Kinesin-7 CENP-E mediates chromosome alignment and spindle assembly checkpoint in meiosis I.

In eukaryotes, meiosis is the genetic basis for sexual reproduction, which is important for chromosome stability and species evolution. The defects in meiosis usually lead to chromosome aneuploidy, reduced gamete number, and genetic diseases, but the pathogenic mechanisms are not well clarified. Kinesin-7 CENP-E is a key regulator in chromosome alignment and spindle assembly checkpoint in cell division. However, the functions and mechanisms of CENP-E in male meiosis remain largely unknown. In this study, we have revealed that the CENP-E gene was highly expressed in the rat testis. CENP-E inhibition influences chromosome alignment and spindle organization in metaphase I spermatocytes. We have found that a portion of misaligned homologous chromosomes is located at the spindle poles after CENP-E inhibition, which further activates the spindle assembly checkpoint during the metaphase-to-anaphase transition in rat spermatocytes. Furthermore, CENP-E depletion leads to abnormal spermatogenesis, reduced sperm count, and abnormal sperm head structure. Our findings have elucidated that CENP-E is essential for homologous chromosome alignment and spindle assembly checkpoint in spermatocytes, which further contribute to chromosome stability and sperm cell quality during spermatogenesis.

Loss-of-function of kinesin-5 KIF11 causes microcephaly, chorioretinopathy, and developmental disorders through chromosome instability and cell cycle arrest.

Kinesin motors play a fundamental role in development by controlling intracellular transport, spindle assembly, and microtubule organization. In humans, patients carrying mutations in KIF11 suffer from an autosomal dominant inheritable disease called microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR). While mitotic functions of KIF11 proteins have been well documented in centrosome separation and spindle assembly, cellular mechanisms underlying KIF11 dysfunction and MCLMR remain unclear. In this study, we generate KIF11-inhibition chick and zebrafish models and find that KIF11 inhibition results in microcephaly, chorioretinopathy, and severe developmental defects in vivo. Notably, loss-of-function of KIF11 causes the formation of monopolar spindle and chromosome misalignment, which finally contribute to cell cycle arrest, chromosome instability, and cell death. Our results demonstrate that KIF11 is crucial for spindle assembly, chromosome alignment, and cell cycle progression of progenitor stem cells, indicating a potential link between polyploidy and MCLMR. Our data have revealed that KIF11 inhibition cause microcephaly, chorioretinopathy, and development disorders through the formation of monopolar spindle, polyploid, and cell cycle arrest.

miR-129-5p inhibits anchorage-independent growth through silencing of ACTN1 and the ELK4/c-FOS axis in HPV-transformed keratinocytes.

A persistent infection with human papillomavirus (HPV) can induce precancerous lesions of the cervix that may ultimately develop into cancer. Cervical cancer development has been linked to altered microRNA (miRNA) expression, with miRNAs regulating anchorage-independent growth being particularly important for the progression of precancerous lesions to cancer. In this study, we set out to identify and validate targets of miR-129-5p, a previously identified tumor suppressive miRNA involved in anchorage-independent growth and HPV-induced carcinogenesis. We predicted 26 potential miR-129-5p targets using online databases, followed by KEGG pathway enrichment analysis. RT-qPCR and luciferase assays confirmed that 3'UTR regions of six genes (ACTN1, BMPR2, CAMK4, ELK4, EP300, and GNAQ) were targeted by miR-129-5p. Expressions of ACTN1, CAMK4, and ELK4 were inversely correlated to miR-129-5p expression in HPV-transformed keratinocytes, and their silencing reduced anchorage-independent growth. Concordantly, miR-129-5p overexpression decreased protein levels of ACTN1, BMPR2, CAMK4 and ELK4 in anchorage-independent conditions. Additionally, c-FOS, a downstream target of ELK4, was downregulated upon miR-129-5p overexpression, suggesting regulation through the ELK4/c-FOS axis. ACTN1 and ELK4 expression was also upregulated in high-grade precancerous lesions and cervical cancers, supporting their clinical relevance. In conclusion, we identified six targets of miR-129-5p involved in the regulation of anchorage-independent growth, with ACTN1, BMPR2, ELK4, EP300, and GNAQ representing novel targets for miR-129-5p. For both ACTN1 and ELK4 functional and clinical relevance was confirmed, indicating that miR-129-5p-regulated ACTN1 and ELK4 expression contributes to HPV-induced carcinogenesis.

