Interactions between Age-Related Type 2 Diabetes and the Small Intestine.

The number of patients with type 2 diabetes is increasing worldwide. The mechanisms leading to type 2 diabetes and its complications is being researched; however, the pathological mechanisms of diabetes in the small intestine remain unclear. Therefore, we examined these pathological mechanisms in the small intestine using a mouse model of type 2 diabetes (KK-Ay/TaJcl) aged 10 and 50 weeks. The results showed that diabetes worsened with age in the mice with type 2 diabetes. In these mice, advanced glycation end products (AGEs) in the small intestine and mast cell expression increased, whereas diamine oxidase (DAO) decreased; increased tumor necrosis factor (TNF)-α and histamine levels in the plasma and small intestine were also detected. Additionally, the expression of zonula occludens (ZO)-1 and Claudin1 and cell adhesion molecules in the small intestine reduced. These results exacerbated with age. These findings indicate that type 2 diabetes causes AGE/mast cell/histamine and TNF-α signal transmission in the small intestine and decreases small intestinal wall cell adhesion molecules cause TNF-α and histamine to flow into the body, worsening the diabetic condition. In addition, this sequence of events is suggested to be strengthened in aged mice with type 2 diabetes, thus exacerbating the disease. These findings of this study may facilitate the elucidation of the pathological mechanisms of type 2 diabetes and its associated complications.

The Mechanism of 5-Fluorouracil-Induced Hyperpigmentation in HRM-2 Hairless Mice: Focus on the Increase of Blood Vessels.

5-Fluorouracil (5-FU), an effective chemotherapeutic agent for many solid tumors, has long been reported to cause pigmentation in patients treated intravenously, which occurs with increasing frequency of administration and decreases the QOL of the patients. Although melanin accumulation is thought to be the cause, the mechanism of pigmentation induced by 5-FU administration remains unclear, and there is no effective treatment for this problem. In this study, we investigated the mechanism of pigmentation induced by continuous 5-FU administration in 9-week-old male HRM-2 hairless mice for 8 weeks by focusing on the blood vessels for basic verification. In the auricular skin of 5-FU-administered mice, hyperpigmentation caused by melanin accumulation was observed macroscopically and by Fontana-Masson Staining. In addition, the expression of tyrosinase, melanin synthase, and blood vessel markers in the auricular skin was increased by 5-FU-administration in mice auricular skin. Other anticancer agents, cytarabine (Ara-C) and irinotecan (CPT-11), were also administered, and the differences between them and 5-FU were investigated; these changes were not observed in the auricles of these mice. These results suggest that tyrosinase is associated with 5-FU-induced melanin production and that an increase in blood vessels may be involved. Furthermore, pigmentation with melanin accumulation in the basal epidermal layer is a characteristic finding of 5-FU compared with Ara-C and CPT-11. In conclusion, this study indicates that 5-FU causes hyperpigmentation by melanin accumulation in a characteristic manner, including an increase in blood vessels.

Dementia Is Induced via the AGEs/Iba1/iNOS Pathway in Aged KK-Ay/Tajcl Mice.

The onset and exacerbation of dementia have been observed in elderly patients with type 2 diabetes. However, the underlying mechanism remains unclear. In this study, we investigated the effects of aging on the cognitive function in a mouse model of type 2 diabetes. Pathogen-free KK-Ay/TaJcl mice were used in this study. The cognitive abilities and memory declined in the mice and worsened in the 50-week-olds. The levels of advanced glycation end products (AGEs), receptor for AGE (RAGE), and Iba1 in the hippocampus were increased in the mice compared to those in the control mice. Hippocampal levels of CC-chemokine receptor 7 and inducible nitric oxide synthase, which are from M1-type macrophages that shift from microglia, were higher in KK-Ay/TaJcl mice than in control mice. Tumor necrosis factor (TNF)-α and nitric oxide (NO) levels secreted by M1-type macrophages were similarly elevated in the mice and were even higher at the age of 50 weeks. NO levels were markedly elevated in the 50-week-old mice. In contrast, differentiation of CD163 and arginase-1 did not change in both mouse types. Memory and learning declined with age in diabetic mice, and the AGEs/RAGE/M1-type macrophage/NO and TNF-α pathways played an important role in exacerbating memory and learning in those mice.

