Advances of Iron and Ferroptosis in Diabetic Kidney Disease.

Diabetes mellitus presents a significant threat to human health because it disrupts energy metabolism and gives rise to various complications, including diabetic kidney disease (DKD). Metabolic adaptations occurring in the kidney in response to diabetes contribute to the pathogenesis of DKD. Iron metabolism and ferroptosis, a recently defined form of cell death resulting from iron-dependent excessive accumulation of lipid peroxides, have emerged as crucial players in the progression of DKD. In this comprehensive review, we highlight the profound impact of adaptive and maladaptive responses regulating iron metabolism on the progression of kidney damage in diabetes. We summarize the current understanding of iron homeostasis and ferroptosis in DKD. Finally, we propose that precise manipulation of iron metabolism and ferroptosis may serve as potential strategies for kidney management in diabetes.

Random fluctuations and synaptic plasticity enhance working memory activities in the neuron-astrocyte network.

Random fluctuations are inescapable feature in biological systems, but appropriate intensity of randomness can effectively facilitate information transfer and memory encoding within the nervous system. In the study, a modified spiking neuron-astrocyte network model with excitatory-inhibitory balance and synaptic plasticity is established. This model considers external input noise, and allows investigating the effects of intrinsic random fluctuations on working memory tasks. It is found that the astrocyte network, acting as a low-pass filter, reduces the noise component of the total input currents and improves the recovered images. The memory performance is enhanced by selecting appropriate intensity of random fluctuations, while excessive intensity can inhibit signal transmission of network. As the intensity of random fluctuations gradually increases, there exists a maximum value of the working memory performance. The cued recall of the network markedly decreases excessive input noise relative to test images. Meanwhile, a greater contrast effect is observed as the external input noise increases. In addition, synaptic plasticity reduces the firing rates and firing peaks of neurons, thus stabilizing the working memory activity during the test. The outcomes of this study may provide some inspirations for comprehending the role of random fluctuations in working memory mechanisms and neural information processing within the cerebral cortex.

Alternations in the human skin, gut and vaginal microbiomes in perimenopausal or postmenopausal Vulvar lichen sclerosus.

Vulvar lichen sclerosus (VLS) is a chronic and progressive dermatologic condition that can cause physical dysfunction, disfigurement, and impaired quality of life. However, the etiology of VLS remains unknown. The vulvar skin, intestinal and vaginal microbiomes have been postulated to play important roles in the pathogenesis of this disease. The aim of this study was to compare the compositional characteristics of the vulvar skin, vagina, and gut microbiota between perimenopausal or postmenopausal VLS patients and healthy controls. The study involved six perimenopausal or postmenopausal VLS patients which were based on characteristic clinical manifestations and histologic confirmation and five healthy controls. The pruritus severity of each patient was evaluated using the NRS scale, and the dermatology-specific health-related quality of life was assessed using the Skindex-16. Metagenomic sequencing was performed, and the results were analyzed for alpha and beta diversity. LEfSe analysis were used to investigate the microbial alterations in vulvar skin, gut and vagina. KEGG databases were used to analyze differences in functional abundance. The study found significant differences in alpha diversity between the two groups in stool and vaginal samples (P < 0.05). Patients with VLS had a higher abundance of Enterobacter cloacae, Flavobacterium_branchiophilum, Mediterranea_sp._An20, Parabacteroides_johnsoniiand Streptococcus_bovimastitidis on the vulvar skin, while Corynebacterium_sp._zg-913 was less abundant compared to the control group. The relative abundance of Sphingomonas_sp._SCN_67_18, Sphingobium_sp._Ant17, and Pontibacter_sp_BT213 was significantly higher in the gut samples of patients with VLS.Paenibacillus_popilliae,Gemella_asaccharolytica, and Coriobacteriales_bacterium_DNF00809 compared to the control group. Additionally, the vaginal samples of patients with VLS exhibited a significantly lower relative abundance of Bacteroidales_bacterium_43_8, Bacteroides_sp._CAG:20, Blautia_sp._AM28-10, Fibrobacter_sp._UWB16, Lachnospiraceae_bacterium_AM25-39, Holdemania_filiformis, Lachnospiraceae_bacterium_GAM79, and Tolumonas_sp. Additionally, the butyrate-producing bacterium SS3/4 showed a significant difference compared to the controls. The study found a negative relationship between Sphingobium_sp._Ant17 in stool and Skindex-16 (P < 0.05), while Mediterranea_sp._An20 had a positive correlation with Skindex-16 (P < 0.05) in the skin. Additionally, our functional analysis revealed alterations in Aminoacyl_tRNA_biosynthesis, Glutathione_metabolism, the pentose phosphate pathway, and Alanine__aspartate_and_glutamate_metabolism in the VLS patient group. The study suggests that perimenopausal or postmenopausal patients with VLS have a modified microbiome in the vulvar skin, gut, and vagina. This modification is linked to abnormal energy metabolism, increased oxidative stress, and abnormal amino acid metabolism.