Solamargine enhanced gefitinib antitumor effect via regulating MALAT1/miR-141-3p/Sp1/IGFBP1 signaling pathway in non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) showed great therapeutic efficacy for non-small cell lung cancer (NSCLC) patients. However, acquired resistance severely limits the clinical application and efficacy of EGFR-TKIs. In the current study, we found that solamargine (SM), a natural alkaloid derived from the fruit of Lycium tomato lobelia, has been found to inhibit the progression of NSCLC and enhance the anticancer effect of EGFR-TKIs. In brief, SM significantly inhibited the cell viability of NSCLC cells and enhanced the anticancer effect of gefitinib (GFTN) and erlotinib (ERL). Mechanistically, SM decreased the expression of MALAT1 and induced miR-141-3p, whereas reduced SP1 protein levels. Interestingly, both MALAT1 and Sp1 have classical and conservative binding sites of miR-141-3p in their 3'-UTR regions. Silence of MALAT1 and overexpression of miR-141-3p both decreased the protein expression of Sp1. Subsequently, promoter activity and protein expression of IGFBP1 were upregulated by SM, which was not observed in cells with SP1 overexpression. Moreover, the inhibitory effect of SM on cell growth was significantly blocked by knockdown of IGFBP1 expression. More importantly, the combination of SM and GFTN synergistically inhibited the progression of lung cancer. Similar results were observed in experiments in vivo. Finally, the clinical relevance of MALAT1, Sp1 and IGFBP1 was further validated using bioinformatics analysis. Taken together, we confirmed that SM significantly enhanced the anticancer effect of EGFR-TKIs by regulating the MALAT1/miR-141-3p/Sp1/IGFBP1 signaling pathway. This study unravels a novel mechanism and suggests a new potential NSCLC-associated therapy.

Copper-Catalyzed Hydroamination: Enantioselective Addition of Pyrazoles to Cyclopropenes.

Chiral N-cyclopropyl pyrazoles and structurally related heterocycles are prepared using an earth-abundant copper catalyst under mild reaction conditions with high regio-, diastereo-, and enantiocontrol. The observed N2:N1 regioselectivity favors the more hindered nitrogen of the pyrazole. Experimental and DFT studies support a unique mechanism that features a five-centered aminocupration.

Downregulation of miR-193a/b-3p during HPV-induced cervical carcinogenesis contributes to anchorage-independent growth through PI3K-AKT pathway regulators.

Cervical cancer is caused by a persistent infection with high-risk types of human papillomavirus (HPV) and an accumulation of (epi)genetic alterations in the host cell. Acquisition of anchorage-independent growth represents a critical hallmark during HPV-induced carcinogenesis, thereby yielding the most valuable biomarkers for early diagnosis and therapeutic targets. In a previous study, we found that miR-193a-3p and miR-193b-3p were involved in anchorage-independent growth. This study aimed to delineate the role of miR-193a/b-3p in HPV-induced carcinogenesis and to identify their target genes related to anchorage-independent growth. Cell viability and colony formation were assessed in SiHa cancer cells and HPV-16 and -18 immortalized keratinocytes upon miR-193a/b-3p overexpression. Both microRNAs reduced cell growth of all three cell lines in low-attachment conditions and showed a minor effect in adherent conditions. Online target-predicting programs and publicly available expression data were used to find candidate messenger RNA (mRNA) targets of miR-193a/b-3p. Seven targets showed reduced mRNA expression upon miR-193a/b-3p overexpression. For three targets, Western blot analysis was also performed, all showing a reduced protein expression. A direct interaction was confirmed using luciferase assays for six genes: LAMC1, PTK2, STMN1, KRAS, SOS2, and PPP2R5C, which are phosphatidylinositol 3-kinase/protein kinase B (PI3K-AKT) regulators. All six targets were overexpressed in cervical cancers and/or precursor lesions. Together with an observed downregulation of phosphorylated-AKT upon miR-193a/b-3p overexpression, this underlines the biological relevance of miR-193a/b-3p downregulation during HPV-induced cervical carcinogenesis. In conclusion, the downregulation of miR-193a-3p and miR-193b-3p is functionally involved in the acquisition of HPV-induced anchorage independence by targeting regulators of the PI3K-AKT pathway.

