Trace Amount of Bi-Doped Core-Shell Pd@Pt Mesoporous Nanospheres with Specifically Enhanced Peroxidase-Like Activity Enable Sensitive and Accurate Detection of Acetylcholinesterase and Organophosphorus Nerve Agents.

The urgent need for sensitive and accurate assays to monitor acetylcholinesterase (AChE) activity and organophosphorus pesticides (OPs) arises from the imperative to safeguard human health and protect the ecosystem. Due to its cost-effectiveness, ease of operation, and rapid response, nanozyme-based colorimetry has been widely utilized in the determination of AChE activity and OPs. However, the rational design of nanozymes with high activity and specificity remains a great challenge. Herein, trace amount of Bi-doped core-shell Pd@Pt mesoporous nanospheres (Pd@PtBi2) have been successfully synthesized, exhibiting good peroxidase-like activity and specificity. With the incorporation of trace bismuth, there is a more than 4-fold enhancement in the peroxidase-like performance of Pd@PtBi2 compared to that of Pd@Pt. Besides, no significant improvement of oxidase-like and catalase-like activities of Pd@PtBi2 was found, which prevents interference from O2 and undesirable consumption of substrate H2O2. Based on the blocking impact of thiocholine, a colorimetric detection platform utilizing Pd@PtBi2 was constructed to monitor AChE activity with sensitivity and selectivity. Given the inhibition of OPs on AChE activity, a biosensor was further developed by integrating Pd@PtBi2 with AChE to detect OPs, capitalizing on the cascade amplification strategy. The OP biosensor achieved a detection limit as low as 0.06 ng mL-1, exhibiting high sensitivity and anti-interference ability. This work is promising for the construction of nanozymes with high activity and specificity, as well as the development of nanozyme-based colorimetric biosensors.

Alcohol consumption and accelerated biological ageing in middle-aged and older people: A longitudinal study from two cohorts.

BACKGROUND AND AIMS: The relationship between alcohol consumption and age-related diseases is inconsistent. Biological age (BA) serves as both a precursor and a predictor of age-related diseases; however, longitudinal associations between alcohol consumption and BA in middle-aged and older people remain unclear. We measured whether there was a longitudinal association between drinking frequency and pure alcohol intake with BA among middle-aged and older people. DESIGN AND SETTING AND PARTICIPANTS: This study involved two prospective cohort studies, set in Southwestern China and the United Kingdom. A total of 8046 participants from the China Multi-Ethnic Cohort study (CMEC) and 5412 participants from the UK Biobank (UKB), aged 30-79 years, took part, with complete data from two waves of clinical biomarkers. MEASUREMENTS: BA was calculated by the Klemera Doubal's method. Accelerated BA equalled BA minus chronological age. Drinking frequency and pure alcohol intake were obtained through self-reported questionnaires. Drinking frequency in the past year was classified as current non-drinking, occasional (monthly drinking) and regular (weekly drinking). FINDINGS: Compared with consistent current non-drinkers, more frequent drinkers [CMEC: ß = 0.46, 95% confidence interval (CI) = 0.13-0.80; UKB: ß = 0.65, 95% CI = 0.01-1.29)], less frequent drinkers (CMEC: ß = 0.62, 95% CI = 0.37-0.87; UKB: ß = 0.54, 95% CI = -0.01-1.09), consistent occasional drinkers (CMEC: ß = 0.51, 95% CI = 0.23-0.79; UKB: ß = 0.63, 95% CI = 0.13-1.13) and consistent regular drinkers (CMEC: ß = 0.56, 95% CI = 0.17-0.95; UKB: ß = 0.46, 95% CI = 0.00-0.91) exhibited increased accelerated BA. A non-linear relationship between pure alcohol intake and accelerated BA was observed among consistent regular drinkers. CONCLUSIONS: In middle-aged and older people, any change in drinking frequency and any amount of pure alcohol intake seem to be positively associated with acceleration of biological ageing, compared with maintaining abstinence.