Changes in the AGE/Macrophage/TNF-α Pathway Affect Skin Dryness during KK-Ay/Tajcl Mice Aging.

Skin dryness associated with type 2 diabetes worsens with age; however, the underlying mechanisms remain unclear. Herein, we investigated the effects of aging on skin dryness using a type 2 diabetes mice model. Specific pathogen-free KK-Ay/TaJcl mice of different ages (10, 27, 40, and 50 weeks) were used in this study. The results confirmed that skin dryness worsens with age. Furthermore, increased levels of advanced glycation end products (AGE), prostaglandin E2 (PGE2), and tumor necrosis factor (TNF)-α, along with an increased expression of the major AGE receptor (RAGE), an increased macrophage number, and decreased collagen expression were observed in the skin of aged KK-Ay/TaJcl mice. In conclusion, dry skin conditions worsen with age in diabetic mice, and the AGE/RAGE/PGE2 and TNF-α pathways play an important role in exacerbating skin dryness during aging in these mice.

ACTH/cAMP-Mediated Skin Pigmentation Caused by 5-Fluorouracil Administration.

Anticancer drugs exhibit many side effects, including skin pigmentation, which often lowers patient QOL. However, the mechanism of pigmentation caused by anticancer drugs remains unknown. The purpose of this study was to elucidate the mechanism of anticancer drug-induced skin pigmentation using 5-fluorouracil (5-FU), a widely used anticancer drug. Specific pathogen-free, 9-week-old Hos:HRM-2 male mice were intraperitoneally administered 5-FU daily for 8 weeks. Skin pigmentation was observed at the end of the study. Mice treated with 5-FU were also administered inhibitors of cAMP, α-melanocyte-stimulating hormone (α-MSH), and adrenocorticotropic hormone (ACTH) for analysis. Administration of oxidative stress, nuclear factor-kappa B (NF-κB), cAMP, and ACTH inhibitors reduced pigmentation in 5-FU-treated mice. These results indicate that the oxidative stress/NF-κB/ACTH/cAMP/tyrosinase pathway plays an important role in pigmentation in 5-FU-treated mice.

Japan Geriatrics Society "Statement for the use of telemedicine in geriatric care: Telemedicine as a complement to in-person medical practice": Geriatric Medical Practice Committee consensus statement.

Telemedicine has changed from a way to treat patients with limited access to hospitals to a necessary method of treatment for non-urgent conditions during the coronavirus disease 2019 pandemic. There are two styles of telemedicine, namely "hybrid medical care" and "gateway medical care," which take advantage of the characteristics of online medical care and might become important in the near future. During hybrid medical care, a patient and their primary care physician have face-to-face medical care while simultaneously being examined by a specialist physician through telemedicine, leading to an overall improvement in the level of local medical care and expansion in the number of treatable diseases. Gateway medical practice is a form of telemedicine used for patients who would otherwise refuse or not receive in-person medical care to engage in consultation with a physician. Telemedicine allows physicians to determine disease severity and triage patients, while reducing unnecessary home visits, emergency hospitalizations and the spread of infection. Telemedicine is less intense than in-person medical care, and allows for easier collaboration with other healthcare providers. However, telemedicine is not optimal for conditions requiring a definitive diagnosis and a comprehensive understanding of the patient's medical history. It is limited by the patient's ability to use telemedicine devices, and the risk of accidental treatments and fraud. The use of telemedicine might result in the development of new, online comprehensive geriatric assessment tools and technologies. Geriatr Gerontol Int 2022; 22: 913-916.