The 32-Item Multilingual Naming Test: Cultural and Linguistic Biases in Monolingual Chinese-Speaking Older Adults.

OBJECTIVES: This study describes the performance of the Multilingual Naming Test (MINT) by Chinese American older adults who are monolingual Chinese speakers. An attempt was also made to identify items that could introduce bias and warrant attention in future investigation. METHODS: The MINT was administered to 67 monolingual Chinese older adults as part of the standard dementia evaluation at the Alzheimer's Disease Research Center (ADRC) at the Icahn School of Medicine at Mount Sinai (ISMMS), New York, USA. A diagnosis of normal cognition (n = 38), mild cognitive impairment (n = 12), and dementia (n = 17) was assigned to all participants at clinical consensus conferences using criterion sheets developed at the ADRC at ISMMS. RESULTS: MINT scores were negatively correlated with age and positively correlated with education, showing sensitivity to demographic factors. One item, butterfly, showed no variations in responses across diagnostic groups. Inclusion of responses from different regions of China changed the answers from "incorrect" to "correct" on 20 items. The last five items, porthole, anvil, mortar, pestle, and axle, yielded a high nonresponse rate, with more than 70% of participants responding with "I don't know." Four items, funnel, witch, seesaw, and wig, were not ordered with respect to item difficulty in the Chinese language. Two items, gauge and witch, were identified as culturally biased for the monolingual group. CONCLUSIONS: Our study highlights the cultural and linguistic differences that might influence the test performance. Future studies are needed to revise the MINT using more universally recognized items of similar word frequency across different cultural and linguistic groups.

Smartphone ownership and usage in Chinese- and English-speaking older adults.

BACKGROUND: Data collection by smartphone is becoming more widespread in healthcare research. Previous studies reported racial/ethnical differences in the use of digital health technology. However, cross-language group comparison (Chinese- and English-speaking older adults) were not performed in these studies. This project will expand to smartphone technology use in diverse older populations with a focus on Chinese American older adults who are monolingual Chinese-speakers. METHOD: The Alzheimer's Disease Research Center (ADRC) at Icahn School of Medicine at Mount Sinai (ISMMS) evaluates diverse older populations using National Alzheimer's Coordinating Center's Uniform Data Set (NACC UDS). The UDS has different language versions, including English and Chinese. The evaluation includes a medical examination, cognitive assessments, and a research blood draw. Smartphone ownership and usage were captured using a local questionnaire developed by our ADRC. The questionnaire, available in English and Chinese, was administered by our ADRC coordinators during the COVID-19 pandemic. Multivariate analysis of variance (MANOVA) was used to examine differences in technology ownership and usages between the two language groups, while controlling for age, gender, education, and cognitive status (measured by Clinical Dementia Rating). RESULT: 33 Chinese- and 117 English-speaking older adults who received a diagnosis of normal cognition or mild cognitive impairment at consensus were included in the data analysis. Results reveal a high prevalence of smartphone ownership in our Chinese- (100%) and English-speaking older participants (86.3%). Participants in both language groups use mobile technology for a wide range of purposes, such as getting news and other information (Chinese=90.9%; English=87.2%), sending/receiving text (Chinese=97.0%; English=96.6%), watching videos/TV shows (Chinese=78.8%; English=69.2%), and taking classes (Chinese=57.5%; English=57.3%). However, Chinese-speaking older adults were less likely than English-speaking older adults to use mobile technology to post their own reviews or comments online (Chinese=9.1%; English=39.3%, p=0.001), download or purchase an app (Chinese=21.2%; English=70.9%, p<0.001), track health/ fitness via apps/website (Chinese=12.1%; English=47.9%, p<0.001) and manage/receive medical care (Chinese=15.2%; English=67.5%, p<0.001). CONCLUSION: Our findings highlight potential barriers to smartphone usage in Chinese American older adults with limited English proficiency. The results have implications for how smartphone technology can be used in clinical practice and aging research.