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Objective: To investigate the longitudinal association between alcohol abstinence and accelerated biological aging among middle-aged and older adults and to explore the potential effect modifiers influencing the association. Methods: Utilizing the clinico-biochemical and anthropometric data from the baseline and first repeat survey of the UK Biobank (UKB), we employed the Klemera and Doubal method (KDM) to construct the biological age (BA) and calculate BA acceleration. Change analysis based on multivariate linear regression models was employed to explore the association between changes in alcohol abstinence and changes in BA acceleration. Age, sex, smoking status, tea and coffee consumption, and body mass index were considered as the stratification factors for conducting stratified analysis. Results: A total of 5 412 participants were included. Short-term alcohol abstinence (ß=1.00, 95% confidence interval [CI]: 0.15-1.86) was found to accelerate biological aging when compared to consistent never drinking, while long-term abstinence (ß=-0.20, 95% CI: -1.12-0.71) did not result in a significant acceleration of biological aging. Body mass index may be a potential effect modifier. Conclusion: Short-term alcohol abstinence was associated with accelerated biological aging, but the effect gradually diminishes over extended periods of abstinence.

Realization of Fine-Tuning the Lattice Thermal Conductivity and Anharmonicity in Layered Semiconductors via Entropy Engineering.

Entropy engineering is widely proven to be effective in achieving ultra-low thermal conductivity for well-performed thermoelectric and heat management applications. However, no strong correlation between entropy and lattice thermal conductivity is found until now, and the fine-tuning of thermal conductivity continuously via entropy-engineering in a wide entropy range is still lacking. Here, a series of high-entropy layered semiconductors, Ni1- x(Fe0.25Co0.25Mn0.25Zn0.25)xPS3, where 0 ≤ x < 1, with low mass/size disorder is designed. High-purity samples with mixing configuration entropy of metal atomic site in a wide range of 0-1.61R are achieved. Umklapp phonon-phonon scattering is found to be the dominating phonon scattering mechanism, as revealed by the linear T-1 dependence of thermal conductivity. Meanwhile, fine tuning of the lattice thermal conductivity via continuous entropy engineering at metal atomic sites is achieved, in an almost linear dependence in middle-/high- entropy range. Moreover, the slope of the κ - T-1 curve reduces with the increase in entropy, and a linear response of the reduced Grüneisen parameter is revealed. This work provides an entropy engineering strategy by choosing multiple metal elements with low mass/size disorder to achieve the fine tuning of the lattice thermal conductivity and the anharmonic effect.

Triggers for the onset and recurrence of psoriasis: a review and update.

Psoriasis is an immune-mediated inflammatory skin disease, involving a complex interplay between genetic and environmental factors. Previous studies have demonstrated that genetic factors play a major role in the pathogenesis of psoriasis. However, non-genetic factors are also necessary to trigger the onset and recurrence of psoriasis in genetically predisposed individuals, which include infections, microbiota dysbiosis of the skin and gut, dysregulated lipid metabolism, dysregulated sex hormones, and mental illness. Psoriasis can also be induced by other environmental triggers, such as skin trauma, unhealthy lifestyles, and medications. Understanding how these triggers play a role in the onset and recurrence of psoriasis provides insights into psoriasis pathogenesis, as well as better clinical administration. In this review, we summarize the triggers for the onset and recurrence of psoriasis and update the current evidence on the underlying mechanism of how these factors elicit the disease. Video Abstract.

Evidence for the Clinical Association between Demodex and Rosacea: A Review.

BACKGROUND: Rosacea is a chronic inflammatory dermatological condition in humans, and its pathogenesis remains unclear. However, the development of rosacea is suspected to be related to Demodex, a microscopic commensal organism that resides in or near hair follicles and sebaceous glands. Although Demodex is known to be a host-specific, obligate commensal organism, it is currently difficult to be cultured in vitro to parasitize and infect other animal hosts. Therefore, direct evidence for a pathogenic role of Demodex in rosacea is currently lacking. SUMMARY: As circumstantial evidence, non-invasive skin-detecting techniques have shown abnormally elevated numbers of Demodex in rosacea patients. Increased cytokine levels such as IL-10, IL-8, and IL-12p70 have been observed in human sebocytes following the Demodex challenge, and acaricides have been found to be effective in rosacea therapy, all point to a close relationship between Demodex and rosacea. Based on these findings, we conducted a comprehensive literature review to summarize the current state of knowledge, research insights, and clinical treatment recommendations for Demodex-associated rosacea, with the ultimate goal of improving patient outcomes.