Skin, Liver, and Kidney Interactions Contribute to Skin Dryness in Aging KK-Ay/Tajcl Mice.

Type 2 diabetes is a lifestyle-related disease that affects people worldwide and is especially prevalent in the elderly. Many elderly people with diabetes also complain of dry skin; however, the relationship between aging and dry skin in type 2 diabetes is unknown. The purpose of this study was to examine the interaction between aging and dry skin using the specific pathogen-free KK-Ay/TaJcl type 2 diabetes mouse model. Skin dryness in this model increases with age and was evaluated at 10, 27, 40, and 50 weeks. We observed increased mast cell expression, increased histamine and matrix metalloproteinase-1 levels, and decreased collagen expression in the skin of aging KK-Ay/TaJcl mice. In addition, the increased expression of angiopoietin 2, interleukin-6, tumor necrosis factor-α, and endostatin in the blood indicated kidney damage in this model. Aging KK-Ay/TaJcl mice also showed fatty liver pathology, which led to increased reactive oxygen species in the blood and liver, as well as the increased expression of M1 macrophages in the liver. These results showed that dry skin is associated with skin, kidney, and liver interactions in an aging type 2 diabetes mouse model.

Effect of Celecoxib Administration on the Skin of 40-Week-Old Mice.

Various side effects associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in analgesia have been reported. Among the NSAIDs, celecoxib has fewer side effects and is often used in therapeutic applications. However, the effect of celecoxib on aged skin is unknown. In this study, we investigated the effects of celecoxib administration on the skin of aged mice. We analyzed a 40-week-old mouse model and a 10-week-old mouse as the control group. The animals were orally administered celecoxib for four consecutive days and then killed and dissected the day after the last dose. In aged mice treated with celecoxib, the water content of the stratum corneum, which is one of the markers of dry skin, was lower than that in the control and young mice groups. In addition, serum hyaluronic acid, creatinine, and inflammatory cytokines in the collected blood samples of aged mice were elevated compared to those in other mice groups, suggesting the onset of acute renal injury. Therefore, it was considered that acute renal injury occurred from the administration of celecoxib to aged mice, whereas dry skin developed by the promotion of inflammatory cytokine secretion and release into the bloodstream in this group.

Relationships of pain-causing substances with dry skin and effects of zaltoprofen on alleviation of symptoms in arthritis model mice.

Purpose: Skin dryness is a symptom of rheumatoid arthritis (RA). However, the mechanisms through which dry skin is induced in RA are unclear. Accordingly, in this study, we characterized substances related to pruritus and pain and then evaluated whether oral administration of zaltoprofen (ZLT) alleviated the symptom of dry skin induced by RA in model mice.Material and Methods: DBA/1JJmsSlc collagen-induced arthritis model mice were treated with ZLT, and transepidermal water loss (TEWL), capacitance, and inflammation-, pruritus-, and pain-related markers were assessed.Results: Our findings demonstrated that arthritis model mice treated with ZLT exhibited suppression of increases in TEWL and decreases in capacitance. Furthermore, ZLT also blocked the increase in mast cell numbers, substance P expression, and cyclo-oxygenase-2 expression in the skin and prevented enhancement of plasma levels of thymic stromal lymphopoietin, tumour necrosis factor-α, interleukin-6, histamine, and bradykinin. No changes in plasma levels of corticosterone or reactive oxygen species or skin levels of glucocorticoid receptor were observed in ZLT-treated arthritis model mice.Conclusions: Overall, these findings suggested that patients with RA may benefit from biopharmacy to alleviate joint symptoms and nonsteroidal anti-inflammatory drugs for pain relief and alleviation of skin symptoms.

Skin Dryness Induced in the KK-Ay/TaJcl Type 2 Diabetes Mouse Model Deteriorates Following Dapagliflozin Administration.