A close look at therapist contributions to narrative-emotion shifting in a case illustration of brief dynamic therapy.

Objective: In a secondary analysis of Friedlander et al.'s [(2018). "If those tears could talk, what would they say?" multi-method analysis of a corrective experience in brief dynamic therapy. Psychotherapy Research, 28, 217-234. doi:10.1080/10503307.2016.1184350] case study of Hanna Levenson's Brief Dynamic Therapy over Time (from APA's Psychotherapy in Six Sessions DVD series), we re-visited the Narrative-Emotion Process Coding (Angus, L. E., Boritz, T., Bryntwick, E., Carpenter, N., Macaulay, C., & Khattra, J. (2017). The Narrative-Emotion Process Coding System 2.0: A multi-methodological approach to identifying and assessing narrative-emotion process markers in psychotherapy. Psychotherapy Research, 27, 253-269. doi:10.1080/10503307.2016.1238525) to identify specific therapist behaviors that may have facilitated the client's movement from expressing mostly Problem markers in early sessions to expressing considerably more Transition and Change markers in later sessions. Method: Using open coding and constant comparison qualitative methods, we identified Levenson's behaviors immediately preceding the client's "change shifts" (Problem → Transition/Change and Transition → Change) and "problem shifts" (Transition/Change → Problem). Results: Compared to problem shifts, change shifts were preceded by more therapist behavior reflecting Attaching New Meaning (e.g., linking the client's self-deprecation to her avoidant behavior) and Exploring/Expanding emotions (e.g., inviting the client to give voice to her tears), cognitions (e.g., pointing out the client's self-talk) and motivation (e.g., reflecting on the client's dissatisfaction with her defenses). Conclusions: In this successful case, facilitative therapist behavior reflected common therapeutic responses (e.g., validating the client's perspective) as well as responses characteristic of brief dynamic therapy (e.g., interpreting the client's defenses) and the therapist's personal style (e.g., repeating the client's words for emphasis).

Prevalence and type-specific distribution of human papillomavirus infection among women in mid-western rural, Nepal- A population-based study.

BACKGROUND: Cervical cancer is the most common cancer among women in Nepal. The prevalence of human papillomavirus (HPV) 16 and or HPV 18 among women with cervical pre-cancer and cancer is higher than the incidence of HPV in the world population. The population-based epidemiological data of HPV in the general population in most parts of the country remains unknown. The objective of this study was to assess the prevalence and type distribution of HPV infection and association of abnormal cytology with high risk HPV infection among women in mid-western rural, Nepal. METHODS: A population-based cross sectional study was conducted in Jumla, one of the most remote districts in Nepal. A total of 1050 cervical samples were collected from married and non- pregnant women aged 20-65 years during mobile Cervical Cancer Screening Clinics conducted from May 2016 to January 2017. The presence of HPV DNA was firstly confirmed by HPV consensus PCR using PGMY09/PGMY11 designed primers, then HPV positive samples were further genotyped by the membrane hybridization method to detect the 21 high-risk HPV (HR-HPV) and low-risk HPV types. The prevalence of HR-HPV among women with normal and abnormal cytology was calculated. Data were analyzed using SPSS software for Windows. P < 0.05 was considered statistically significant. RESULTS: A total of 998 women were eligible for this study with the mean age 32.6 ± 8.6 years, and the mean marital age was 16.7 ± 3.8 years. The overall prevalence of HPV infections was 19.7%. HR-HPV and low-risk HPV were 11.7 and 8.7% respectively. The six most common HR-HPV types were HPV16, 39, 58, 33, 51 and 18. HR-HPV infection among the women with abnormal and normal cytology was of 27.3 and 10.8% respectively. CONCLUSIONS: There was a higher prevalence of HR-HPV infection among women living in Jumla than other parts of Nepal. This study provides preliminary information on overall HPV and type-specific HR-HPV prevalence, HR-HPV 16, 39, 58, 33, 51, and 18 are the most prevalent genotypes in this region. The data contribute to the epidemiological knowledge about HPV and type-specific HR-HPV genotypes prevalence in mid-Western Nepal.

