Phase Of Cycle Research Articles

Molecular and cellular rhythms in excitatory and inhibitory neurons in the mouse prefrontal cortex.

This is the first study to examine translatomic rhythms in the mouse PFC with cell-type specificity. We find that the core molecular clock cycles in phase across cell types, indicating that previously described daily oscillations in the cortical excitation/inhibition balance are not the consequence of a phase offset between PV and pyramidal cells. Nevertheless, rhythmic transcripts and their associated biological processes differ by both sex and cell type, suggesting that molecular rhythms may play a unique role in different cell types and between sexes. Therefore, our results, such as the enrichment of transcripts associated with mitochondrial function in PV cells from males, point towards possible cell and sex-specific mechanisms that could contribute to psychiatric and cognitive diseases upon rhythm disruption.

The pontine Kölliker-Fuse nucleus is important for reduced post-inspiratory airflow elicited by stimulation of the ventral respiratory parafacial region.

Considering that the retrotrapezoid nucleus/respiratory parafacial region (RTN/pFRG) would be an important center in the central nervous system involved in the maintenance and modulation of respiratory activity, we hypothesized that neurons in this nucleus would also be involved in the postinspiratory phase of the respiratory cycle through a connection with the pontine Kölliker-Fuse (KF) region. Here we performed pharmacogenetic manipulation (AAV-hM3D(Gq)-mCherry or AAV-hM4D(Gi)-mCherry) in VGlut2-cre, Ai6 conscious mice to evaluate breathing parameters through whole body plethysmography under baseline conditions (normoxia: FiO2 = 0.21) or under hypercapnia or hypoxia challenges (FiCO2 = 0.07 or FiO2 = 0.08). Under normoxia, selective stimulation of RTN/pFRG resulted in a smaller increase in VE (1,272 ± 102.5, vs. RTN/pFRG stimulation: 1,878 ± 122.1 ml/kg/min), due to a smaller increase in VT (5.4 ± 0.35, vs. RTN/pFRG stimulation: 7.77 ± 0.21 ml/kg) without changing fR in a condition of KF inhibition. However, inhibition of the VGlut2 neurons in the KF did affect the TE1 produced by selective activation of RTN/pFRG (119.9 ± 2.53, vs. RTN/pFRG stimulation: 104 ± 2.46 ms). Both the hypercapnia and hypoxia ventilatory response were reduced after inhibition of VGlut2-expressing KF neurons. Therefore, consistent with anatomical projections RTN/pFRG neurons regulate lung ventilation by controlling all aspects of breathing, i.e breathing frequency, inspiration, postinspiration and active expiration. All the modulation seems to be dependent on the integrity of the glutamatergic neurons in the KF region.

Abnormal Gas Generation during First Discharge Process of Sodium Ion Battery.

In recent years, sodium-ion batteries (SIBs) have attracted a lot of attention and are considered an ideal alternative to lithium-ion batteries (LIBs). The hard carbon (HC) anode in SIBs presents a unique challenge for studying the formation process of the solid electrolyte interphase (SEI) during initial cycling, owing to its distinctive porous structure. This study employs a combination of ultrasonic scanning techniques and differential electrochemical mass spectrometry to conduct an in-depth analysis of the two-dimensional distribution and composition of gases during the formation process. The findings reveal distinct gas evolution behaviors in SIBs compared to LIBs during formation. Notably, significant gas evolution is observed during the discharge phase of the formation cycle in SIBs, with higher discharge rates leading to increased gas evolution rates. This phenomenon is likely attributed to the adsorption of CO2 gas by the abundant pores in HC, followed by desorption during discharge. Furthermore, the study demonstrates that the addition of 5A molecular sieves, which competitively adsorb gases, effectively reduces gas adsorption on the anode during formation, thereby significantly enhancing battery performance. This research elucidates the gas adsorption and desorption behavior at the battery interface, providing new insights into the SEI formation process in SIBs.

Unveiling the role of protein kinase A (PKA) activity in bovine oviductal epithelial cells: implications on apoptotic signaling pathways during the estrous cycle.

