mRNA expression levels of cytochrome P450 CYP1A2, CYP3A4, and CYP3A5 in the epidermis: a focus on individual differences among Japanese individuals.

Various cytochrome P450 enzymes (CYPs) that contribute to drug metabolism are expressed in the skin. However, variation among individuals in CYP expression profiles is not well-understood.To investigate CYPs related to the metabolism of transdermal preparations in Japan, multiple skin tissue specimens of individuals of Japanese descent were prepared, and the mRNA expression levels of CYP1A2, CYP3A4, and CYP3A5 were measured. Associations between the expression patterns of these CYPs and body mass index (BMI) were also investigated.There were considerable individual differences in epidermal CYP1A2 mRNA expression levels, and CYP1A2 showed a weak positive correlation with CYP3A4 mRNA expression levels. In contrast to previous results for other organs, epidermal CYP3A4 mRNA expression levels showed a weak positive correlation with BMI.CYP3A4 in the epidermis may have been locally enhanced as a defence mechanism against xenobiotics in response to impaired barrier function. These differences in mRNA expression in the skin may affect the transdermal absorption of drugs, such as lidocaine and fentanyl, which are metabolised by multiple overlapping CYPs.Our study provides new insights into drug metabolism in the skin. These results are valuable for predicting drug effects and transdermal drug transfer rates in Japanese patients.

Association Between Anxiety and Depressive Symptoms During Prehospitalization Waiting Period and Quality of Recovery at Postoperative Day 3 in Perioperative Cancer Patients.

PURPOSE: Perioperative depressive symptoms are associated with poor postoperative quality of life (QOL), leading to prolonged hospital stays, and delayed return to society. Previous studies show that physical and mental states change on the third day after surgery, and there is a correlation between quality of recovery (QoR) on this day and QOL at 3 months after surgery. QoR after surgery is an important indicator of postoperative QOL. However, there are no reports on the association between depressive symptoms, and postoperative QoR. Therefore, the study purpose was to clarify the relationship between depressive symptoms in perioperative cancer patients during the prehospitalization waiting period, and QoR on the third postoperative day. DESIGN: This was a prospective cohort study. METHODS: We examined whether depressive symptoms during the prehospitalization waiting period were related to QoR on day 3 after surgery in perioperative cancer patients. Subjects were patients with primary tumors who underwent surgery under general anesthesia. Subjects completed self-administered questionnaires during the prehospitalization waiting period and on postoperative day 3. The presence and/or absence of depressive symptoms was measured using the Hospital Anxiety and Depression Scale. Subjects were divided into two groups: depressive symptoms or non-depressive symptoms. Postoperative QoR was determined using the QoR-40 questionnaire and we calculated the rate of change in QoR-40 global and dimension scores from preoperation to postoperation. FINDINGS: 231 individuals met the inclusion criteria and agreed to participate in the study. Of these, 173 were included in the analysis. Only the rate of change in emotional state differed significantly between groups (P = .022). Both global and dimension QoR-40 scores were lower in the depressive symptoms group than in the non-depressive symptoms group. CONCLUSIONS: These findings demonstrate the need to provide both psychological and physical support continuously from the preoperative to early postoperative stage for cancer patients with depressive symptoms in the prehospitalization waiting period.

CRMP1 and CRMP2 have synergistic but distinct roles in dendritic development.

Collapsin response mediator protein 2, CRMP2, has been identified as an intracellular signaling mediator for Semaphorin 3A (Sema3A). CRMP2 plays a key role in axon guidance, dendritic morphogenesis, and cell polarization. It has been also implicated in a variety of neurological and psychiatric disorders. However, the in vivo functions of CRMP2 remain unknown. We generated CRMP2 gene-deficient (crmp2(-/-) ) mice. The crmp2(-/-) mice showed irregular development of dendritic spines in cortical neurons. The density of dendritic spines was reduced in the cortical layer V pyramidal neurons of crmp2(-/-) mice as well as in those of sema3A(-/-) and crmp1(-/-) mice. However, no abnormality was found in dendritic patterning in crmp2(-/-) compared to wild-type (WT) neurons. The level of CRMP1 was increased in crmp2(-/-) , but the level of CRMP2 was not altered in crmp1(-/-) compared to WT cortical brain lysates. Dendritic spine density and branching were reduced in double-heterozygous sema3A(+/-) ;crmp2(+/-) and sema3A(+/-) ;crmp1(+/-) mice. The phenotypic defects had no genetic interaction between crmp1 and crmp2. These findings suggest that both CRMP1 and CRMP2 mediate Sema3A signaling to regulate dendritic spine maturation and patterning, but through overlapping and distinct signaling pathways.

Reduction and fragmentation of elastic fibers in the skin of obese mice is associated with altered mRNA expression levels of fibrillin-1 and neprilysin.