Associations between gestational exposure to perfluoroalkyl substances, fetal growth, and the mediation effect of thyroid hormones.

Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) may cause adverse birth outcomes. Thyroid hormones may play a key role in mediating the effects of PFAS. We enrolled 374 mother-infant pairs from the Ezhou birth cohort study between 2019 and 2020. Eight PFASs and six thyroid hormones were measured in maternal serum during the first trimester of pregnancy. Neonatal growth metrics, including birth weight, length, head circumference, and gestational age, were acquired. Multivariate linear regression was performed to determine the associations between maternal serum PFAS and thyroid hormone levels and birth outcomes and a mediation analysis was also conducted. Except for perfluoroheptanoic acid (41.2%), the other seven PFAS detection rates were more than 85%, and the highest median concentration was observed for PFOSA with levels of 5.21 ng/mL. After controlling for typical confounders, we observed a decrease in birth length (cm) with increasing serum concentrations of perfluorononanoic acid (PFNA) (ß = -0.54; 95% CI = -1.0, -0.08) and perfluorohexane sulfonate (PFHxS) (ß = -0.64; 95% CI = -0.86, -0.42). Additionally, a decrease in birth head circumference was observed with increasing concentrations of perfluorooctanote (PFOA) (ß = -0.73, 95% CI = -1.19, -0.27) and PFHxS (ß = -0.30; 95% CI = -0.53, -0.07). Maternal free triiodothyronine (FT3) mediated 36.7% of the negative association between PFNA and birth length, and free thyroxine (FT4) mediated 30.8% of the effect of PFOA on head circumference. When performing stratified analysis by infant sex, the associations might differ between boys and girls. Our study suggested prenatal exposure to some PFASs was negatively associated with birth length and circumference, and FT3 and FT4 may partly mediate the association.

Effects of virtual exposure to urban greenways on mental health.

Urban greenways (UGW) are increasingly recognized as vital components of urban green infrastructure (UGI). While existing research has provided empirical evidence on the positive impacts of UGW on physical health, studies focusing on the effects on mental health remain limited. Moreover, previous investigations predominantly compare UGW as a whole with other built environments, neglecting the influence of specific vegetation designs along UGW on mental health. To address this research gap, we conducted a randomized controlled experiment to examine the impact of vegetation design along UGW on stress reduction and attention restoration. A total of 94 participants were randomly assigned to one of four UGW conditions: grassland, shrubs, grassland and trees, or shrubs and trees. Utilizing immersive virtual reality (VR) technology, participants experienced UGW through a 5-min video presentation. We measured participants' subjective and objective stress levels and attentional functioning at three time-points: baseline, pre-video watching, and post-video watching. The experimental procedure lasted approximately 40 minutes. Results of the repeated-measures ANOVA revealed that participants experienced increased stress and mental fatigue after the stressor and decreased levels following the UGW intervention. Furthermore, between-group analyses demonstrated that the shrubs group and the grassland and trees group exhibited significantly greater stress reduction than the grassland group. However, there are no significant differences in attention restoration effects between the four groups. In conclusion, virtual exposure to UGW featuring vegetation on both sides positively affected stress reduction and attention restoration. It is recommended that future UGW construction incorporates diverse vegetation designs, including shrubs or trees, instead of solely relying on grassland. More research is needed to explore the combined effects of shrubs and trees on mental health outcomes.

