preclinical models of dementia. The current study used a 7PA2 CM intracerebroventricular injection model of Alzheimer's disease (AD) to assess acute memory impairment, and a bilateral intrahippocampal (IH) injection model of AD (aggregated Aß1-42 injections) and a bilateral IH injection model of dementia with Lewy bodies (aggregated NAC61-95 injections) to assess chronic memory impairment in the rat. An alternating-lever cyclic-ratio schedule of operant responding was used for data collection, where incorrect lever perseverations measured executive function (memory) and running response rates (RRR) measured behavioral output (agitation). The results indicate that bilateral IH injections of Aß1-42 and bilateral IH injections of NAC61-95 decreased memory function and increased RRRs, whereas intracerebroventricular injections of 7PA2 CM decreased memory function but did not increase RRRs. These findings show that using the aggregated peptide IH injection models of dementia to induce chronic neurotoxicity, memory decline was accompanied by elevated behavioral output. This demonstrates that IH peptide injection models of dementia provide a preclinical screen for pharmacological interventions used in the treatment of increased behavioral output (agitation), which also establish detrimental side effects on memory.

Caspase-9 activation and Apaf-1 cleavage by MMP-3.

We have previously demonstrated that matrix metalloprotease-3 (MMP-3) can act inside the cell to trigger apoptosis in response to various cell stresses in dopaminergic neuronal cells. However, the mechanism by which MMP-3 activity leads to caspase-3 activation in apoptotic signaling was not known. In the present study, we found that MMP-3 acts upstream of caspase-9. Overexpression of wild type MMP-3, but not mutant MMP-3, generated the enzymatically active 35kD caspase-9. The caspase-9 activation was absent in MMP-3 knockout cells, but was present when these cells were transfected with wild type MMP-3 cDNA. It was elevated in cells that were under a MMP-3-inducing ER stress condition, and this was attenuated by pharmacologic inhibition and gene knockdown of MMP-3. Incubation of recombinant catalytic domain of MMP-3 (cMMP-3) with procaspase-9 was not sufficient to cause caspase-9 activation, and an additional cytosolic factor was required. cMMP-3 was found to bind to the cytosolic protein Apaf-1, as determined by changes in surface plasmon resonance, and to cleave Apaf-1. Pharmacological inhibition, knockout, and knockdown of MMP-3 attenuated the cleavage. Taken together, the present study demonstrates that MMP-3 leads to caspase-9 activation and suggests that this occurs indirectly via a cytosolic protein, possibly involving Apaf-1.

Novel 5-aryloxypyrimidine SEN1576 as a candidate for the treatment of Alzheimer's disease.

Prefibrillar assembly of amyloid-ß (Aß) is a major event underlying the development of neuropathology and dementia in Alzheimer's disease (AD). This study determined the neuroprotective properties of an orally bioavailable Aß synaptotoxicity inhibitor, SEN1576. Binding of SEN1576 to monomeric Aß 1-42 was measured using surface plasmon resonance. Thioflavin-T and MTT assays determined the ability of SEN1576 to block Aß 1-42-induced aggregation and reduction in cell viability, respectively. In vivo long-term potentiation (LTP) determined effects on synaptic toxicity induced by intracerebroventricular (i.c.v.) injection of cell-derived Aß oligomers. An operant behavioural schedule measured effects of oral administration following i.c.v. injection of Aß oligomers in normal rats. SEN1576 bound to monomeric Aß 1-42, protected neuronal cells exposed to Aß 1-42, reduced deficits in in vivo LTP and behaviour. SEN1576 exhibits the necessary features of a drug candidate for further development as a disease modifying treatment for the early stages of AD-like dementia.

Advances in Liquid Biopsy for Diagnosis of Bladder Cancer.

Bladder cancer (BCa) is the most common malignancy of the urinary system. It has a high recurrence rate and requires longterm follow-up. Significant advances in BCa research have been made in recent years; however, the initial diagnosis and follow-up of BCa relies on cystoscopy, which is an invasive and expensive procedure. Over the past decade, liquid biopsies (e.g., blood and urine) have proven to be highly efficient methods for the discovery of BCa biomarkers. This noninvasive sampling method is used to analyze unique tumor components released into body fluids and enables serial sampling and longitudinal monitoring of tumor progression. Several liquid biopsy biomarkers have been studied extensively and have shown promising results in the clinical applications of BCa, including early detection, microscopic residual disease detection, recurrence prediction, and treatment response. Therefore, this review aims to provide an update on various new liquid biopsy markers and the advantages and current limitations of liquid biopsy in the diagnosis of BCa.

