Skin-brain axis in Alzheimer's disease - Pathologic, diagnostic, and therapeutic implications: A Hypothetical Review.

The dynamic interaction between the brain and the skin is termed the 'skin-brain axis.' Changes in the skin not only reflect conditions in the brain but also exert direct and indirect effects on the brain. Interestingly, the connection between the skin and brain is crucial for understanding aging and neurodegenerative diseases. Several studies have shown an association between Alzheimer's disease (AD) and various skin disorders, such as psoriasis, bullous pemphigoid, and skin cancer. Previous studies have shown a significantly increased risk of new-onset AD in patients with psoriasis. In contrast, skin cancer may reduce the risk of developing AD. Accumulating evidence suggests an interaction between skin disease and AD; however, AD-associated pathological changes mediated by the skin-brain axis are not yet clearly defined. While some studies have reported on the diagnostic implications of the skin-brain axis in AD, few have discussed its potential therapeutic applications. In this review, we address the pathological changes mediated by the skin-brain axis in AD. Furthermore, we summarize (1) the diagnostic implications elucidated through the role of the skin-brain axis in AD and (2) the therapeutic implications for AD based on the skin-brain axis. Our review suggests that a potential therapeutic approach targeting the skin-brain axis will enable significant advances in the treatment of AD.

The associations between maternal and fetal exposure to endocrine-disrupting chemicals and asymmetric fetal growth restriction: a prospective cohort study.

Recent evidence has revealed associations between endocrine-disrupting chemicals (EDCs) and placental insufficiency due to altered placental growth, syncytialization, and trophoblast invasion. However, no epidemiologic study has reported associations between exposure to EDCs and asymmetric fetal growth restriction (FGR) caused by placenta insufficiency. The aim of this study was to evaluate the association between EDC exposure and asymmetric FGR. This was a prospective cohort study including women admitted for delivery to the Maternal Fetal Center at Seoul St. Mary's Hospital between October 2021 and October 2022. Maternal urine and cord blood samples were collected, and the levels of bisphenol-A (BPA), monoethyl phthalates, and perfluorooctanoic acid in each specimen were analyzed. We investigated linear and non-linear associations between the levels of EDCs and fetal growth parameters, including the head circumference (HC)/abdominal circumference (AC) ratio as an asymmetric parameter. The levels of EDCs were compared between fetuses with and without asymmetric FGR. Of the EDCs, only the fetal levels of BPA showed a linear association with the HC/AC ratio after adjusting for confounding variables (ß = 0.003, p < 0.05). When comparing the normal growth and asymmetric FGR groups, the asymmetric FGR group showed significantly higher maternal and fetal BPA levels compared to the normal growth group (maternal urine BPA, 3.99 µg/g creatinine vs. 1.71 µg/g creatinine [p < 0.05]; cord blood BPA, 1.96 µg/L vs. -0.86 µg/L [p < 0.05]). In conclusion, fetal exposure levels of BPA show linear associations with asymmetric fetal growth patterns. High maternal and fetal exposure to BPA might be associated with asymmetric FGR.

Genipin and pyrogallol: Two natural small molecules targeting the modulation of disordered proteins in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the aggregation of disordered proteins, such as amyloid beta (Aß) and tau, leading to neurotoxicity and disease progression. Despite numerous efforts, effective inhibitors of Aß and tau aggregates have not been developed. Thus, we aimed to screen natural small molecules from crude extracts that target various pathologies and are prescribed for patients with neurological diseases. In this study, we screened 162 natural small molecules prescribed for neurological diseases and identified genipin and pyrogallol as hit compounds capable of simultaneously regulating the aggregation of Aß and tau K18. Moreover, we confirmed the dual modulatory effects of these compounds on the reduction of amyloid-mediated neurotoxicity in vitro and the disassembly of preformed Aß42 and tau K18 fibrils. Furthermore, we observed the alleviatory effects of genipin and pyrogallol against AD-related pathologies in triple transgenic AD mice. Molecular dynamics and docking simulations revealed the molecular interaction dynamics of genipin and pyrogallol with Aß42 and tau K18, providing insights into their suppression of aggregation. Our findings suggest the therapeutic potential of genipin and pyrogallol as dual modulators for the treatment of AD by inhibiting aggregation or promoting dissociation of Aß and tau.