An Opto-electrophysiology Neural Probe with Photoelectric Artifact-Free for Advanced Single-Neuron Analysis.

Opto-electrophysiology neural probes targeting single-cell levels offer an important avenue for elucidating the intrinsic mechanisms of the nervous system using different physical quantities, representing a significant future direction for brain-computer interface (BCI) devices. However, the highly integrated structure poses significant challenges to fabrication processes and the presence of photoelectric artifacts complicates the extraction and analysis of target signals. Here, we propose a highly miniaturized and integrated opto-electrophysiology neural probe for electrical recording and optical stimulation at the single-cell/subcellular level. The design of a total internal reflection layer addresses the photoelectric artifacts that are more pronounced in single-cell devices compared to conventional implantable BCI devices. Finite element simulations and electrical signal tests demonstrate that the opto-electrophysiology neural probe eliminates the photoelectric artifacts in the time domain, which represents a significant breakthrough for optoelectrical integrated BCI devices. Our proposed opto-electrophysiology neural probe holds substantial potential for promoting the development of in vivo BCI devices and developing advanced therapeutic strategies for neurological disorders.

CETSA-MS-based target profiling of anti-aging natural compound quercetin.

BACKGROUND: Quercetin is widely distributed in nature and abundant in the human diet, which exhibits diverse biological activities and potential medical benefits. However, there remains a lack of comprehensive understanding about its cellular targets, impeding its in-depth mechanistic studies and clinical applications. PURPOSE: This study aimed to profile protein targets of quercetin at the proteome level. METHODS: A label-free CETSA-MS proteomics technique was employed for target enrichment and identification. The R package Inflect was used for melting curve fitting and target selection. D3Pocket and LiBiSco tools were used for binding pocket prediction and binding pocket analysis. Western blotting, molecular docking, site-directed mutagenesis and pull-down assays were used for target verification and validation. RESULTS: We curated a library of direct binding targets of quercetin in cells. This library comprises 37 proteins that show increased thermal stability upon quercetin binding and 33 proteins that display decreased thermal stability. Through Western blotting, molecular docking, site-directed mutagenesis and pull-down assays, we validated CBR1 and GSK3A from the stabilized protein group and MAPK1 from the destabilized group as direct binding targets of quercetin. Moreover, we characterized the shared chemical properties of the binding pockets of quercetin with targets. CONCLUSION: Our findings deepen our understanding of the proteins pivotal to the bioactivity of quercetin and lay the groundwork for further exploration into its mechanisms of action and potential clinical applications.

In situ self-referenced intracellular two-electrode system for enhanced accuracy in single-cell analysis.

Since the emergence of single-cell electroanalysis, the two-electrode system has become the predominant electrochemical system for real-time behavioral analysis of single-cell and multicellular populations. However, due to the transmembrane placement of the two electrodes, cellular activities can be interrupted by the transmembrane potentials, and the test results are susceptible to influences from factors such as intracellular solution, membrane, and bulk solution. These limitations impede the advancement of single-cell analysis. Here, we propose a highly miniaturized and integrated in situ self-referenced intracellular two-electrode system (IS-SRITES), wherein both the working and reference electrodes are positioned inside the cell. Additionally, we demonstrated the stability (0.28 mV/h) of the solid-contact in situ Ag/AgCl reference electrode and the ability of the system to conduct standard electrochemical testing in a wide pH range (pH 6.0-8.0). Cell experiments confirmed the non-destructive performance of the electrode system towards cells and its capacity for real-time monitoring of intra- and extracellular pH values. Moreover, through equivalent circuits, finite element simulations, and drug delivery experiments, we illustrated that the IS-SRITES can yield more accurate test results and exhibit enhanced resistance to interference from the extracellular environment. Our proposed system holds the potential to enable the precise detection of intracellular substances and optimize the existing model of the electrode system for intracellular signal detection, thereby spearheading advancements in single-cell analysis.