Various diabetic drugs have been developed as the number of patients with type 2 diabetes has increased. Sodium-glucose cotransporter (SGLT)-2 inhibitors have been developed as novel therapeutic agents. However, SGLT-2 inhibitors cause skin dryness. The mechanism through which SGLT-2 inhibitors cause skin dryness is unknown. The purpose of this study was to investigate the mechanism through which dapagliflozin, a SGLT-2 inhibitor, induces skin dryness. Specific pathogen-free KK-Ay/TaJcl (type 2 diabetes model) mice were orally administered with SGLT-2 inhibitor (dapagliflozin) daily for 4 weeks at a dose of 1 mg/kg/d. Skin dryness induced in KK-Ay/TaJcl mice became severe after dapagliflozin administration. Dapagliflozin treatment decreased collagen type I and hyaluronic acid levels in mice; additionally, it affected the transforming growth factor (TGF)-ß/hyaluronan synthase pathway, further reducing hyaluronic acid levels. The results indicate that the reduction in hyaluronic acid levels plays an important role in the occurrence of dry skin in diabetes.

Indomethacin, a Non-steroidal Anti-inflammatory Drug, Induces Skin Dryness via PPARγ in Mice.

Cyclooxygenase (COX)-1-selective inhibitors have side effects such as itching and dryness of the skin. In this study, the degree of skin dryness and the onset mechanism of this condition were investigated by comparing the effects of three non-steroidal anti-inflammatory drugs (NSAIDs) in mice. Mice were orally administered either indomethacin, loxoprofen sodium, or celecoxib (n = 5 per group) once daily for four consecutive days, and blood samples as well as skin and jejunal tissues were isolated on day 5. In the mice treated with indomethacin, transepidermal water loss was significantly increased, and dry skin was observed. In addition, the expression of matrix metalloproteinase (MMP)-I, mast cells, CD163, CD23, CD21, histamine, and peroxisome proliferation-activated receptor (PPAR)γ in the skin and jejunum was increased, and the blood levels of interleukin-10 and immunoglobulin E were also increased. In contrast, the expression of collagen type I in the skin was decreased. These results show that indomethacin activates PPARγ in the skin and jejunum, changes the polarity of macrophages, increases the secretion of MMP-1 from mast cells, and decomposes collagen type I, leading to dry skin.

Onset Mechanism and Pharmaceutical Management of Dry Skin.

Dry skin is a common symptom of various conditions, and elderly individuals commonly exhibit this physiological symptom. Dry skin develops owing to sebum deficiency; however, the use of moisturizers can typically overcome this issue, particularly in patients in whom there are no other skin problems. If dry skin is left untreated, itching and eczema can occur, resulting in skin damage. Additionally, hemodialysis patients exhibit reduced barrier function and can experience pain associated with repeated needle insertion; the repeated use of lidocaine tape to manage the pain can cause further skin damage. To reduce the occurrence of dry skin, the skin is hydrated using moisturizers. Dry skin is also prominent in patients with varicose veins in the lower extremities, and many biochemical studies have shown that skin immunity is altered in patients with dry skin. Moreover, the incidences of dry skin and pruritus differ in male and female patients. Furthermore, in elderly patients, zinc deficiency is likely to cause dry skin, and zinc supplementation may maintain skin hydration. To date, few reports have described dry skin from a clinical point of view. In this review, research on dry skin is presented, and the findings of basic research studies are integrated.

High-Dose Vitamin C Exerts Its Anti-cancer Effects in a Xenograft Model of Colon Cancer by Suppressing Angiogenesis.