The Origin and Invasion Pathway of Brown Rats Rattus norvegicus on Dok-Do Island Revealed by Genome-Wide Markers from 3-RADseq Approach.

Biological invasions are known to cause local extinctions on islands. Dok-do, a small, remote volcanic island in the East Sea of Korea in the western Pacific, has recently been invaded by rats, posing ecological problems. To infer their origin and invasion pathway, we collected rats from Dok-do and from the potential introduction source locations, Ulleung-do in the Pacific Ocean, and four east coastal ports. First, we identified that the brown rat (Rattus norvegicus) was the only rat species occurring at collecting sites based on the key morphological characteristics. To determine the population-level genetic diversity pattern, we applied the 3-RADseq approach. After a series of filtrations (minor allele frequency < 0.05, Hardy-Weinberg equilibrium p < 1 × 10-7), 4042 SNPs were retained for the final dataset from the 25,439 SNPs initially isolated. The spatial structure and genetic diversity pattern of brown rats suggested that the rat population on Dok-do was likely introduced from Ulleung-do. Our work provides practical information that will assist in the management of invasive brown rats in vulnerable island ecosystems.

Relationship between adult subventricular neurogenesis and Alzheimer's disease: Pathologic roles and therapeutic implications.

Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by irreversible cognitive declines. Senile plaques formed by amyloid-ß (Aß) peptides and neurofibrillary tangles, consisting of hyperphosphorylated tau protein accumulation, are prominent neuropathological features of AD. Impairment of adult neurogenesis is also a well-known pathology in AD. Adult neurogenesis is the process by which neurons are generated from adult neural stem cells. It is closely related to various functions, including cognition, as it occurs throughout life for continuous repair and development of specific neural pathways. Notably, subventricular zone (SVZ) neurogenesis, which occurs in the lateral ventricles, transports neurons to several brain regions such as the olfactory bulb, cerebral cortex, striatum, and hippocampus. These migrating neurons can affect cognitive function and behavior in different neurodegenerative diseases. Despite several studies indicating the importance of adult SVZ neurogenesis in neurodegenerative disorders, the pathological alterations and therapeutic implications of impaired adult neurogenesis in the SVZ in AD have not yet been fully explained. In this review, we summarize recent progress in understanding the alterations in adult SVZ neurogenesis in AD animal models and patients. Moreover, we discuss the potential therapeutic approaches for restoring impaired adult SVZ neurogenesis. Our goal is to impart to readers the importance of adult SVZ neurogenesis in AD and to provide new insights through the discussion of possible therapeutic approaches.

Enantioselective Organocatalyzed Michael Addition of Isobutyraldehyde to Maleimides in Aqueous Media.

Thiourea was introduced into (R,R)-1,2-diphenylethylenediamine as an organocatalyst to promote the reaction between isobutyraldehydes and maleimides. Enantioselective Michael addition reaction was carried out as an eco-friendly method using water as the solvent. As a result of the reaction between isobutyraldehyde and maleimide, ≥97% yield and 99% enantioselectivity were obtained at a low catalyst loading of 0.01 mol%. The solvent effect can be explained by theoretical calculations that indicate the participation of a transition state, in which the CF3 substituent of the catalyst is a hydrogen bond activated by the surrounding water molecules. This discovery enabled the use of low catalyst loading in the organic reactions of chiral substances for pharmaceutical applications. Furthermore, a solvent effect for Michael reaction of the organocatalysts was proposed, and the organic reaction mechanisms were determined through quantum calculations.

Alteration of Neural Pathways and Its Implications in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease accompanied by cognitive and behavioral symptoms. These AD-related manifestations result from the alteration of neural circuitry by aggregated forms of amyloid-ß (Aß) and hyperphosphorylated tau, which are neurotoxic. From a neuroscience perspective, identifying neural circuits that integrate various inputs and outputs to determine behaviors can provide insight into the principles of behavior. Therefore, it is crucial to understand the alterations in the neural circuits associated with AD-related behavioral and psychological symptoms. Interestingly, it is well known that the alteration of neural circuitry is prominent in the brains of patients with AD. Here, we selected specific regions in the AD brain that are associated with AD-related behavioral and psychological symptoms, and reviewed studies of healthy and altered efferent pathways to the target regions. Moreover, we propose that specific neural circuits that are altered in the AD brain can be potential targets for AD treatment. Furthermore, we provide therapeutic implications for targeting neuronal circuits through various therapeutic approaches and the appropriate timing of treatment for AD.