Functional hydrogels for the repair and regeneration of tissue defects.

Tissue defects can be accompanied by functional impairments that affect the health and quality of life of patients. Hydrogels are three-dimensional (3D) hydrophilic polymer networks that can be used as bionic functional tissues to fill or repair damaged tissue as a promising therapeutic strategy in the field of tissue engineering and regenerative medicine. This paper summarises and discusses four outstanding advantages of hydrogels and their applications and advances in the repair and regeneration of tissue defects. First, hydrogels have physicochemical properties similar to the extracellular matrix of natural tissues, providing a good microenvironment for cell proliferation, migration and differentiation. Second, hydrogels have excellent shape adaptation and tissue adhesion properties, allowing them to be applied to a wide range of irregularly shaped tissue defects and to adhere well to the defect for sustained and efficient repair function. Third, the hydrogel is an intelligent delivery system capable of releasing therapeutic agents on demand. Hydrogels are capable of delivering therapeutic reagents and releasing therapeutic substances with temporal and spatial precision depending on the site and state of the defect. Fourth, hydrogels are self-healing and can maintain their integrity when damaged. We then describe the application and research progress of functional hydrogels in the repair and regeneration of defects in bone, cartilage, skin, muscle and nerve tissues. Finally, we discuss the challenges faced by hydrogels in the field of tissue regeneration and provide an outlook on their future trends.

Hydrogel systems for targeted cancer therapy.

When hydrogel materials with excellent biocompatibility and biodegradability are used as excellent new drug carriers in the treatment of cancer, they confer the following three advantages. First, hydrogel materials can be used as a precise and controlled drug release systems, which can continuously and sequentially release chemotherapeutic drugs, radionuclides, immunosuppressants, hyperthermia agents, phototherapy agents and other substances and are widely used in the treatment of cancer through radiotherapy, chemotherapy, immunotherapy, hyperthermia, photodynamic therapy and photothermal therapy. Second, hydrogel materials have multiple sizes and multiple delivery routes, which can be targeted to different locations and types of cancer. This greatly improves the targeting of drugs, thereby reducing the dose of drugs and improving treatment effectiveness. Finally, hydrogel can intelligently respond to environmental changes according to internal and external environmental stimuli so that anti-cancer active substances can be remotely controlled and released on demand. Combining the abovementioned advantages, hydrogel materials have transformed into a hit in the field of cancer treatment, bringing hope to further increase the survival rate and quality of life of patients with cancer.

Novel pH-Responsive CaO2@ZIF-67-HA-ADH Coating That Efficiently Enhances the Antimicrobial, Osteogenic, and Angiogenic Properties of Titanium Implants.

Titanium-based implants often lead to premature implant failure due to the lack of antimicrobial, osteogenic, and angiogenic properties. To this end, a new strategy was developed to fabricate CaO2@ZIF-67-HA-ADH coating on titanium surfaces by combining calcium peroxide (CaO2) nanoparticles, zeolite imidazolate framework-67 (ZIF-67), and the chemical coupling hyaluronic acid-adipic acid dihydrazide (HA-ADH). We characterized CaO2@ZIF-67-HA-ADH with scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), and inductively coupled plasma-atomic emission spectrometry (ICP-AES). The results demonstrated that CaO2@ZIF-67-HA-ADH was pH-sensitive and decomposed rapidly under acidic conditions, and it released inclusions slowly under neutral conditions. Antibacterial experiments showed that the CaO2@ZIF-67-HA-ADH coating had excellent antibacterial properties and effectively killed methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PAO-1). Cell experiments revealed that the CaO2@ZIF-67-HA-ADH coating promoted pro-osteoblast adhesion, proliferation, and differentiation and also promoted the migration and angiogenesis of human umbilical vein endothelial cells (HUVECs), exhibiting excellent osteogenic and angiogenic properties. In in vivo animal implantation experiments, the CaO2@ZIF-67-HA-ADH coating exhibited strong antimicrobial activity early after implantation and excellent osseointegration later after implantation. In conclusion, the pH-responsive CaO2@ZIF-67-HA-ADH coating conferred excellent antibacterial, osteogenic, and angiogenic properties to titanium implants, which effectively enhanced osseointegration of the implants and prevented bacterial infection; the coating shows promise for use in the treatment of bone defects.