AIM OF THE STUDY: Our previous research suggested that obesity induces structural fragility in the skin. Elastic fibers impart strength and elasticity. In this study, we determined whether elastic fibers decrease in the skin of obese mice. MATERIALS AND METHODS: To confirm alterations in elastic fiber content due to obesity, we used spontaneously obese model mice (TSOD) and control mice (TSNO). Furthermore, to evaluate the elastin structure and gene expression dependent on the severity of obesity, an obesity-enhanced mouse model was developed by feeding a high fat diet to TSOD (TSOD-HF). Back skin samples were stained with hematoxylin and eosin and Elastica van Gieson for microscopic examination, and the samples were stained for immunohistochemical analysis of neprilysin. Gene expression levels were determined using a real-time PCR system. RESULTS: The abundance of elastic fibers beneath the epidermis was remarkably reduced and fragmented in TSOD as compared with TSNO. Fibrillin-1 mRNA levels in TSOD were significantly suppressed compared with those in TSNO, whereas neprilysin mRNA levels and immunohistochemical expression in TSOD were significantly increased, as compared with those in TSNO. The reduction of elastic fibers was enhanced and the expression levels of elastic fiber formed factors were significantly suppressed in TSOD-HF, as compared with those in the TSOD. CONCLUSIONS: The abundance of elastic fibers was reduced and fragmented in obesity, suggesting that the reduction in elastic fibers is initially caused by increased neprilysin and decreased fibrillin-1 expression, which may inhibit formation and stabilization of elastic fibers, resulting in skin fragility in obesity.

Gallic Acid, the Active Ingredient of Terminalia bellirica, Enhances Adipocyte Differentiation and Adiponectin Secretion.

Visceral obesity induces the onset of metabolic disorders such as insulin resistance and diabetes mellitus. Adipose tissue is considered as a potential pharmacological target for treating metabolic disorders. The fruit of Terminalia bellirica is extensively used in Ayurvedic medicine to treat patients with diseases such as diabetes mellitus. We previously investigated the effects of a hot water extract of T. bellirica fruit (TB) on obesity and insulin resistance in spontaneously obese type 2 diabetic mice. To determine the active ingredients of TB and their molecular mechanisms, we focused on adipocyte differentiation using mouse 3T3-L1 cells, which are widely used to study adipocyte physiology. We show here that TB enhanced the differentiation of 3T3-L1 cells to mature adipocytes and that one of the active main components was identified as gallic acid. Gallic acid (10-30 µM) enhanced the expression and secretion of adiponectin via adipocyte differentiation and also that of fatty acid binding protein-4, which is the target of peroxisome proliferator-activated receptor gamma (PPARγ), although it does not alter the expression of the upstream genes PPARγ and CCAAT enhancer binding protein alpha. In the PPARγ ligand assay, the binding of gallic acid to PPARγ was undetectable. These findings indicate that gallic acid mediates the therapeutic effects of TB on metabolic disorders by regulating adipocyte differentiation. Therefore, TB shows promise as a candidate for preventing and treating patients with metabolic syndrome.

Oral Intake of Linseed Oil Inhibits Skin Barrier Dysfunction in Obese Mice.

OBJECTIVE: Obesity is not only a risk factor for lifestyle-related diseases but also causes skin barrier dysfunction, which leads to a reduced quality of life due to dryness, itching, and scratching, and thus requires appropriate treatment. However, there are no studies on this issue. Therefore, this study aimed to examine whether oral intake of linseed oil is effective for skin barrier function in obesity and to confirm how the effect is demonstrated. METHODS: TSOD mice received either sterile distilled water (Control group) or linseed oil (Omega group), containing a high level of omega-3 fatty acids, including α-linolenic acid, orally for eight weeks. Mice were then irradiated with ultraviolet B (UVB) and three days later, transepidermal water loss (TEWL), which is the primary outcome of skin barrier function, was measured and gross skin appearance was observed. Hematoxylin and eosin (HE) staining and Ki-67 immunostaining were performed on skin samples. mRNA expression levels of the inflammatory markers Tnfα, Cox2, Mcp1, and Hmox1 were measured by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). We also performed fatty acid analysis of skin and erythrocytes by gas chromatography. Statistical analysis was performed using unpaired Student's t-test and Pearson's correlation analysis. RESULTS: Compared with the Control group, the Omega group exhibited lower TEWL values and little skin erythema. Histological analysis revealed thinner epidermis and fewer Ki-67 positive cells. Additionally, in the Omega group, mRNA levels of four inflammation-related genes were lower, α-linolenic acid levels in both skin and erythrocytes were higher, and a lower n-6/n-3 ratio was observed. And α-linolenic acid levels in the skin were negatively correlated with the expression levels of inflammation-related genes. CONCLUSION: Oral intake of linseed oil was found to inhibit skin barrier dysfunction in obesity. This effect was mediated by α-linolenic acid, a major component of linseed oil with anti-inflammatory properties, which was taken up by erythrocytes and supplied to the skin. Therefore, oral intake of linseed oil is expected to be a useful therapeutic method for skin barrier dysfunction in obesity.

Identification of Drugs and Patient Profiles at Risk for Severe Skin Injuries Due to Extravasation: Analysis of a Spontaneous Reporting System.