The Critical Role of Intracellular Bacterial Communities in Uncomplicated Recurrent Urinary Cystitis: A Comprehensive Review of Detection Methods and Diagnostic Potential.

Urinary tract infections (UTIs) are among the most common bacterial infections worldwide and are particularly prevalent in women. Recurrent UTIs significantly diminish quality of life due to their symptoms and frequent relapses. Patients often experience immediate relapse following slightly strenuous activities or intense psychological stress. In this review, we explore why infections persist despite the advent of various treatments and suggest strategies to manage recurrent cystitis by targeting the mechanisms of adhesion and infection. Vitamin D levels and the expression of neutrophil gelatinase-associated lipocalin are linked to the recurrence of UTIs. During a UTI, bacteria employ adhesins to invade the urinary tract, adhere to urothelial cells, and then penetrate these cells, where they rapidly multiply to establish intracellular bacterial communities. Bacteria can also form quiescent intracellular reservoirs that escape immune responses and antibiotic treatments, leading to recurrence under certain conditions. The surface proteins of bacteria and D-mannose are crucial in the adhesion of bacteria to the urothelium. Understanding these processes provides valuable insights into potential therapeutic approaches that focus on preventing bacterial attachment and cluster formation. By disrupting the ability of bacteria to adhere to and form clusters on cells, we can better manage recurrent UTIs and improve patient outcomes.

Helix-coiled gold nanowires for molecular sensing.

Helix-coiled gold nanowires were fabricated by a templating route using unique composite templates consisting of anodic aluminum oxide (AAO) nanotubular membrane and confined mesoporous silica therein. A different degree of confinement energy induces a different degree of helix curvature of confined porous silica nanochannels in an AAO, which works as a hard template for the electrochemical deposition of gold, thereby rationally enabling a different degree of helix curvature of gold nano-replicas. From surface-enhanced Raman scattering experiments, we first found that helix-coiled gold nanowires show more distinctly enhanced molecule sensing efficiency than those from simple smooth gold nanowires, and gold nanowires with the narrower lateral width show more enhanced molecule sensing efficiency than those of thicker width helix nanowires.

Proteomics for Early Detection of Non-Muscle-Invasive Bladder Cancer: Clinically Useful Urine Protein Biomarkers.

Bladder cancer is the fourth most common cancer in men, and most cases are non-muscle-invasive. A high recurrence rate is a critical problem in non-muscle-invasive bladder cancer. The availability of few urine tests hinders the effective detection of superficial and small bladder tumors. Cystoscopy is the gold standard for diagnosis; however, it is associated with urinary tract infections, hematuria, and pain. Early detection is imperative, as intervention influences recurrence. Therefore, urinary biomarkers need to be developed to detect these bladder cancers. Recently, several protein candidates in the urine have been identified as biomarkers. In the present narrative review, the current status of the development of urinary protein biomarkers, including FDA-approved biomarkers, is summarized. Additionally, contemporary proteomic technologies, such as antibody-based methods, mass-spectrometry-based methods, and machine-learning-based diagnosis, are reported. Furthermore, new strategies for the rapid and correct profiling of potential biomarkers of bladder cancer in urine are introduced, along with their limitations. The advantages of urinary protein biomarkers and the development of several related technologies are highlighted in this review. Moreover, an in-depth understanding of the scientific background and available protocols in research and clinical applications of the surveillance of non-muscle bladder cancer is provided.

Issues pertaining to Mg, Zn and Cu in the 2020 Dietary Reference Intakes for Koreans.

In the current years, it has now become necessary to establish standards for micronutrient intake based on scientific evidence. This review discusses issues related to the development of the 2020 Dietary Reference Intakes for Koreans (KDRI) for magnesium (Mg), zinc (Zn), and copper (Cu), and future research directions. Following issues were encountered when establishing the KDRI for these minerals. First, characteristics of Korean subjects need to be applied to estimate nutrient requirements. When calculating the estimated average requirement (EAR), the KDRI used the results of balance studies for Mg absorption and factorial analysis for Zn, which is defined as the minimum amount to offset endogenous losses for Zn and Mg. For Cu, a combination of indicators, such as depletion/repletion studies, were applied, wherein all reference values were based on data obtained from other countries. Second, there was a limitation in that it was difficult to determine whether reference values of Mg, Zn, and Cu intakes in the 2020 KDRI were achievable. This might be due to the lack of representative previous studies on intakes of these nutrients, and an insufficient database for Mg, Zn, and Cu contents in foods. This lack of database for mineral content in food poses a problem when evaluating the appropriateness of intake. Third, data was insufficient to assess the adequacy of Mg, Zn, and Cu intakes from supplements when calculating reference values, considering the rise in both demand and intake of mineral supplements. Mg is more likely to be consumed as a multi-nutrient supplement in combination with other minerals than as a single supplement. Moreover, Zn-Cu interactions in the body need to be considered when determining the reference intake values of Zn and Cu. It is recommended to discuss these issues present in the 2020 KDRI development for Mg, Zn, and Cu intakes in a systematic way, and to find relevant solutions.