The complex interactome crucial for successful pregnancy is constituted by the intricate network of endocrine and paracrine signaling pathways, involving gametes, embryos, and the female reproductive tract. Specifically, the oviduct exhibits distinct responses to gametes and early embryos during particular phases of the estrus cycle, a process tightly regulated by reproductive hormones. Moreover, these hormones play a pivotal role in orchestrating cyclical changes within oviductal epithelial cells. To unravel the molecular mechanisms underlying these dynamic changes, our study aimed to investigate the involvement of protein kinase A (PKA) in oviductal epithelial cells throughout the estrus cycle and in advanced pregnancy, extending our studies to oviductal epithelial cell in primary culture. By a combination of 2D-gel electrophoresis, Western blotting, and mass spectrometry, we identified 17 proteins exhibiting differential phosphorylation status mediated by PKA. Among these proteins, we successfully validated the phosphorylation status of heat shock 70kDa protein (HSP70), aconitase 2 (ACO2), and lamin B1 (LMNB1). Our findings unequivocally demonstrate the dynamic regulation of PKA throughout the estrus cycle in oviductal epithelial cells. Also, analysis by bioinformatics tools suggest its pivotal role in mediating cyclical changes possibly through modulation of apoptotic pathways. This research sheds light on the intricate molecular mechanisms underlying reproductive processes, with implications for understanding fertility and reproductive health.

Abnormal Gas Generation during First Discharge Process of Sodium Ion Battery

In recent years, sodium‐ion batteries (SIBs) have attracted a lot of attention and are considered an ideal alternative to lithium‐ion batteries (LIBs). The hard carbon (HC) anode in SIBs presents a unique challenge for studying the formation process of the solid electrolyte interphase (SEI) during initial cycling, owing to its distinctive porous structure. This study employs a combination of ultrasonic scanning techniques and differential electrochemical mass spectrometry to conduct an in‐depth analysis of the two‐dimensional distribution and composition of gases during the formation process. The findings reveal distinct gas evolution behaviors in SIBs compared to LIBs during formation. Notably, significant gas evolution is observed during the discharge phase of the formation cycle in SIBs, with higher discharge rates leading to increased gas evolution rates. This phenomenon is likely attributed to the adsorption of CO2 gas by the abundant pores in HC, followed by desorption during discharge. Furthermore, the study demonstrates that the addition of 5A molecular sieves, which competitively adsorb gases, effectively reduces gas adsorption on the anode during formation, thereby significantly enhancing battery performance. This research elucidates the gas adsorption and desorption behavior at the battery interface, providing new insights into the SEI formation process in SIBs.

Menstrual Cycle Variations in Wearable-Detected Finger Temperature and Heart Rate, But Not in Sleep Metrics, in Young and Midlife Individuals.

Most studies about the menstrual cycle are laboratory-based, in small samples, with infrequent sampling, and limited to young individuals. Here, we use wearable and diary-based data to investigate menstrual phase and age effects on finger temperature, sleep, heart rate (HR), physical activity, physical symptoms, and mood. A total of 116 healthy females, without menstrual disorders, were enrolled: 67 young (18-35 years, reproductive stage) and 53 midlife (42-55 years, late reproductive to menopause transition). Over one menstrual cycle, participants wore Oura ring Gen2 to detect finger temperature, HR, heart rate variability (root mean square of successive differences between normal heartbeats [RMSSD]), steps, and sleep. They used luteinizing hormone (LH) kits and daily rated sleep, mood, and physical symptoms. A cosinor rhythm analysis was applied to detect menstrual oscillations in temperature. The effect of menstrual cycle phase and group on all other variables was assessed using hierarchical linear models. Finger temperature followed an oscillatory trend indicative of ovulatory cycles in 96 participants. In the midlife group, the temperature rhythm's mesor was higher, but period, amplitude, and number of days between menses and acrophase were similar in both groups. In those with oscillatory temperatures, HR was lowest during menses in both groups. In the young group only, RMSSD was lower in the late-luteal phase than during menses. Overall, RMSSD was lower, and number of daily steps was higher, in the midlife group. No significant menstrual cycle changes were detected in wearable-derived or self-reported measures of sleep efficiency, duration, wake-after-sleep onset, sleep onset latency, or sleep quality. Mood positivity was higher around ovulation, and physical symptoms manifested during menses. Temperature and HR changed across the menstrual cycle; however, sleep measures remained stable in these healthy young and midlife individuals. Further work should investigate over longer periods whether individual- or cluster-specific sleep changes exist, and if a buffering mechanism protects sleep from physiological changes across the menstrual cycle.