This study aimed to identify risk factors and combinations thereof that are associated with severe skin injuries due to the extravasation of injectable drugs. A cross-sectional study using the Japanese Adverse Drug Event Report database was conducted according to the RECORD-PE checklist. Adverse event reports related to necrosis, ulcers, or erosions due to extravasation were considered "with severe skin injury," and others were considered "without severe skin injury." Approximately 255 cases "with" and 260 cases "without" severe skin injury were identified. The relationship between the incidence of severe skin injury and age, sex, drugs, and primary disease was evaluated using the χ2 test. Association rule mining was used to evaluate the correlation between each combination of factors and skin injury. Nine factors were identified as independent risk factors for severe skin injury, including age (<10 or ≥70 years), peripheral parenteral nutrition use, and mental disorders. The association rule mining results suggested that a combination of specific patient backgrounds and drug use was associated with the incidence of necrosis or ulcers. The findings of this study reiterate that nurses might consider closely observing patients with the risk factors identified in this study for the prevention and early detection of extravasation-related skin injuries.

Why and by How Much is Insulin Absorption Reduced by Insulin-derived Amyloidosis? A Scoping Review.

Insulin therapy is one of the central treatments for diabetes mellitus. Insulin-derived localized amyloidosis (IDLA) is a known skin-related complication of insulin injection. This is one of the causes of poor glycemic control in diabetic patients on insulin therapy. The aim of this study was to review and update the findings on the extent and mechanism of reduced insulin absorption in IDLA. A literature search was conducted on decreased insulin absorption and its mechanisms, and nine references were selected, with seven of these on decreased insulin absorption and four on mechanisms. Insulin absorption at IDLA sites was reported to be 27-94% lower compared with normal sites. In addition, a comparison between nonpalpable and palpable IDLA sites revealed a significant decrease in insulin absorption at the palpable IDLA site. The mechanism of insulin malabsorption was found to be a reduction in insulin absorption at the palpable IDLA sites. Four mechanisms of decreased insulin absorption were identified: decreased subcutaneous blood flow, adsorption of administered insulin onto insulin amyloid fibers, impaired diffusion of insulin subcutaneously, and physical factors such as shaking of the insulin preparation. These mechanisms should be investigated in vivo in the future.

Novel biomarkers for the detection of wound infection by wound fluid RT-PCR in rats.

Wound infection is a form of host damage resulting from an imbalance in pathogen virulence and the host immune response. However, at present, diagnosis is based solely on bacterial numbers or inflammatory signs and is therefore not precise. Thus, infection diagnosis requires indicators of both of these factors. We focused on wound fluid because it includes both bacteria and host cells. The purpose of this study was to establish biomarkers that reflect both bacterial and host factors using the reverse transcription-polymerase chain reaction method on the centrifugal precipitation of wound fluids (wound fluid RT-PCR). We created full thickness wounds in animal models of the three groups: control, colonization and infection, which were conditioned by administration of different concentrations of Pseudomonas aeruginosa dispersion. Messenger RNA expression in bacteria and host cells was analysed. Expression of bacterial housekeeping genes was detected in the samples in the colonization and infection groups. Expression of host housekeeping genes was detected in all samples from the three groups. Expression of toxA, encoding the virulence factor exotoxin A, was detected in 90% of samples in the infection group only. Expression of Foxp3, encoding the transcription factor forkhead box P3, was detected in 100% of samples only in the colonization group. These results revealed that wound fluid RT-PCR analysis reflected both bacterial virulence and the host immune status, and we determined the combination of novel biomarkers that can discriminate these three groups. We anticipate that wound fluid RT-PCR could be applied in the future to diagnose wound infection.

Skin fragility in obese diabetic mice: possible involvement of elevated oxidative stress and upregulation of matrix metalloproteinases.

The purpose of this study was to test the hypothesis that obese diabetic mice exhibit marked skin fragility, which is caused by increased oxidative stress and increased matrix metalloproteinase (MMP) gene expression in the subcutaneous adipose tissue. Scanning electron microscopy of skin samples from Tsumura-Suzuki obese diabetic (TSOD) mice revealed thinner collagen bundles, and decreased density and convolution of the collagen fibres. Furthermore, skin tensile strength measurements confirmed that the dorsal skin of TSOD mice was more fragile to tensile force than that of non-obese mice. The mRNA expressions of heme oxygenase 1 (Hmox1), a marker of oxidative stress, Mmp2 and Mmp14 were increased in the adipose tissue of TSOD mice. Antioxidant experiments were subsequently performed to determine whether the changes in collagen fibres and skin fragility were caused by oxidative stress. Strikingly, oral administration of the antioxidant dl-α-tocopherol acetate (vitamin E) decreased Hmox1, Mmp2 and Mmp14 mRNA expressions, and improved the skin tensile strength and structure of collagen fibres in TSOD mice. These findings suggest that the skin fragility in TSOD mice is associated with dermal collagen damage and weakened tensile strength, and that oxidative stress and MMP overexpression in the subcutaneous adipose tissue may, at least in part, affect dermal fragility via a paracrine pathway. These observations may contribute to novel clinical interventions, such as dietary supplementation with antioxidants or application of skin cream containing antioxidants, which may overcome skin fragility in obese patients with diabetes.