Neuroprotective effects of ATPase inhibitory factor 1 preventing mitochondrial dysfunction in Parkinson's disease.

Mitochondrial dysfunction is a key element in the progression of Parkinson's disease (PD). The inefficient operation of the electron transport chain (ETC) impairs energy production and enhances the generation of oxidative stress contributing to the loss of dopaminergic cells in the brain. ATPase inhibitory factor 1 (IF1) is a regulator of mitochondrial energy metabolism. IF1 binds directly to the F1Fo ATP synthase and prevents ATP wasting during compromised energy metabolism. In this study, we found treatment with IF1 protects mitochondria against PD-like insult in vitro. SH-SY5Y cells treated with IF1 were resistant to loss of ATP and mitochondrial inner membrane potential during challenge with rotenone, an inhibitor of complex I in the ETC. We further demonstrated that treatment with IF1 reversed rotenone-induced superoxide production in mitochondria and peroxide accumulation in whole cells. Ultimately, IF1 decreased protein levels of pro-apoptotic Bax, cleaved caspase-3, and cleaved PARP, rescuing SH-SY5Y cells from rotenone-mediated apoptotic death. Administration of IF1 significantly improved the results of pole and hanging tests performed by PD mice expressing human α-synuclein. This indicates that IF1 mitigates PD-associated motor deficit. Together, these findings suggest that IF1 exhibits a neuroprotective effect preventing mitochondrial dysfunction in PD pathology.

Refracture After Removal of the PFNA in a Healed Intertrochanteric Femoral Fracture: Case Report.

Hardware removal in a healed intertrochanteric fracture in elderly, which is not a routine procedure, should be needed in the case of irritable hardware. The reports of refracture after hardware removal can be seen as sparse in current literature, which are focused to secondary femoral neck fracture after removal of the lag screw or blade. We experienced a case of the intertrochanteric refracture and varus collapse after the PFNA removal in a healed fracture, treated with valgus trochanteric osteotomy and angled blade plate fixation. The PFNA is an innovative device for the treatment of the trochanteric fracture; however, the complications after removal never end. Therefore, the removal from healed fracture in elderly who have osteoporosis should not be recommended unless intractable pain had persisted.

How to achieve an optimal alignment in medial opening wedge high tibial osteotomy?

Medial opening wedge high tibial osteotomy (MOWHTO) is a widely used surgical treatment option for medial compartmental osteoarthritis with varus deformity. It is important that proper lower limb alignment is achieved. However, there has been no consensus about an optimal alignment in MOWHTO. Most studies suggest that achieving valgus alignment is necessary, and recent studies support slight valgus mechanical alignment of less than 3° of mechanical femorotibial angle. Overcorrection and undercorrection is not recommended for achieving good surgical outcomes. To prevent undercorrection and overcorrection in MOWHTO, the method of placing the weight-bearing line in the target range must be precise. There are several ways to place a weight-bearing line within the target range. While the most important factor for a successful MOWHTO is achieving an ideal mechanical axis correction, there are a few other factors to consider, including joint line obliquity, posterior tibial slope, ligament balancing, and patellar height. Several factors exist that lead to undercorrection and overcorrection. Preoperative amount of varus deformity, lateral hinge fracture, and fixation failure can result in undercorrection, while medial soft tissue laxity and the amount of correction angle and target point beyond hypomochlion can result in overcorrection. This study aimed to review the literature on optimal alignment in MOWHTO and report on the factors to be considered to prevent correction errors and how to achieve an optimal alignment.

Eupatilin Suppresses Pancreatic Cancer Cells via Glucose Uptake Inhibition, AMPK Activation, and Cell Cycle Arrest.