Tea consumption and attenuation of biological aging: a longitudinal analysis from two cohort studies.

Background: The biological aging process can be modified through lifestyle interventions to prevent age-related diseases and extend healthspan. However, evidence from population-based studies on whether tea consumption could delay the biological aging process in humans remains limited. Methods: This study included 7931 participants aged 30-79 years from the China Multi-Ethnic Cohort (CMEC) Study and 5998 participants aged 37-73 years from the UK Biobank (UKB) who participated in both the baseline and first follow-up surveys. Tea consumption information was collected through questionnaires. Biological age (BA) acceleration was calculated using clinical biomarkers and anthropometric measurements based on the Klemera Doubal method (KDM). Change-to-change analyses were performed to estimate the associations between changes in tea consumption status and changes in BA acceleration using multiple linear models. Follow-up adjusted for baseline analyses were further conducted to examine the prospective exposure-response relationship between tea consumption and BA acceleration among individuals with constant tea consumption status. Findings: During a median follow-up of 1.98 (1.78, 2.16) years in the CMEC and 4.50 (3.92, 5.00) years in the UKB, tea consumption was consistently associated with attenuated BA acceleration in both cohorts. Transitioning from nondrinking to tea-drinking was associated with decreased BA acceleration (CMEC: ß = -0.319, 95% CI: -0.620 to -0.017 years; UKB: ß = -0.267, 95% CI: -0.831 to 0.297 years) compared to consistent nondrinking. Even stronger associations were found in consistent tea drinkers. The exposure-response relationship suggested that consuming around 3 cups of tea or 6-8 g of tea leaves per day may offer the most evident anti-aging benefits. Interpretation: Tea consumption was associated with attenuated BA acceleration measured by KDM, especially for consistent tea drinkers with moderate consumption. Our findings highlight the potential role of tea in developing nutrition-oriented anti-aging interventions and guiding healthy aging policies. Funding: National Natural Science Foundation of China (Grant No. 82273740).

Study on aging behavior of polyethylene glycol under three wavelengths of ultraviolet light irradiation.

PEG2000 (polyethylene glycol, molecular weight: 2000) is commonly used for the dehydration and reinforcement of waterlogged wooden cultural relics, but its photo-aging degradation will seriously affect the long-term conservation of the wooden cultural relics. In this study, the photo-aging characteristics and mechanisms of PEG2000 under UV (ultraviolet) irradiations of three wavelengths were comprehensively investigated, and the surface morphology, crystal structure, and relative molecular weight of PEG2000 were systematically characterized. The results showed that PEG2000 showed a higher gloss loss rate, carbonyl index and crystallinity, and a wider molecular weight distribution with increasing aging time, especially under the irradiation of 313 nm ultraviolet light. The evolution of the PEG2000 from surface to interior during photoaging was elucidated by SEM (scanning electron microscopy) and FTIR (Fourier transform infrared spectroscopy), and it was determined that photodegradation not only occurs on the surface of PEG2000 but also gradually extends to the interior of the sample with the prolongation of irradiation time, resulting in the transformation of the basic component unit of spherical crystals in PEG2000 from fibrous crystals to spherical particles. Based on 1H-NMR (nuclear magnetic resonance spectroscopy), the photochemical reactions for the generation of degradation products were proposed, and it was found that the degradation occurred at the C-H and C-O-C bonds on the main chain, forming a large number of ester and ethoxy structures. The aging degree of PEG2000 was evaluated from the perspective of surface morphology and chemical structure by gloss and FTIR spectroscopy, and it was found that the combination of gloss loss rate and carbonyl index was more suitable to evaluate the aging degree of the sample. The relevant theoretical research will provide reliable guidance for the preservation of polyethylene glycol in waterlogged wooden cultural relics.

Lipoxin A4 Ameliorates Imiquimod-Induced Psoriasis-Like Dermatitis via Promoting the Regression of Inflammation.