Several studies have been conducted to investigate the anti-cancer effects of vitamin C (VC). However, the effect of high-dose VC administration on tumor angiogenesis remains unclear. Focusing on our high-dose VC, our study investigated the effect of high-dose VC (4 g/kg) on vascular endothelial growth in mice with xenografts of a rectal cancer cell line referred to as Colon 26. Male mice harboring Colon 26 tumors were established, and high-dose VC solution was orally administered once daily for 14 d. On the final day of the study, the lower limb tumor tissues and serum samples were collected and analyzed for the expression of tumor angiogenesis related proteins as well as the levels of reactive oxygen species (ROS). Oral VC administration decreased tumor volumes and increased p53 and endostatin levels. In addition, plasma and in tumor part ROS levels and tissue hypoxia inducible factor-1α (HIF-1α) were reduced by VC administration. In addition, the levels of vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor D (VEGFD) were decreased by VC administration. These results suggest that VC exerts its anti-cancer effects by suppressing angiogenesis.

High-Dose Vitamin C Administration Inhibits the Invasion and Proliferation of Melanoma Cells in Mice Ovary.

Several studies have been conducted to explore the anticancer effects of vitamin C (VC). However, the effect of high-dose VC administration on melanoma is still unknown. Therefore, in this study, we investigated the effects of high-dose VC (4 g/kg) on the invasion and proliferation of melanoma cells in various organs of mice. B16 melanoma cells (1 × 106 cells/100 µL) were intravenously injected into the tails of female mice, and VC solution (4 g/kg) was orally administered once a day for 14 d. On the 15th day, samples from the liver, lungs, jejunum, and ovaries were collected and analyzed for invasion and proliferation of melanoma cells. Oral VC administration decreased the number of dihydroxyphenylalanine (DOPA)-positive cells and gp100-positive melanoma cells in the ovaries and suppressed the invasion and proliferation of melanoma. Compared to melanoma-administered mice, macrophage inflammatory protein-2 levels and number of neutrophils were increased in the VC + melanoma-administered mice. Furthermore, the concentrations of VC, iron, and hydrogen peroxide, and the number of terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling (TUNEL)-positive cells were significantly increased in the ovaries of VC + melanoma-administered mice compared to those of melanoma-administered mice. These results suggest that VC can reduce the invasion and proliferation of melanoma cells in the ovaries, and neutrophils in the ovaries play an important role in achieving this melanoma-suppressive effect.

Differences in the mechanism of type 1 and type 2 diabetes-induced skin dryness by using model mice.

Diabetes induces dry skin that may cause infective diseases. In this study, we aimed to clarify the mechanism of diabetes-induced skin dryness in animal models. We also examined the difference in the mechanism of skin dryness in type 1 and type 2 diabetes. We examined skin dryness in type 1 diabetes model mice (streptozotocin [STZ] induction), non-obesity type 2 diabetes model mice (newborn STZ injection), and obesity type 2 diabetes model mice (KK-Ay/TaJcl). An increase in transepidermal water loss was observed in the type 1 diabetes model mice, and reduced skin hydration was observed in the type 2 diabetes model mice. In the type 1 diabetes model mice, an increase in advanced glycation end products and matrix metalloproteinase-9 led to a decline in collagen IV level, inducing skin dryness. In the obesity type 2 diabetes model mice, an increase in the release of histamine and hyaluronidase by mast cells resulted in a decline in the level of hyaluronic acid, inducing skin dryness. However, in the non-obesity type 2 diabetes model mice, the main factors of skin dryness could not be clearly identified. Nevertheless, inflammatory cytokine levels increased. We hypothesize that inflammatory cytokines disrupt the collagen of the skin. Diabetes caused skin dryness in each mouse model, and the mechanism of skin dryness differed by diabetes type.

[Transepidermal Water Loss (TEWL)-decreasing Effect by Administration of Zinc in the Elderly People].