BACKGROUND/AIM: Pancreatic cancer is one of the most devastating malignancies worldwide. Because of the disappointing outcome of traditional treatment, new drug candidates are being investigated. This study analysed the effect of eupatilin on pancreatic cancer cells. MATERIALS AND METHODS: Cell viability assay, western blot, siRNA transfection, 2-deoxyglucose uptake assay, AMP/ADP/ATP assay, and fluorescent activated cell sorting were performed. RESULTS: Eupatilin decreased cell viability and activated AMPK in MIA-PaCa2 cells. Eupatilin decreased glucose uptake in pancreatic cancer, which led to cell starvation and AMPK activation. It is well known that AMPK induces p21 and cell cycle arrest by activating p53. In MIA-PaCa2 cells, p53 is mutated and wild-type p53 protein is suppressed. Treatment with eupatilin induced p21 expression but inhibited the expression of mutated p53. Eupatilin activated Tap73, a p53 family member, which can substitute wild-type p53's role. CONCLUSION: Eupatilin shows an anticancer effect against pancreatic cancer cells via glucose uptake inhibition, AMPK activation, and cell cycle arrest.

Metformin induces muscle atrophy by transcriptional regulation of myostatin via HDAC6 and FoxO3a.

BACKGROUND: Skeletal muscle atrophy is a severe condition that involves loss of muscle mass and quality. Drug intake can also cause muscle atrophy. Biguanide metformin is the first-line and most widely prescribed anti-diabetic drug for patients with type 2 diabetes. The molecular mechanism of metformin in muscle is unclear. METHODS: Myostatin expression was investigated at the protein and transcript levels after metformin administration. To investigate the pathways associated with myostatin signalling, we used real-time polymerase chain reaction, immunoblotting, luciferase assay, chromatin immunoprecipitation assay, co-immunoprecipitation, immunofluorescence, primary culture, and confocal microscopy. Serum analysis, physical performance, and immunohistochemistry were performed using our in vivo model. RESULTS: Metformin induced the expression of myostatin, a key molecule that regulates muscle volume and triggers the phosphorylation of AMPK. AMPK alpha2 knockdown in the background of metformin treatment reduced the myostatin expression of C2C12 myotubes (-49.86 ± 12.03%, P < 0.01) and resulted in increased myotube diameter compared with metformin (+46.62 ± 0.88%, P < 0.001). Metformin induced the interaction between AMPK and FoxO3a, a key transcription factor of myostatin. Metformin also altered the histone deacetylase activity in muscle cells (>3.12-fold ± 0.13, P < 0.001). The interaction between HDAC6 and FoxO3a induced after metformin treatment. Confocal microscopy revealed that metformin increased the nuclear localization of FoxO3a (>3.3-fold, P < 0.001). Chromatin immunoprecipitation revealed that metformin induced the binding of FoxO3a to the myostatin promoter. The transcript-level expression of myostatin was higher in the gastrocnemius (GC) muscles of metformin-treated wild-type (WT) (+68.9 ± 10.01%, P < 0.001) and db/db mice (+55.84 ± 6.62%, P < 0.001) than that in the GC of controls (n = 4 per group). Average fibre cross-sectional area data also showed that the metformin-treated C57BL/6J (WT) (-31.74 ± 0.75%, P < 0.001) and C57BLKS/J-db/db (-18.11 ± 0.94%, P < 0.001) mice had decreased fibre size of GC compared to the controls. The serum myoglobin level was significantly decreased in metformin-treated WT mice (-66.6 ± 9.03%, P < 0.01). CONCLUSIONS: Our results demonstrate that metformin treatment impairs muscle function through the regulation of myostatin in skeletal muscle cells via AMPK-FoxO3a-HDAC6 axis. The muscle-wasting effect of metformin is more evident in WT than in db/db mice, indicating that more complicated mechanisms may be involved in metformin-mediated muscular dysfunction.

Gram-negative bacteria and their lipopolysaccharides in Alzheimer's disease: pathologic roles and therapeutic implications.