Matrix metalloproteinase-3 is increased and participates in neuronal apoptotic signaling downstream of caspase-12 during endoplasmic reticulum stress.

Although endoplasmic reticulum (ER) stress-induced apoptosis has been associated with pathogenesis of neurodegenerative diseases, the cellular components involved have not been well delineated. The present study shows that matrix metalloproteinase (MMP)-3 plays a role in the ER stress-induced apoptosis. ER stress induced by brefeldin A (BFA) or tunicamycin (TM) increases gene expression of MMP-3, selectively among various MMP subtypes, and the active form of MMP-3 (actMMP-3) in the brain-derived CATH.a cells. Pharmacological inhibition of enzyme activity, small interference RNA-mediated gene knockdown, and gene knock-out of MMP-3 all provide protection against ER stress. MMP-3 acts downstream of caspase-12, because both pharmacological inhibition and gene knockdown of caspase-12 attenuate the actMMP-3 increase, but inhibition and knock-out of MMP-3 do not alter caspase-12. Furthermore, independently of the increase in the protein level, the catalytic activity of MMP-3 enzyme can be increased via lowering of its endogenous inhibitor protein TIMP-1. Caspase-12 causes liberation of MMP-3 enzyme activity by degrading TIMP-1 that is already bound to actMMP-3. TIMP-1 is decreased in response to ER stress, and TIMP-1 overexpression leads to cell protection and a decrease in MMP-3 activity. Taken together, actMMP-3 protein level and catalytic activity are increased following caspase-12 activation during ER stress, and this in turn plays a role in the downstream apoptotic signaling in neuronal cells. MMP-3 and TIMP-1 may therefore serve as cellular targets for therapy against neurodegenerative diseases.

Role of matrix metalloproteinase-3 in neurodegeneration.

Matrix metalloproteinase-3 (MMP-3) is a member of the class of zinc-dependent proteases known to degrade the extracellular matrix. MMP-3 activity is regulated at three different levels: gene expression, proteolytic activation of the zymogen, and inhibition by the endogenous tissue inhibitors of metalloproteinase. A line of evidence indicates a role of MMP-3 in neurodegeneration. In neuronal cells, MMP-3 expression is increased in response to cell stress, and the cleaved, active MMP-3 participates in apoptotic signaling. In the extracellular space, MMP-3 triggers microglia to produce proinflammatory and cytotoxic molecules as well as MMP-3, which in turn contribute to neuronal damage. MMP-3 is increased in various experimental models of Parkinson's disease that are produced by selective toxins and by inflammagen, and the neuronal death is attenuated by various ways that inhibit MMP-3. α-Synuclein, whose gene mutations are associated with familial forms of Parkinson's disease, is proteolyzed by MMP-3. Contribution of MMP-3 toward the pathogenesis of Alzheimer's disease and other neurodegenerative diseases has also been suggested. Thus, modulation of MMP-3 expression and/or activity could be of therapeutic value for neurodegenerative diseases.

Long-term effect of simplified dietary education on the nutritional status of patients after a gastrectomy.

Dietary education is regarded as an important and useful tool for influencing nutritional status. Since long, dietary education has been performed to improve the nutritional status of patients after a gastrectomy. This study aimed to investigate the effect of simplified dietary education on the nutritional status of patients after a gastrectomy. A total of 1,150 patients with gastric cancer underwent surgery between March 2014 and October 2015 at the Samsung Medical Center (SMC). Of these, we used the case-control matching method (1:1 match) by stratifying the factors of age and sex and included 100 patients in each group. The clinicopathologic data of the patients for two years after the gastrectomy were prospectively collected and retrospectively analyzed. The educated group (ED, N = 100) was provided with a simplified, ordinary dietary education at regular outpatient clinic visits that occurred at 1, 3, 6, and 12 months after gastrectomy and at 1-year intervals thereafter. The clinicopathologic characteristics and nutritional parameters of the educated group (ED) (N = 100) and the non-educated group (NED) (n = 100) were compared. There were no significant differences between the two groups in terms of clinical characteristics and serological parameters. Nutritional parameters, which included body weight loss, body mass index (BMI) change, and prognostic nutritional index (PNI), were also not significantly different between the two groups. Simplified dietary education at regular outpatient clinic visits was ineffective in reducing weight loss after a subtotal gastrectomy. Further research or other methods may be needed to reduce weight loss after a gastrectomy.