Introduction: As a mediator of inflammation resolution, lipoxin A4 (LXA4) mainly plays an anti-inflammatory role and promotes inflammation resolution. LXA4 plays an inhibiting inflammatory role in a variety of diseases, tissues and cells, including keratinocytes. Psoriasis is a chronic inflammatory skin disease mediated by dysregulation of inflammation of immune cells and keratinocytes. However, the expression and role of LXA4 in psoriasis-like mouse models are still unclear. Methods: Imiquimod (IMQ) topical treatment of dorsal skin induces psoriasis-like dermatitis in BALB/c mice, pretreated intraperitoneally with or without LXA4 prior to IMQ application. Severity of dorsal lesions is assessed by using a modified human scoring system and histopathology. The concentration of LXA4 and the expression of ALOX15 (a key gene in LXA4 metabolic synthesis) in lesional skins were detected by ELISA and Western blot. Quantitative PCR and ELISA were conducted to detect the mRNA and secretion levels of inflammatory cytokines. The proportion of IL-17A-producing γδT cells in skin and skin draining cervical lymph nodes and helper (Th) 17 cells in spleens was evaluated by flow cytometry. Western blotting was used to analyze the expressions of p-STAT3 and TRAF6. Results: The concentration of LXA4 and the expression of ALOX15 were decreased in IMQ-induced lesional skin. LXA4 significantly relieved psoriasis-like lesions in IMQ-induced mouse models. Furthermore, LXA4 decreased IMQ-induced systemic inflammation, including reduced the proportion of IL-17A-producing gdT cells in skin and skin draining cervical lymph nodes and Th17 cells in spleens, the secretion and expression of CCL20, IL-17A, IL-1ß, and TNF-α in skin and serum. LXA4 markedly inhibited IMQ-induced expression of TRAF6 and p-STAT3. Conclusion: LXA4 significantly ameliorates IMQ-induced psoriasis-like inflammation, and LXA4 can be used as a target for psoriasis treatment.

α-Mangostin Suppresses Melanoma Growth, Migration, and Invasion and Potentiates the Anti-tumor Effect of Chemotherapy.

Purpose: Melanoma is a highly malignant tumor, which metastasizes and has poor prognosis in late-stage cancer patients. α-Mangostin possesses pharmacological properties, including antioxidant, anti-infective, and anticarcinogenic activities. We investigated α-Mangostin effect on melanoma growth, migration, and invasion and its possible molecular mechanism. Methods: Melanoma cells growth inhibition was determined by the colorimetric 4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay. Morphological changes of α-Mangostin-treated melanoma cells were evaluated by transmission electron microscopy and JC-1 staining. Cell apoptosis and cell cycle arrest were assessed by flow cytometry. The effect of α-Mangostin on tumor cells migration and invasion was observed by migration and invasion in vitro assay. Furthermore, the nude and C57BL/6 mouse subcutaneous melanoma models were used to evaluate the in vivo anti-tumor effect of α-Mangostin. Western blot and real time-PCR were performed to analyze the influence of α-Mangostin on some of the common signaling pathways in melanoma cell lines. Signaling pathways were further verified in dissected tumor tissues. Results: α-Mangostin inhibited in vitro melanoma cells proliferation, migration, and invasion of melanoma cells, induced cell cycle arrest in G0/G1 phase, and caused mitochondrial swelling and membrane depolarization, whereas it effectively suppressed melanoma growth in xenografted mice. In addition, α-Mangostin potentiated the in vitro and in vivo anti-tumor effects of cisplatin both in vitro and in vivo. Mechanistically, α-Mangostin down-regulated expression of RAS protein and mRNA, as well as phosphorylation of PI3K in A375, B16F10, M14 and SK-MEL-2 cells. MITF protein and mRNA were inhibited only in M14 cells. Conclusion: α-Mangostin suppresses melanoma cells growth, migration and invasion, and synergistically enhances the anti-tumor effect of chemotherapy, whose mechanism may be mediated through inhibiting Ras, PI3K and MITF.

Clinical applications of smart wearable sensors.

Smart wearable sensors are electronic devices worn on the body that collect, process, and transmit various physiological data. Compared to traditional devices, their advantages in terms of portability and comfort have made them increasingly important in the medical field. This review takes a unique clinical physician's standpoint, diverging from conventional sensor-type-based classifications, and provides a comprehensive overview of the diverse clinical applications of wearable sensors in recent years. In this review, we categorize these applications according to different diseases, encompassing skin diseases and injuries, cardiovascular diseases, abnormal human motion, as well as endocrine and metabolic disorders. Additionally, we discuss the challenges and perspectives hindering the development of sensors for clinical use, emphasizing the critical need for interdisciplinary collaboration between medical and engineering professionals. Overall, this review would serve as an important reference for the future direction of sensor devices in clinical use.