Alzheimer's disease (AD) is the most serious age-related neurodegenerative disease and causes destructive and irreversible cognitive decline. Failures in the development of therapeutics targeting amyloid-ß (Aß) and tau, principal proteins inducing pathology in AD, suggest a paradigm shift towards the development of new therapeutic targets. The gram-negative bacteria and lipopolysaccharides (LPS) are attractive new targets for AD treatment. Surprisingly, an altered distribution of gram-negative bacteria and their LPS has been reported in AD patients. Moreover, gram-negative bacteria and their LPS have been shown to affect a variety of AD-related pathologies, such as Aß homeostasis, tau pathology, neuroinflammation, and neurodegeneration. Moreover, therapeutic approaches targeting gram-negative bacteria or gram-negative bacterial molecules have significantly alleviated AD-related pathology and cognitive dysfunction. Despite multiple evidence showing that the gram-negative bacteria and their LPS play a crucial role in AD pathogenesis, the pathogenic mechanisms of gram-negative bacteria and their LPS have not been clarified. Here, we summarize the roles and pathomechanisms of gram-negative bacteria and LPS in AD. Furthermore, we discuss the possibility of using gram-negative bacteria and gram-negative bacterial molecules as novel therapeutic targets and new pathological characteristics for AD.

Enantioselective Thiolysis and Aminolysis of Cyclic Anhydrides Using a Chiral Diamine-Derived Thiourea Catalyst.

Catalytic desymmetrization of cyclic anhydrides has been widely investigated in the field of organocatalysis. Using this approach, many stereocenters can be established in a single, symmetry-breaking transformation. Herein, a thiourea organocatalyst was prepared in a single step from a chiral diamine, (R,R)-1,2-diphenylethylenediamine, and used for the desymmetrization of various cyclic anhydrides through double hydrogen-bonding activation. The asymmetric ring-opening reaction of the cyclic anhydride proceeded via the enantioselective addition reaction catalyzed by diamine thiourea. Thiolysis afforded the desired products in the yields of 86-98% and enantioselectivities of 60-94%, while aminolysis afforded the yields of 90-94% and enantioselectivities of 90-95%.

Dehydrozingerone inhibits renal lipotoxicity in high-fat diet-induced obese mice.

Ectopic fat accumulation in the kidneys causes oxidative stress, inflammation and cell death. Dehydrozingerone (DHZ) is a curcumin analog that exhibits antitumour, antioxidant and antidiabetic effects. However, the efficacy of DHZ in diabetic nephropathy (DN) is unknown. Here, we verified the efficacy of DHZ on DN. We divided the experimental animals into three groups: regular diet, 60% high-fat diet (HFD) and HFD with DHZ for 12 weeks. We analysed levels of renal triglycerides and urinary albumin and albumin-creatinine ratio, renal morphological changes and molecular changes via real-time polymerase chain reaction and immunoblotting. Furthermore, high glucose (HG)- or palmitate (PA)-stimulated mouse mesangial cells or mouse podocytes were treated with DHZ for 24 h. As a result, DHZ markedly reduced renal glycerol accumulation and albuminuria excretion through improvement of thickened glomerular basement membrane, podocyte loss and slit diaphragm reduction. In the renal cortex in the HFD group, phospho-AMPK and nephrin expression reduced, whereas arginase 2 and CD68 expression increased; however, these changes were recovered after DHZ administration. Increased reactive oxygen species (ROS) stimulated by HG or PA in podocytes was inhibited by DHZ treatment. Collectively, these findings indicate that DHZ ameliorates DN via inhibits of lipotoxicity-induced inflammation and ROS formation.

Biglycan reduces body weight by regulating food intake in mice and improves glucose metabolism through AMPK/AKT dual pathways in skeletal muscle.

While biglycan (BGN) is suggested to direct diverse signaling cascades, the effects of soluble BGN as a ligand on metabolic traits have not been studied. Herein, we tested the effects of BGN on obesity in high-fat diet (HFD)-induced obese animals and glucose metabolism, with the underlying mechanism responsible for observed effects in vitro. Our results showed that BGN administration (1 mg/kg body weight, intraperitoneally) significantly prevented HFD-induced obesity, and this was mainly attributed to reduced food intake. Also, intracerebroventricular injection of BGN reduced food intake and body weight. The underlying mechanism includes modulation of neuropeptides gene expression involved in appetite in the hypothalamus in vitro and in vivo. In addition, BGN regulates glucose metabolism as shown by improved glucose tolerance in mice as well as AMPK/AKT dual pathway-driven enhanced glucose uptake and GLUT4 translocation in L6 myoblast cells. In conclusion, our results suggest BGN as a potential therapeutic target to treat risk factors for metabolic diseases.