Enhanced homogeneity and flexibility in a humidity sensor using cellulose nanocrystal-based composite film with circular shear flow.

Cellulose nanocrystal (CNC) film is known to be one kind of dynamic color-sensing material, capable of reversible color changes in response to varying humidity levels. However, the brittleness, low hygroscopicity and poor homogeneity of these films have hindered their development. To address this limitation, we present a novel approach where we combine natural deep eutectic solvents (NADES) with sorbitol under the influence of circular shear flow to craft a CNC humidity-sensitive film with enhanced flexibility, hygroscopicity and homogeneity. The inclusion of sorbitol and NADES enhances hygroscopicity and improves the flexibility. Surprisingly, the introduction of circular shear flow was found not only to improve homogeneity, macroscopically and microscopically, but also to further enhance flexibility, toughness, and water absorption capability. The resulting composite films demonstrated highly reversible color changes across the whole visible spectrum depending on the relative humidity, showing their capability to be reliable humidity-sensing materials. Thanks to the improved homogeneity and flexibility, the obtained humidity-sensing composite film can be employed in its entirety without the need for cutting, making it a promising candidate for various applications.

Low-molecular-weight organic acids-mediated transport of neonicotinoid pesticides through saturated soil porous media: Combined effects of the molecular structures of organic acids and the chemical properties of contaminants.

Empirical information about the transport properties of neonicotinoid pesticides through the soil as affected by the ubiquitous low molecular weight organic acids (LMWOAs) is lacking. Herein, the impacts of three LMWOAs with different molecular structures, including citric acid, acetic acid, and malic acid, on the mobility characteristics of two typical neonicotinoid pesticides (Dinotefuran (DTF) and Nitenpyram (NTP)) were explored. Interestingly, under acidic conditions, different mechanisms were involved in transporting DTF and NTP by adding exogenous LMWOAs. Concretely, acetic acid and malic acid inhibited DTF transport, ascribed to the enhanced electrostatic attraction between DTF and porous media and the additional binding sites provided by the deposited LMWOAs. However, citric acid slightly enhanced DTF mobility due to the fact that the inhibitory effect was weakened by the steric hindrance effect induced by the deposited citric acid with a large molecular size. In comparison, all three LMWOAs promoted NTP transport at pH 5.0. Because the interaction between NTP with soil organic matter (e.g., via π-π stacking interaction) was masked by the LMWOAs coating on soil surfaces. Nevertheless, LMWOAs could promote the mobility of both neonicotinoid pesticides at pH 7.0 due to the steric hindrance effect caused by the deposited organic acids and the competitive retention between LMWOAs and pesticides for effective surface deposition sites of soil particles. Furthermore, the extent of the promotion effects of LMWOAs generally followed the order of citric acid > malic acid > acetic acid. This pattern was highly related to their molecular structures (e.g., number and type of functional groups and molecular size). Additionally, when the background solutions contained Ca2+, the bridging effect of cations also contributed to the transport-enhancement effects of LMWOAs. The findings provide valuable information about the mobility behaviors of neonicotinoid pesticides co-existing with LMWOAs in soil-water systems.

Working memory depends on the excitatory-inhibitory balance in neuron-astrocyte network.

Previous studies have shown that astrocytes are involved in information processing and working memory (WM) in the central nervous system. Here, the neuron-astrocyte network model with biological properties is built to study the effects of excitatory-inhibitory balance and neural network structures on WM tasks. It is found that the performance metrics of WM tasks under the scale-free network are higher than other network structures, and the WM task can be successfully completed when the proportion of excitatory neurons in the network exceeds 30%. There exists an optimal region for the proportion of excitatory neurons and synaptic weight that the memory performance metrics of the WM tasks are higher. The multi-item WM task shows that the spatial calcium patterns for different items overlap significantly in the astrocyte network, which is consistent with the formation of cognitive memory in the brain. Moreover, complex image tasks show that cued recall can significantly reduce systematic noise and maintain the stability of the WM tasks. The results may contribute to understand the mechanisms of WM formation and provide some inspirations into the dynamic storage and recall of memory.