Effects of ß-Si3N4 Seeds on Microstructure and Performance of Si3N4 Ceramics in Semiconductor Package.

Among the various ceramic substrate materials, Si3N4 ceramics have demonstrated high thermal conductivity, good thermal shock resistance, and excellent corrosion resistance. As a result, they are well-suited for semiconductor substrates in high-power and harsh conditions encountered in automobiles, high-speed rail, aerospace, and wind power. In this work, Si3N4 ceramics with various ratios of α-Si3N4 and ß-Si3N4 in raw powder form were prepared by spark plasma sintering (SPS) at 1650 °C for 30 min under 30 MPa. When the content of ß-Si3N4 was lower than 20%, with the increase in ß-Si3N4 content, the ceramic grain size changed gradually from 1.5 µm to 1 µm and finally resulted in 2 µm mixed grains. However, As the content of ß-Si3N4 seed crystal increased from 20% to 50%, with the increase in ß-Si3N4 content, the ceramic grain size changed gradually from 1 µm and 2 µm to 1.5 µm. Therefore, when the content of ß-Si3N4 in the raw powder is 20%, the sintered ceramics exhibited a double-peak structure distribution and the best overall performance with a density of 97.5%, fracture toughness of 12.1 MPa·m1/2, and a Vickers hardness of 14.5 GPa. The results of this study are expected to provide a new way of studying the fracture toughness of silicon nitride ceramic substrates.

Krüppel-like factor 4 (KLF4) facilitates lipid production in immortalized human sebocytes via regulating the expression of SREBP1.

BACKGROUND: Acne is associated with the excessive production of sebum, a complex mixture of lipids, in the sebaceous glands. The transcription factor Krüppel-like factor 4 (KLF4) plays an important role in skin morphogenesis, but its role in sebum production by sebocytes is not well known. PURPOSE: In this study, we investigated the possible action mechanism of KLF4 during calcium-induced lipogenesis in immortalized human sebocytes. METHODS: Sebocytes were treated with calcium, and lipid production was confirmed by thin-layer chromatography (TLC) and Oil Red O staining. To investigate the effect of KLF4, sebocytes were transduced with the KLF4-overexpressing adenovirus, and then lipid production was evaluated. RESULTS: Calcium treatment resulted in increased sebum production in terms of squalene synthesis in sebocytes. In addition, calcium increased the expression of lipogenic regulators such as sterol-regulatory element binding protein 1 (SREBP1), sterol-regulatory element binding protein 2 (SREBP2), and stearoyl-CoA desaturase (SCD). Similarly, the expression of KLF4 was increased by calcium in sebocytes. To investigate the effect of KLF4, we overexpressed KLF4 in sebocytes using recombinant adenovirus. As a result, KLF4 overexpression increased the expression of SREBP1, SREBP2, and SCD. Parallel to this result, lipid production was also increased by KLF4 overexpression. Chromatin immunoprecipitation revealed the binding of KLF4 to the SREBP1 promoter, indicating that KLF4 may directly regulate the expression of lipogenic regulators. CONCLUSION: These results suggest that KLF4 is a novel regulator of lipid production in sebocytes.

Applications and perspectives of quaternized cellulose, chitin and chitosan: A review.

Recently, increasing attention has been paid to natural polysaccharides for their low cost, biocompatibility and biodegradability. Quaternization is a modification method to improve the solubility and antibacterial ability of natural polysaccharides. Water-soluble derivatives of cellulose, chitin and chitosan offer the prospect of diverse applications in a wide range of fields, such as antibacterial products, drug delivery, wound healing, sewage treatment and ion exchange membranes. By combining the inherent properties of cellulose, chitin and chitosan with the inherent properties of the quaternary ammonium groups, new products with multiple functions and properties can be obtained. In this review, we summarized the research progress in the applications of quaternized cellulose, chitin and chitosan in recent five years. Moreover, ubiquitous challenges and personal perspectives on the further development of this promising field are also discussed.