Identification of novel DNA hypermethylation of the adenylate kinase 5 promoter in colorectal adenocarcinoma.

Adenylate kinase 5 (AK5) belongs to the adenylate kinase family that catalyses reversible phosphate transfer between adenine nucleotides, and it is related to various energetic signalling mechanisms. However, the role of AK5 in colorectal cancer (CRC) has not been reported. In this study, AK5 was significantly hypermethylated in CRC compared to adjacent normal tissues (P < 0.0001) and normal tissues (P = 0.0015). Although the difference in mRNA expression was not statistically significant in all of them, the selected 49 cases of CRC tissues with AK5 hypermethylation with the cut off value of 40% showed a significant inverse correlation with mRNA expression (P = 0.0003). DNA methylation of AK5 promoter significantly decreased and AK5 expression recovered by 5-aza-2'-deoxycytidine, DNA methyltransferase inhibitor in CRC cell lines. In addition, AK5 promoter activity significantly decreased due to DNA methyltransferase, and it increased due to 5-aza. Moreover, AK5 regulated the phosphorylated AMPK and mTOR phosphorylation and inhibited the cell migration and cell invasion in CRC cell lines. Furthermore, low AK5 expression is associated with poor differentiation (P = 0.014). These results demonstrate that the AK5 promoter is frequently hypermethylated and induced methylation-mediated gene down-regulation. AK5 expression regulates AMPK/mTOR signalling and may be closely related to metastasis in colorectal adenocarcinoma.

Visible Light-Cured Antibacterial Collagen Hydrogel Containing Water-Solubilized Triclosan for Improved Wound Healing.

Infection is one of several factors that can delay normal wound healing. Antibacterial wound dressings can therefore promote normal wound healing. In this study, we prepared an antibacterial wound dressing, consisting of visible light-cured methacrylated collagen (ColMA) hydrogel and a 2-hydroxypropyl-beta-cyclodextrin (HP-ß-CD)/triclosan (TCS) complex (CD-ic-TCS), and evaluated its wound healing effects in vivo. The 1H NMR spectra of ColMA and CD-ic-TCS revealed characteristic peaks at 1.73, 5.55, 5.94, 6.43, 6.64, 6.84, 6.95, 7.31, and 7.55 ppm, indicating successful preparation of the two material types. In addition, ultraviolet-visible (UV-vis) spectroscopy proved an inclusion complex formation between HP-ß-CD and TCS, judging by a unique peak observed at 280 cm-1. Furthermore, ColMA/CD-ic-TCS exhibited an interconnected porous structure, controlled release of TCS, good biocompatibility, and antibacterial activity. By in vivo animal testing, we found that ColMA/CD-ic-TCS had a superior wound healing capacity, compared to the other hydrocolloids evaluated, due to synergistic interaction between ColMA and CD-ic-TCS. Together, our findings indicate that ColMA/CD-ic-TCS has a clinical potential as an antibacterial wound dressing.

ß-Cyclodextrin/Triclosan Complex-Grafted Methacrylated Glycol Chitosan Hydorgel by Photocrosslinking via Visible Light Irradiation for a Tissue Bio-Adhesive.

Accelerating wound healing with minimized bacterial infection has become a topic of interest in the development of the new generation of tissue bio-adhesives. In this study, we fabricated a hydrogel system (MGC-g-CD-ic-TCS) consisting of triclosan (TCS)-complexed beta-cyclodextrin (ß-CD)-conjugated methacrylated glycol chitosan (MGC) as an antibacterial tissue adhesive. Proton nuclear magnetic resonance (1H NMR) and differential scanning calorimetry (DSC) results showed the inclusion complex formation between MGC-g-CD and TCS. The increase of storage modulus (G') of MGC-g-CD-ic-TCS after visible light irradiation for 200 s indicated its hydrogelation. The swollen hydrogel in aqueous solution resulted in two release behaviors of an initial burst and sustained release. Importantly, in vitro and in vivo results indicated that MGC-g-CD-ic-TCS inhibited bacterial infection and improved wound healing, suggesting its high potential application as an antibacterial tissue bio-adhesive.