Prevalence and factors associated with anxiety and depression among community-dwelling older adults in Hunan, China: a cross-sectional study.

BACKGROUND: Older adults' psychological health is a public health issue that cannot be ignored, especially when these psychological health problems and related factors change across different social backgrounds because of rapid changes in traditions and family structures and the epidemic responses after the outbreak of COVID-19 in China. The aim of our study is to determine the prevalence of anxiety and depression and their associated factors among community-dwelling older adults in China. METHODS: A cross-sectional study was conducted from March to May 2021 with 1173 participants aged 65 years or above from three communities in Hunan Province, China who were selected using convenience sampling. A structured questionnaire including sociodemographic characteristics, clinical characteristics, the Social Support Rating Scale (SSRS), the 7-Item Generalized Anxiety Disorder scale (GAD-7), and the Patient Health Questionnaire-9 Item (PHQ-9) was used to collect relevant demographic and clinical data and to measure social support status, anxiety symptoms, and depressive symptoms, respectively. Bivariate analyses were conducted to explore the difference in anxiety and depression based on samples' different characteristics. The multivariable logistic regression analysis was performed to test for significant predictors of anxiety and depression. RESULTS: The prevalence of anxiety and depression were 32.74% and 37.34%, respectively. Multivariable logistic regression analysis revealed that being female, being unemployed before retirement age, lacking physical activity, having physical pain, and having three or more comorbidities were significant predictors for anxiety. Subjective social support and support utilization were significant protective factors. Regarding depression, religion, lacking physical activity, having physical pain, having three or more comorbidities were found to be significant predictors. Support utilization was a significant protective factor. CONCLUSIONS: The study group showed a high prevalence of anxiety and depression. Gender, employment status, physical activity, physical pain, comorbidities, and social support were associated with psychological health problems of older adults. These findings suggest that governments should focus on the psychological health problems of older adults by raising community awareness of issues related to older adults' psychological health. They should also screen for anxiety and depression among high-risk groups and encourage individuals to seek supportive counseling.

Energy-efficiency computing of up and down transitions in a neural network.

Spontaneous periodic up and down transitions of membrane potentials are considered to be a significant spontaneous activity of slow-wave sleep. Previous theoretical studies have shown that stimulation frequency and the dynamics of intrinsic currents have a major influence on synchronicity and firing rate of spontaneous fluctuation. Energy consumption is driven by internal spontaneous activity. However, its energy consumption and energy efficiency are not clear. Therefore, this article simulates the up and down transitions based on a neural network and discusses the energy consumption and energy efficiency. It is found that the dynamics of intrinsic currents have a great impact on the energy consumption and energy efficiency in the process. The energy consumption is influenced by the size of the period and the average power consumption of the state. The average power consumption by the up state is always greater than the consumption by the down state, and the energy consumption of the transition is more than firing. In addition, the lower average proportion of duration of the up state in the cycle leads to higher energy efficiency. Energy consumption is reduced and energy efficiency is enhanced by adjusting parameters of the network. The study helps us to understand and further explore the metabolic consumption of spontaneous activities.NEW & NOTEWORTHY We use a more biological neural network to explore energy consumption and energy efficiency of up and down transitions. Specifically, we find that average energy consumption is more than that caused by action potentials, which proves that metabolic consumption is acquired substantially in the resting state as well. We also find that energy efficiency is influenced by the proportion of duration of the up state in the cycle. These findings may further improve the economy of the nervous system.

Night shifts, insomnia, anxiety, and depression among Chinese nurses during the COVID-19 pandemic remission period: A network approach.