In recent years, it has become clear that zinc deficiency is closely related in several skin disorders. In elderly people, chronic itch and dry skin are common. In addition, the zinc concentrations are known to decrease with age. Therefore, we examined the beneficial effects of oral zinc supplementation on dry skin and itch in elderly people. Patients 65 years of age or older who visited the Jose Clinic (Odai-town, Mie Pref.) with serum zinc concentrations below 80 µg/dL were enrolled in the study (low zinc group). The participants were administered zinc acetate hydrate for 12 weeks from the start of the study, and transepidermal water loss (TEWL) and stratum corneum moisture content measurements, blood collection, and itch evaluation were performed every 4 weeks. Patients in the control group had serum zinc concentrations of ≥80 µg/dL (the normal zinc group). Results showed that TEWL was significantly higher in the low zinc group than in the normal zinc group, indicating that skin barrier function is impaired in the low zinc group. Serum zinc concentrations increased and TEWL decreased significantly over the 12 weeks of treatment. In addition, a negative correlation was observed between serum zinc concentrations and TEWL. Our results indicate that zinc supplementation is effective to improve the skin barrier function in elderly people.

Carbon Monoxide Rescues the Developmental Lethality of Experimental Rat Models of Rhabdomyolysis-Induced Acute Kidney Injury.

Many victims, after being extricated from a collapsed building as the result of a disaster, suffer from disaster nephrology, a term that is referred to as the crush syndrome (CS). Recommended treatments, which include dialysis or the continuous administration of massive amounts of fluid are not usually easy in cases of such mass natural disasters. In the present study, we examined the therapeutic performance of a biomimetic carbon monoxide (CO) delivery system, CO-enriched red blood cells (CO-RBCs), on experimental animal models of an acute kidney injury (AKI) induced by traumatic and nontraumatic rhabdomyolysis, including CS and rhabdomyolysis with massive hemorrhage shock. A single CO-RBC treatment was found to effectively suppress the pathogenesis of AKI with the mortality in these model rats being improved. In addition, in further studies using glycerol-induced rhabdomyolysis model rats, the pathogenesis of which is similar to that for the CS, AKI and mortality were also reduced as the result of a CO-RBC treatment. Furthermore, CO-RBCs were found to have renoprotective effects via the suppression of subsequent heme protein-associated renal oxidative injury; the oxidation of myoglobin in the kidneys, the generation of reactive oxygen species by free heme produced from degraded-cytochrome P450 and hemoglobin-associated renal injury. Because CO-RBCs can be prepared and used at both hospitals and at a disaster site, these findings suggest that CO-RBCs have the potential for use as a novel cell therapy against both nontraumatic and traumatic rhabdomyolysis including CS-induced AKI. SIGNIFICANCE STATEMENT: After mass natural and man-made disasters, people who are trapped in collapsed buildings are in danger of acute kidney injury (AKI), including crush syndrome (CS)-related AKI. This paper reports that carbon monoxide-enriched red blood cells (CO-RBCs), which can be prepared at both hospitals and disaster sites, dramatically suppressed the pathogenesis of CS-related AKI, thus improving mortality via suppressing heme protein-associated renal injuries. CO-RBCs have the potential for serving as a practical therapeutic agent against disaster nephrology associated with the CS.

[Protection of the Skin Barrier Function in Inflammatory Disease].

The skin is the largest human organ, comprising the epidermis that is composed of epithelial tissue, the dermis composed of connective tissue, and the innermost subcutaneous tissue. Generally, skin conditions are due to aging and the influence of the external environment, but empirically patients with gastrointestinal diseases are more prone to pruritus and inflammation caused by dry skin. A decrease in the skin barrier function, involving immunocompetent mast cells and oxidative stress, was noted in indomethacin-induced small intestine inflammation, dextran sodium sulfate (DSS)-induced ulcerative colitis, and azoxymethane+DSS-induced colorectal cancer. A possible correlation was found to exist between inflammatory gastrointestinal diseases and the skin, and this correlation was investigated using a rheumatoid arthritis model as representative of inflammatory diseases. Similar to previously reported results, deterioration of the skin barrier function was observed, and new information was obtained by analyzing changes in inflammatory markers in the blood and skin tissues. Understanding the underlying mechanism of decreased skin barrier function will help in establishing effective prophylaxis and treatment methods and clarify the importance of crosstalk between organs. It will also help accelerate drug development.