Maternal and Fetal Risk Factors for Neonatal Hypoxic-Ischemic Encephalopathy: A Retrospective Study.

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) leads to different degree of neurological sequelae. The incidence of HIE is relatively high, and the risk factors associated with HIE are still controversial. It is necessary to identify the risk factors associated with HIE. Methods: A total of 258 neonates (110 HIE patients and 148 controls) were enrolled in this study. The characteristics of pregnant women and fetuses during pregnancy and delivery were compared between HIE patients and controls, and the risk factors of HIE were analyzed. Results: The proportions of premature infants, low-birth-weight infants and the levels of 1-minute Apgar score, 5-minute Apgar score in HIE group were significantly lower than those in control group, while the proportion of amniotic fluid contamination in the HIE group was significantly higher than those of the controls. When HIE was taken as the end point of 1-minute Apgar score, and 5-minute Apgar score, the cut-off value of 1-minute Apgar score was 3, and 5-minute Apgar score was 7 by receiver operating characteristic (ROC) curve analysis. The results of multivariate logistic regression analysis showed that low birth weight (<2.5 kg) (OR 1.780, 95% CI: 0.124-25.463, P=0.016), amniotic fluid contamination (OR 3.223, 95% CI: 1.049-9.901, P=0.041), low 1-minute Apgar score (≤3) (OR 92.425, 95% CI: 15.522-550.343, P<0.001), and low 5-minute Apgar score (≤7) (OR 12.641, 95% CI: 2.894-55.227, P=0.001) may increase risk of HIE. In addition, amniotic fluid contamination, low 1-minute Apgar score (≤3), and low 5-minute Apgar score (≤7) may increase risk of HIE among newborns born to women without previous childbearing history, but not in newborns born to women with previous childbearing history. Conclusion: Low birth weight (<2.5 kg), amniotic fluid contamination, low 1-minute Apgar score (≤3), and 5-minute Apgar score (≤7) may increase risk of HIE.

Role of Type I Cannabinoid Receptor in Sensory Neurons in Psoriasiform Skin Inflammation and Pruritus.

Type I cannabinoid receptor (CB1R) has been reported to exhibit favorable anti-inflammation and antipruritus effects against inflammation-based skin diseases, but the specific mechanism remains to be explored. In this study, we found that the activation of CB1R significantly relieved the scratching behavior and skin inflammation in a psoriatic mouse model, whereas CB1R antagonist aggravated these symptoms. Because the expression of CB1R was abundant in dorsal root ganglia, we constructed mice with conditional CB1R knockout in primary sensory neurons and found that imiquimod-induced psoriasiform inflammation and itch were both worsened in CB1R-conditional knockout mice. Next, we observed that the CB1R was mostly located in peptidergic neurons, and deletion of CB1R in primary sensory neurons promoted the production and release of substance P to the skin tissue. Furthermore, the elevated substance P in the skin affected the activation of extracellular signal‒regulated kinase in keratinocytes and induced the accumulation of mast cells in the dermis. Finally, we showed that blocking the substance P signal significantly alleviated the exacerbation of psoriasiform inflammation and itch caused by imiquimod in CB1R-conditional knockout mice. Together, our work reveals that CB1R in sensory neurons plays a key role in psoriasiform skin inflammation and pruritus by regulating substance P expression.

Acid/reduction dual-sensitive amphiphilic graft polyurethane with folic acid and detachable poly(ethylene glycol) as anticancer drug delivery carrier.