Background: The outbreak of the COVID-19 pandemic imposed a heavy workload on nurses with more frequent night shifts, which led to higher levels of insomnia, depression, and anxiety among nurses. The study aimed to describe the symptom-symptom interaction of depression, anxiety, and insomnia among nurses and to evaluate the impact of night shifts on mental distress via a network model. Methods: We recruited 4,188 nurses from six hospitals in December 2020. We used the Insomnia Severity Index, Patient Health Questionnaire-9, and Generalized Anxiety Disorder Scale-7 to assess insomnia, depression, and anxiety, respectively. We used the gaussian graphical model to estimate the network. Index expected influence and bridge expected influence was adapted to identify the central and bridge symptoms within the network. We assessed the impact of night shifts on mental distress and compared the network structure based on COVID-19 frontline experience. Results: The prevalence of depression, anxiety, and insomnia was 59, 46, and 55%, respectively. Nurses with night shifts were at a higher risk for the three mental disorders. "Sleep maintenance" was the central symptom. "Fatigue," "Motor," "Restlessness," and "Feeling afraid" were bridge symptoms. Night shifts were strongly associated with sleep onset trouble. COVID-19 frontline experience did not affect the network structure. Conclusion: "Sleep maintenance," "Fatigue," "Motor," and "Restlessness" were important in maintaining the symptom network of anxiety, depression, and insomnia in nurses. Further interventions should prioritize these symptoms.

[Accuracy of key point matrix technology based contactless automatic measurement for joint motion of hand].

Objective: To validate the use of key point matrix technology based contactless automatic measurement for evaluation of joint motion of hand. Methods: Thirty-three volunteers were enrolled to evaluate the extension and flexion of hand joints between May 2021 and November 2021. There were 20 males and 13 females, the age ranged from 16 to 70 years with an average of 30.2 years. The extension angles of 14 joints of 5 fingers (including hyperextension) and the flexion angles of 12 joints of 4 fingers (excluding thumb) of volunteers were measured by key point matrix technology and manual goniometer, respectively. Then 5 participants and repeated measurement experiment were employed to test the system repeatability and accuracy; 28 participants and paired measurement experiment were employed to test the system accuracy. Results: The average repeatability of finger joint motion measured by the key point matrix technology was 1.801° (extension) and 7.823° (flexion), respectively. Compared with manual measurement, the average differences of each finger joint measured by the key point matrix technology were 3.225° in extension and 14.145° in flexion, respectively. The key point matrix technology based contactless automatic evaluation system offered excellent consistency with the manual goniometers ( ICC=0.875). While most of the consistency with manual goniometer of individual joints were at moderate levels (median of ICC, 0.440). The correlation coefficients between the measurement results of the two methods were mainly positive in the extension of the joint ( P<0.05) and negative in the flexion of the joints ( P<0.05). Conclusion: The key point matrix technology based contactless automatic evaluation provides sufficient measurement repeatability and accuracy in evaluation for the joint motion of hand.

Top 100 Most-Cited Articles on Enhanced Recovery After Surgery: A Bibliometric Analysis and Visualized Study.

Background: The enhanced recovery after surgery (ERAS) protocol is widely implemented in surgeries, and this study aims to reveal the characteristics of the 100 most-cited original articles in the field of ERAS research. Methods: The literature was retrieved in the Web of Science database, the 100 most-cited original articles were identified, and their characteristics were analyzed, including the trends of publications and citations; contributions from countries, institutions, and authors; co-cited authors and journals in the references; served surgeries, research endpoints, keywords; and the level of evidence. Results: There was a rising trend in the yearly publications and citations. Denmark and the USA contributed the largest number of highly cited papers. The University of Copenhagen was the most influential institution. Kehlet, Henrik was the most influential author. The British Journal of Surgery was the most often published and cited journal. ERAS protocols were overwhelmingly implemented in colorectal surgeries. The most focused endpoints were "length of stay", "complications", and "readmission". The most frequently used keywords were "fast track", "length of stay", and "laparoscopy". The keyword "enhanced recovery after surgery" burst since 2012. More than half of the highly cited articles presented level IV evidence, but there was no correlation between citations (densities) and the levels of evidence. Conclusions: The highly cited research overwhelming implemented ERAS in colorectal surgeries, the "length of stay" was the most focused element, and Kehlet, Henrik was the most influential researcher. Most of the highly cited ERAS had low levels of evidence, and the total number of citations was not relevant to the level of evidence. Therefore, studies with high levels of evidence are still required in the future.

[Construction of transgenic mice with Δ15 Des enzyme activity by using a PiggyBac transposon].