Correction: Wachs, S., et al. Associations between Witnessing and Perpetrating Online Hate in Eight Countries: The Buffering Effects of Problem-Focused Coping. Int. J. Environ. Res. Public Health 2019, 16, 3992.

The authors wish to add the following corrections to their paper published in the International Journal of Environmental Research and Public Health [...].

Advanced porous gold nanofibers for highly efficient and stable molecular sensing platforms.

Porous gold nanofibers are fabricated through templated electrochemical routes in porous alumina membranes. Gold-silver alloy is electrochemically deposited in the nanocylinders of the porous alumina templates and then the silver phase is selectively dealloyed. The resulting nanofibers present a nanoporous network with a pore dimension of approximately 10 nm and notable surface-enhanced Raman scattering (SERS) efficiencies which are at least seven times higher than from the smooth solid gold nanofibers without porosity. The relative SERS enhancement on porous gold is directly proved by imaging with a Raman microscope for conjugated porous gold/solid gold single nanorods.

Feeding association between the nucleus of the solitary tract and the ventral tegmental area.

Male Sprague-Dawley rats were fitted with two cannulae in the VTA and one cannula in the NTS for co-administration of the micro-opioid receptor agonist DAMGO in one site and the opioid antagonist naltrexone in the other. Injection of DAMGO into the VTA or the NTS stimulated feeding. The increase in food intake after DAMGO injection into the VTA was decreased following injection of naltrexone into the NTS. Furthermore, the increase in food intake after DAMGO injection into the NTS was decreased following injection of naltrexone into the VTA. These results suggest an opioid-mediated feeding association between the VTA and NTS.

Associations between Witnessing and Perpetrating Online Hate in Eight Countries: The Buffering Effects of Problem-Focused Coping.

Online hate is a topic that has received considerable interest lately, as online hate represents a risk to self-determination and peaceful coexistence in societies around the globe. However, not much is known about the explanations for adolescents posting or forwarding hateful online material or how adolescents cope with this newly emerging online risk. Thus, we sought to better understand the relationship between a bystander to and perpetrator of online hate, and the moderating effects of problem-focused coping strategies (e.g., assertive, technical coping) within this relationship. Self-report questionnaires on witnessing and committing online hate and assertive and technical coping were completed by 6829 adolescents between 12 and 18 years of age from eight countries. The results showed that increases in witnessing online hate were positively related to being a perpetrator of online hate. Assertive and technical coping strategies were negatively related with perpetrating online hate. Bystanders of online hate reported fewer instances of perpetrating online hate when they reported higher levels of assertive and technical coping strategies, and more frequent instances of perpetrating online hate when they reported lower levels of assertive and technical coping strategies. In conclusion, our findings suggest that, if effective, prevention and intervention programs that target online hate should consider educating young people about problem-focused coping strategies, self-assertiveness, and media skills. Implications for future research are discussed.

A novel intracellular role of matrix metalloproteinase-3 during apoptosis of dopaminergic cells.

We have previously demonstrated that the active form of matrix metalloproteinase-3 (actMMP-3) is released from dopamine(DA)rgic neurons undergoing apoptosis. Herein, whether actMMP-3 might be generated intracellularly, and if so, whether it is involved in apoptosis of DArgic neurons itself was investigated in primary cultured DArgic neurons of wild-type, MMP-3 knockout animals, and CATH.a cells. During apoptosis, gene expression of MMP-3 is induced, specifically among the various classes of MMPs, generating the proform (55 kDa) which is subsequently cleaved to the catalytically active actMMP-3 (48 kDa) involving a serine protease. Intracellular actMMP-3 activity is directly linked to apoptotic signaling in DArgic cells: (i) Pharmacologic inhibition of enzymatic activity, repression of gene expression by siRNA, and gene deficiency all lead to protection; (ii) pharmacologic inhibition causes attenuation of DNA fragmentation and caspase 3 activation, the indices of apoptosis; and (iii) inhibition of the pro-apoptotic enzyme c-Jun N-terminal protein kinase leads to repression of MMP-3 induction. Under the cell stress condition, MMP-3 is released as actMMP-3 rather than the proform (proMMP-3), and catalytically active MMP-3 added to the medium does not cause cell death. Thus, actMMP-3 seems to have a novel intracellular role in apoptotic DArgic cells and this finding provides an insight into the pathogenesis of Parkinson's disease.