In order to not only improve the stability of nanomicelles in blood circulation but also promote the cellular uptake in tumors and rapidly release the encapsulated drugs in tumor cells, a kind of acid/reduction dual-sensitive amphiphilic graft polyurethane with folic acid and detachable poly(ethylene glycol) (FA-PUSS-gimi-mPEG) was synthesized by grafting folic acid and monomethoxy poly(ethylene glycol) to the polyurethane side chain. FA-PUSS-gimi-mPEG could self-assemble in aqueous solution to form negatively charged nanomicelles, which endowed them good stability under normal physiological condition. Using ultraviolet-visible spectrometer (UV-vis) and dynamic light scattering (DLS), it was found that the hydrophilic poly(ethylene glycol) layer of FA-PUSS-gimi-mPEG micelles could be detached due to the cleavage of benzoic-imine bond under slightly acidic condition, which resulted in reversing the charge of the micellar surface and exposing folic acid to the micellar surface. FA-PUSS-gimi-mPEG micelles could load doxorubicin (DOX), moreover the drug release rate was faster at pH 5.0 and 10 mM glutathione (GSH) than that under normal physiological condition. The results of cell experiments further demonstrated that FA-PUSS-gimi-mPEG micelles had acid/reduction dual-sensitive property. The changes in the structure of FA-PUSS-gimi-mPEG micelles could enhance the cellular uptake under acid condition and the micelles could accelerate the drug release in tumor cells due to the presence of disulfide bonds in the polymer. Therefore, FA-PUSS-gimi-mPEG micelles could efficiently deliver anticancer drug into tumor cells and enhance the inhibition of cellular proliferation through multi-effect synergy.

High Mechanical Strength and Multifunctional Microphase-Separated Supramolecular Hydrogels Fabricated by Liquid-Crystalline Block Copolymer.

The development of multifunctional supramolecular hydrogels with high mechanical strength and multifunction is in high demand. In this work, the diblock copolymer poly(acrylamide-co-1-benzyl-3-vinylimidazolium bromide)-block-polyAzobenzene is synthesized through reversible addition-fragmentation chain transfer polymerization. The dynamic host-guest interactions between the host molecule cucurbit[8] uril and guest units are used to fabricate a 3D network of supramolecular hydrogels. Investigations on the properties of the supramolecular hydrogels show that the tensile stress of the sample is 1.46 MPa, eight times higher than that of hydrogel without liquid-crystalline block copolymer, and the self-healing efficiency of the supramolecular hydrogels at room temperature is 88.3% (fracture stress) and 100% (fracture strain) after 24 h. Results show that microphase-separated structure plays a key role in the high-strength hydrogel, whereas the host-guest interaction endows the hydrogel with self-healing properties. The supramolecular hydrogels with high mechanical strength, photo-responsivity, injectability, and biocompatibility can be used in various potential applications.

Endoplasmic reticulum stress in melanoma pathogenesis and resistance.

Melanoma is the most lethal skin cancer with rising incidence worldwide. Despite significant advances in target therapy and immunotherapy, low response rates and the development of drug resistance remain key clinical barriers affecting patient prognosis. The complex interplay between multiple signaling molecules and pathways has brought little understanding of melanoma pathogenesis and resistance. The genetic mutation and hypermetabolic environment of melanoma cells lead to increasing demands for protein synthesis and perturb proteostasis resulting in endoplasmic reticulum (ER) stress. Subsequently, three unfolded protein response (UPR) signaling branches, represented by IRE1α, PERK and ATF6, are activated to direct cell fate towards pro-survival or pro-apoptosis depending on the intensity and duration of ER stress. In this review, we summarize ER stress and UPR in melanoma cells and tumor-infiltrating immune cells along with the crosstalk among these pathways. We provide the latest advances in understanding melanoma pathogenesis and resistance and discuss the potential of targeting the ER stress or UPR process for melanoma therapy.

ASPM promotes ATR-CHK1 activation and stabilizes stalled replication forks in response to replication stress.

ASPM is a protein encoded by primary microcephaly 5 (MCPH5) and is responsible for ensuring spindle position during mitosis and the symmetrical division of neural stem cells. We recently reported that ASPM promotes homologous recombination (HR) repair of DNA double strand breaks. However, its potential role in DNA replication and replication stress response remains elusive. Interestingly, we found that ASPM is dispensable for DNA replication under unperturbed conditions. However, ASPM is enriched at stalled replication forks in a RAD17-dependent manner in response to replication stress and promotes RAD9 and TopBP1 loading onto chromatin, facilitating ATR-CHK1 activation. ASPM depletion results in failed fork restart and nuclease MRE11-mediated nascent DNA degradation at the stalled replication fork. The overall consequence is chromosome instability and the sensitization of cancer cells to replication stressors. These data support a role for ASPM in loading RAD17-RAD9/TopBP1 onto chromatin to activate the ATR-CHK1 checkpoint and ultimately ensure genome stability.