Essential fatty acids are those that could not be synthesized by the body itself but crucial for health and life. Studies have shown that ω-3 fatty acids may facilitate human physiological functions. Mammals lack ω-3 desaturase gene, and the Δ15 fatty acid desaturase (Δ15 Des) from Caenorhabditis elegans can transform the ω-6 polyunsaturated fatty acids (PUFAs) into ω-3 PUFAs. Transgenic mice expressing Δ15 Des enzyme activity was constructed by using a PiggyBac transposon (PB). Homozygous transgenic mice with stable inheritance was bred in a short time, with a positive rate of 35.1% achieved. The mice were fed with 6% ω-6 PUFAs and the changes of fatty acids in mice were detected by gas chromatography (GC). The expression level of Δ15 Des in mice was detected by quantitative PCR (qPCR) and Western blotting (WB). qPCR and GC analysis revealed that the percentage of positive mice harboring the active gene was 61.53%. Compared with traditional methods, the transformation efficiency and activity of Δ15 Des were significantly improved, and homozygotes showed higher activity than that of heterozygotes. This further verified the efficient transduction efficiency of the PiggyBac transposon system.

Effect of Carbohydrate-Restricted Dietary Pattern on Insulin Treatment Rate, Lipid Metabolism and Nutritional Status in Pregnant Women with Gestational Diabetes in Beijing, China.

Carbohydrates play an important role in blood glucose control in pregnant women with GDM. Carbohydrate-restricted dietary (CRD) pattern for gestational diabetes mellitus (GDM) has been widely used in clinics, but the change in insulin utilization rate beyond CRD intervention in GDM remains unclear. The aim of the present study was to explore the application of insulin in pregnancy with GDM, as well as the influence of CRD pattern on lipid metabolism and nutritional state. A retrospective study of 265 women with GDM who delivered in Peking University People's Hospital from July 2018 to January 2020 was conducted using a questionnaire survey. Women were divided into a CRD group or a control group according to whether they had received CRD intervention during pregnancy. There was no statistically significant difference in the rate of insulin therapy between the two groups (p > 0.05), the initial gestational week of the CRD group combined with insulin treatment was significantly higher than that of the control group (p < 0.05), and the risk of insulin therapy was positively correlated with fasting plasma glucose (FPG) in early pregnancy (p < 0.05). The incidence of abnormal low-density lipoprotein cholesterol levels in the CRD group was significantly lower than that in the control group (p < 0.05). There were no significant differences in nutritional indexes between the two groups. The results indicate that CRD intervention may be effective in delaying the use of insulin and improving the blood lipids metabolism during GDM pregnancy, while nutritional status may not be significantly affected under CRD intervention, and a high FPG in early pregnancy with GDM may be a risk factor for combined insulin therapy with CRD intervention.

Sociodemographic, occupational, and personal factors associated with sleep quality among Chinese medical staff: A web-based cross-sectional study.

Background: Sleep quality among medical staff affects not only their own health but also the health of their patients. This study aimed to investigate the sociodemographic, occupational, and personal factors associated with sleep quality among medical staff in mainland China. Methods: An online survey was conducted from January 10 to February 5, 2019, involving 3,684 medical staff (female: 84.9%; mean age: 31.6 ± 7.7; age range: 18-72). Sleep quality was measured by the Chinese version of the Pittsburgh Sleep Quality Index (C-PSQI). Sociodemographic, occupational characteristics, and personal lifestyle factors were measured by standard questions. Binary logistic regression analyses were used to determine the factors associated with sleep quality. Results: 57.9% (95% CI: 56.3-59.5%) of the study population experienced poor sleep quality (C-PSQI > 5). Binary logistic regression showed that poor sleep quality were associated with lower level of education, higher level of hospital care, longer weekly working hours, more than 30 min of cell phone use at bedtime, shift work (OR 1.33, 95% CI[1.12-1.58], P = 0.001), lack of regular naps (OR 1.46, 95% CI[1.26-1.69], P < 0.001) and lack of routine exercise (OR 1.69, 95% CI[1.46-1.97], P < 0.001). Conclusions: Poor sleep quality is highly prevalent among medical staff in mainland China. The findings indicate that appropriate strategies, such as implementing regular breaks, regulating overtime work and vacation interruptions, as well as developing exercise programs, relaxation training, and stress-management programs could help improve the sleep quality of medical staff.

Targeted inhibition of YAP/TAZ alters the biological behaviours of keloid fibroblasts.