Oligomers of the amyloid-beta protein disrupt working memory: confirmation with two behavioral procedures.

Converging lines of evidence suggest that oligomers of amyloid-beta play a role in the cognitive impairment characteristic of Alzheimer's disease, but only three studies have provided experimental evidence of such impairment. To provide additional information about the effects of these oligomers on memory, the present study examined the memory of groups of rats exposed to ICV injections of the culture media (CM) of Chinese Hamster Ovary cells that were (7PA2) and were not (CHO-) transfected with a human mutation of amyloid precursor protein that appears to cause early-onset Alzheimer's disease. The 7PA2 CM, which contained concentrations of soluble amyloid-beta oligomers physiologically relevant to those found in human brain, significantly disrupted working memory in rats tested in a radial-arm maze. In contrast, CHO- CM, which did not contain such oligomers, had no effect on memory. The disruptive effects of 7PA2-derived amyloid-beta oligomers, evident 2h after exposure, disappeared within a day. These findings are compared to results from 7PA2 CM tested under a complex procedure thought to measure aspects of executive function. The results confirm the disruptive effects of low-n amyloid-beta oligomers and extend them to a well-established rat model of memory.

Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer's disease models.

Minocycline is a semi-synthetic tetracycline antibiotic that effectively crosses the blood-brain barrier. Minocycline has been reported to have significant neuroprotective effects in models of cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, and Huntington's and Parkinson's diseases. In this study, we demonstrate that minocycline has neuroprotective effects in in vitro and in vivo Alzheimer's disease models. Minocycline was found to attenuate the increases in the phosphorylation of double-stranded RNA-dependent serine/threonine protein kinase, eukaryotic translation initiation factor-2 alpha and caspase 12 activation induced by amyloid beta peptide1-42 treatment in NGF-differentiated PC 12 cells. In addition, increases in the phosphorylation of eukaryotic translation initiation factor-2 alpha were attenuated by administration of minocycline in Tg2576 mice, which harbor mutated human APP695 gene including the Swedish double mutation and amyloid beta peptide(1-42)-infused rats. We found that minocycline administration attenuated deficits in learning and memory in amyloid beta peptide(1-42)-infused rats. Increased phosphorylated state of eukaryotic translation initiation factor-2 alpha is observed in Alzheimer's disease patients' brains and may result in impairment of cognitive functions in Alzheimer's disease patients by decreasing the efficacy of de novo protein synthesis required for synaptic plasticity. On the basis of these results, minocycline may prove to be a good candidate as an effective therapeutic agent for Alzheimer's disease.

Thyroxine replacement in an animal model of congenital hypothyroidism.

This study examined the effects of thyroxine (T(4)) treatment on spatial learning and memory in congenitally hypothyroid (CH) rats. Forty CH male offspring of methimazole-treated dams were randomly divided into three groups: no T(4) (vehicle) treatment (n=12), T(4) treatment commencing on postnatal day (P-) 7 (n=14), and T(4) treatment commencing on P-21 (n=14). Normal male rats were used as a control group (n=14). T(4) was administered daily (sc, 0.02 microg/g) to the treatment groups for 30 days. A water-maze was used to assess behaviour at 42, 70 and 98 days of age. T(4) treatment beginning at P-7 improved learning and memory associated with CH at 70 and 98 days of age but T(4) treatment beginning at P-21 did not improve CH-impaired learning and memory.

Differences in Friendship Networks and Experiences of Cyberbullying Among Korean and Australian Adolescents.

Cyberbullying is one of the negative consequences of online social interaction. The digital environment enables adolescents to engage in online social interaction beyond the traditional physical boundaries of families, neighborhoods, and schools. The authors examined connections to friendship networks in both online and offline settings are related to their experiences as victims, perpetrators, and bystanders of cyberbullying. A comparative face-to-face survey of adolescents (12-15-year-olds) was conducted in Korea (n = 520) and Australia (n = 401). The results reveal that online networks are partially related to cyberbullying in both countries, showing the size of social network sites was significantly correlated with experience cyberbullying among adolescents in both countries. However there were cultural differences in the impact of friendship networks on cyberbullying. The size of the online and offline networks has a stronger impact on the cyberbullying experiences in Korea than it does in Australia. In particular, the number of friends in cliques was positively related to both bullying and victimization in Korea.