A shape-memory poly(ε-caprolactone) hybridized TiO2/poly(l-lactide) composite with antibacterial properties.

Organic-inorganic composites as an efficient strategy to upgrade the structural and functional properties of synthetic polymers are attracting extensive attentions. However, there are few studies on the shape memory (SM) behavior of organic-inorganic composites. In the work, poly(ε-caprolactone) hybridized TiO2 nanomaterial (PCL-TiO2) is made as the switching phase and integrated into poly (l-lactide) (PLLA) to construct an SM composite. PCL-TiO2/PLLA shows "sea-island" structure and better interfacial adhesion than PCL/PLLA, which facilitates the transmission of elastic power between the switching phase and the fixing phase. PCL-TiO2 as switching phase exhibits lower enthalpy at 57 °C than PCL, and PCL-TiO2 also acts as "heat dispersion pump station", which builds a dynamically responsive system and initiates shape change. The shape fixing and recovery ratio of PCL-TiO2/PLLA are 93.9 % and 94.4 %, respectively, and go back to the original shape within 15 s at 57 °C. At the same time, PCL-TiO2 endows SMP with good antibacterial properties. Then this work provides a well-placed way for developing SM materials with structure-function integration.

Kaempferol promotes non-small cell lung cancer cell autophagy via restricting Met pathway.

BACKGROUND: Kaempferol is extracted from Hedyotis diffusa, exerting an obvious anti-cancer effect. Here in the present study, we explored the anti-cancer effects and mechanism of kaempferol in non-small cell lung cancer cell (NSCLC). PURPOSE: Our objective is to figure out the molecular mechanism by which kaempferol promotes autophagy in NSCLC cells. STUDY DESIGN: A549 and H1299 NSCLC cell lines were used for in vitro experiments. And BALB/c nude mice of NSCLC were used to perform in vivo experiments. METHODS: For in vitro experiments, CCK-8 and EdU assay was used to observe the effect of kaempferol on NSCLC cell proliferation. Confocal microscopy of mCherry-EGFR-LC3 assay and electron microscopy assay were used to detect NSCLC cell autophagy. Protein expression was determined using Western blot, and mRNA expression was determined using qRT-PCR. Flow cytometry was performed to detect the cell apoptosis. For in vivo experiments, a subcutaneously implanted tumor model in BALB/C nude mice was performed using human NSCLC cell line A549-Luc. The kaempferol effect on NSCLC mice model was detected by measuring the tumor weight and bioluminescence intensity. Immunohistochemistry was done to measure the key protein expression from mice tumor tissues. RESULTS: Our results confirmed that kaempferol inhibited NSCLC cell proliferation significantly. And it promoted NSCLC cell autophagy, leading to NSCLC cell death. Interestingly, Met-was greatly inhibited at both protein and mRNA levels. Meanwhile, PI3K/AKT/mTOR signaling pathway was inhibited accordingly. Furthermore, overexpressing Met-reversed the effect of kaempferol on NSCLC cell viability and cell autophagy with significance. Finally, the above effect and pathway were validated using the xenograft model. CONCLUSION: Kaempferol may exert its anti-NSCLC effect by promoting NSCLC cell autophagy. Mechanistically, Met-and its downstream PI3K/AKT/mTOR signaling pathway were involved in the process, which provides a novel mechanism how kaempferol functions in inhibiting NSCLC.