Abnormal activation of fibroblasts plays a crucial role in keloid development. However, the mechanism of fibroblast activation remains to be determined. YAP/TAZ are key molecules in the Hippo signalling pathway that promote cell proliferation and inhibit apoptosis. Here, we show that keloid fibroblasts have higher levels of YAP/TAZ mRNA and proteins on primary culture. Targeted knockdown of endogenous YAP or TAZ significantly inhibited cell proliferation, reduced cell migration, induced cell apoptosis and down-regulated collagen1a1 production by keloid fibroblasts. Moreover, we demonstrate that verteporfin, an inhibitor of YAP/TAZ, has similar but stronger inhibitory effects on fibroblasts compared to YAP/TAZ knockdown. Our study provides evidence that YAP/TAZ may be involved in the pathogenesis of keloids. Targeted inhibition of YAP/TAZ could change the biological behaviours of fibroblasts and can potentially be used as therapy for keloids.

Effects of noise and time delay on E2F's expression level in a bistable Rb-E2F gene's regulatory network.

The bistable Rb-E2F gene regulatory network plays a central role in regulating cellular proliferation-quiescence transition. Based on Gillespie's chemical Langevin method, the stochastic bistable Rb-E2F gene's regulatory network with time delays is proposed. It is found that under the moderate intensity of internal noise, delay in the Cyclin E synthesis rate can greatly increase the average concentration value of E2F. When the delay is considered in both E2F-related positive feedback loops, within a specific range of delay (3-13) hr , the average expression of E2F is significantly increased. Also, this range is in the scope with that experimentally given by Dong et al. [65]. By analysing the quasi-potential curves at different delay times, simulation results show that delay regulates the dynamic behaviour of the system in the following way: small delay stabilises the bistable system; the medium delay is conducive to a high steady-state, making the system fluctuate near the high steady-state; large delay induces approximately periodic transitions between high and low steady-state. Therefore, by regulating noise and time delay, the cell itself can control the expression level of E2F to respond to different situations. These findings may provide an explanation of some experimental result intricacies related to the cell cycle.

Lipidomics profiling of skin surface lipids in senile pruritus.

BACKGROUND: Senile pruritus is common, yet its etiology remains unknown. Aging-associated skin barrier defects and skin surface lipid (SSL) alterations have been postulated to play important roles in its occurrence. In the present study, the lipidomic profiles of SSLs in elderly patients were examined to better understand the potential causes of senile pruritus. METHODS: Transepidermal water loss (TEWL) was evaluated to assess the skin barrier function. The Ameliorated Kawashima Itch Scale score was used to measure the pruritus severity. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and multivariate data analysis were employed to investigate SSL alterations. RESULTS: The results showed that senile pruritus patients had higher TEWL values than control subjects (13.13 ± 4.28 versus 6.71 ± 2.45, p < 0.01). LC-MS/MS revealed significant differences in the lipidomic profiles and identified 81 species of SSLs that differed between the two groups. Compared with control subjects, senile pruritus patients had increased levels of ceramides (Cers), diacylglycerols, fatty acids, phosphatidylcholines, phosphatidylethanolamines, phytosphingosines, sphingosines, diacylceryl-3-O-carboxyhydroxymethylcholine, diacylglyceryl trimethylhomoserine, and unsaturated free fatty acids, but decreased levels of triacylglycerol. Cer-EOS, Cer-NDS, and Cer-NS were positively correlated with TEWL value (p < 0.05). Pruritus severity score was positively correlated with sphingomyelin, Cer-NP, Cer-AS, Cer-NDS, and Cer-NS, but negatively correlated with Cer-BS, Cer-EODS, Cer-EOS, and Cer-AP. CONCLUSIONS: The present study indicated that patients with senile pruritus have impaired skin barrier function and altered SSL composition. Certain SSL species identified in this study may be potential targets for future studies on the pathogenesis of senile pruritus. TRIAL REGISTRATION: Peking University International Hospital (Number: YN2018QN04 ; date: January 2019).

Development of erianin-loaded dendritic mesoporous silica nanospheres with pro-apoptotic effects and enhanced topical delivery.

BACKGROUND: Psoriasis is a malignant skin disease characterized as keratinocyte hyperproliferation and aberrant differentiation. Our previous work reported that a bibenzyl compound, erianin, has a potent inhibitory effect on keratinocyte proliferation. To improve its poor water-solubility, increase anti- proliferation activity, and enhance the skin delivery, erianin loaded dendritic mesoporous silica nanospheres (E/DMSNs) were employed. RESULTS: In this work, DMSNs with pore size of 3.5 nm (DMSN1) and 4.6 nm (DMSN2) were fabricated and E/DMSNs showed pore-size-dependent, significantly stronger anti-proliferative and pro-apoptotic effect than free erianin on human immortalized keratinocyte (HaCaT) cells, resulting from higher cellular uptake efficiency. In addition, compared to free erianin, treatment with E/DMSNs was more effective in reducing mitochondrial membrane potential and increasing cytoplasmic calcium levels, which were accompanied by regulation of mitochondria and endoplasmic reticulum stress (ERS) pathway. Porcine skin was utilized in the ex vivo accumulation and permeation studies, and the results indicated higher drug retention and less drug penetration in the skin when administered as the E/DMSNs-loaded hydrogel compared to the erianin-loaded hydrogel. Conlusions This work not only illustrated the further mechanisms of erianin in anti-proliferation of HaCaT cells but also offer a strategy to enhance the efficiency of erianin and the capacity of skin delivery through the DMSNs drug delivery systems.

Circ-FOXM1 contributes to cell proliferation, invasion, and glycolysis and represses apoptosis in melanoma by regulating miR-143-3p/FLOT2 axis.

BACKGROUND: Numerous literatures have demonstrated that circular RNAs (circRNAs) are involved in multiple types of tumors. However, the effects of circRNAs in melanoma are not very clear. In this study, we aimed to investigate the roles and mechanisms of circ-FOXM1 in melanoma. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to determine the expression of circ-FOXM1, microRNA-143-3p (miR-143-3p), and Flotillin 2 (FLOT2) mRNA. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, flow cytometry analysis, and transwell assay were employed to test cell proliferation, apoptosis, and invasion, respectively. The glucose consumption and lactate production were examined by specific kits. Western blot assay was utilized for the detection of hexokinase2 (HK2), pyruvate kinase isozyme type M2 (PKM2), and FLOT2. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were employed to verify the targeting association between miR-143-3p and circ-FOXM1 or FLOT2. A murine xenograft model was established to explore the effect of circ-FOXM1 in vivo. RESULTS: Circ-FOXM1 was elevated and miR-143-3p was reduced in melanoma tissues and cells. Circ-FOXM1 deficiency impeded cell proliferation, invasion, and glycolysis and facilitated cell apoptosis in melanoma in vitro and tumorigenesis in vivo. Circ-FOXM1 acted as a sponge of miR-143-3p and the impacts of circ-FOXM1 silencing on cell proliferation, apoptosis, invasion, and glycolysis were overturned by miR-143-3p deletion. Moreover, FLOT2 was a target gene of miR-143-3p and FLOT2 overexpression rescued the inhibitory effect of miR-143-3p on melanoma progression. CONCLUSION: Circ-FOXM1 facilitated the development of melanoma by upregulating FLOT2 through miR-143-3p.

Piceatannol attenuates RANKL-induced osteoclast differentiation and bone resorption by suppressing MAPK, NF-κB and AKT signalling pathways and promotes Caspase3-mediated apoptosis of mature osteoclasts.

Osteoclasts are multinuclear giant cells that have unique ability to degrade bone. The search for new medicines that modulate the formation and function of osteoclasts is a potential approach for treating osteoclast-related bone diseases. Piceatannol (PIC) is a natural organic polyphenolic stilbene compound found in diverse plants with a strong antioxidant and anti-inflammatory effect. However, the effect of PIC on bone health has not been scrutinized systematically. In this study, we used RAW264.7, an osteoclast lineage of cells of murine macrophages, to investigate the effects and the underlying mechanisms of PIC on osteoclasts. Here, we demonstrated that PIC treatment ranging from 0 to 40 µM strongly inhibited osteoclast formation and bone resorption in a dose-dependent manner. Furthermore, the inhibitory effect of PIC was accompanied by the decrease of osteoclast-specific genes. At the molecular level, PIC suppressed the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK1/2), NF-κB p65, IκBα and AKT. Besides, PIC promoted the apoptosis of mature osteoclasts by inducing caspase-3 expression. In conclusion, our results suggested that PIC inhibited RANKL-induced osteoclastogenesis and bone resorption by suppressing MAPK, NF-κB and AKT signalling pathways and promoted caspase3-mediated apoptosis of mature osteoclasts, which might contribute to the treatment of bone diseases characterized by excessive bone resorption.