The use of matrine to inhibit osteosarcoma cell proliferation via the regulation of the MAPK/ERK signaling pathway

BackgroundMatrine is an alkaloid extracted from Sophorus beans of the legume family, and it has significant effects and a variety of pharmacological activities. Osteosarcoma(OS) is a common malignant bone tumor that is characterized by high incidence and rapid progression. There have been some preliminary studies on the therapeutic effect of matrine on OS, but the specific mechanism remains unclear.ObjectiveThe aim of this study was to investigate the antitumor effect of matrine on HOS cells and the underlying molecular mechanism.MethodsThe effects of matrine on the proliferation, apoptosis and cell cycle progression of HOS cells were determined by CCK-8 assay, TUNEL assay and flow cytometry in vitro. Wound healing and Transwell invasion assays were used to observe the effect of matrine on the migration and invasion of HOS cells. The mechanism underlying the antitumor effect of matrine on HOS cells was investigated by Western blotting.ResultsMatrine significantly inhibited HOS cell proliferation, promoted HOS cell apoptosis, and arrested HOS cells in the G1 phase of the cell cycle. Both wound healing and Transwell invasion assays showed that matrine inhibited HOS cell migration and invasion. Western blotting results showed that matrine inhibited the activation of the MAPK/ERK signaling pathway. We found that matrine also downregulated Bcl-2 expression, which may be related to protein synthesis inhibition.ConclusionMatrine can inhibit the proliferation of HOS cells, arrest HOS cells in the G1 phase, and promote HOS cell apoptosis through the MAPK/ERK signaling pathway.

Lifetime of Long-Lived Sunspot Groups

Studies of active region (AR) lifetimes are mostly restricted to short-lived ARs. The aim of this paper is to include recurrent ARs, which should be identified unambiguously. The first step is the algorithmic listing of possible returns; then, the candidates are visually checked using the unique HTML-feature of the Debrecen sunspot database. The final step is application of an asymmetric Gaussian function, introduced in previous articles, for short-lived ARs. This function has a surprisingly good fit to the data on correctly identified recurrent sunspot groups over several rotations enabling the reconstruction of the development on the far side of the sun. The Gnevyshev–Waldmeier rule for the area–lifetime relationship is not applicable for recurrent ARs; however, as a novel approach, a linear regression analysis extended to long lifetimes made it possible to recognize two populations of sizes for which two different area–lifetime relationships can be obtained. The lifetimes exhibit weak dependencies on the heliographic latitude and solar cycle phase. If an asymmetric Gaussian cannot be fit to the data, then they presumably belong to consecutive members of an active nest.

Most of the Long-Term Solar Radiation Forcing on the Climate Is Due to the Strong Feedback Mechanisms

The main interactions of the Total Solar Irradiance (TSI) variations with the climatic system are considered. This research introduced new physically based indexes for 11-year cycles: the integral relative energetic power of the cycles solar activity (SA) and TSI, as well as the cycle-weighted mean value both of the TSI and sunspot number. The observed cycle-average TSI value in cycles XXII–XXIV has decreased by more than 0.5 W/m2, indicating its quasi-bicentennial decline. The onset of the Maunder-type Grand minimum phase of the SA and TSI of the quasi-bicentennial cycle (BCC) is expected in the 27th or 28th 11-year cycle in 2042 or 2053. The Earth's thermal inertia will cause a temperature reduction of around 0.25 K due to the deficit in TSI during the declining phase of the bicentennial cycle due to its negative impact on Earth's energy imbalance. As a result, the Bond's albedo will increase, and the abundance of atmospheric water vapor and carbon dioxide will decrease as a response to a direct solar forcing. BCC feedback mechanisms will also continue operating during both its minimum and maximum phases. The feedback mechanisms will continue further in short periods (about 30 years) at the beginning of BCC's growth and decline phases. These long-term self-reinforcing feedback effects will act as a response to the TSI, forcing in such a way as to trigger a strong amplification of the initial direct input to the corresponding temperature changes. They will lead to a significant increasing cooling in 2070 or 2080. Variations of the galactic cosmic rays and cloud cover practically do not affect the climate. The quasi-bicentennial cyclicity of the TSI also provides simultaneous climate variations on all Solar system planets.

CD99 contributes to the EWS::FLI1 transcriptome by specifically affecting FOXM1‐targets involved in the G2/M cell cycle phase, thus influencing the Ewing sarcoma genetic landscape

CD99 contributes to the EWS::FLI1 transcriptome by specifically affecting FOXM1‐targets involved in the G2/M cell cycle phase, thus influencing the Ewing sarcoma genetic landscape

A comparative study of solar activity parameters during the period 2009–2012 and 2020–2023 (ascending phase of solar cycles 24 and 25)

A comparative study of solar activity parameters during the period 2009–2012 and 2020–2023 (ascending phase of solar cycles 24 and 25)

National health examination surveys; a source of critical data.

The aim of this paper is to contribute technical arguments to the debate about the importance of health examination surveys and their continued use during the post-pandemic health financing crisis, and in the context of a technological innovation boom that offers new ways of collecting and analysing individual health data (e.g. artificial intelligence). Technical considerations demonstrate that health examination surveys make an irreplaceable contribution to the local availability of primary health data that can be used in a range of further studies (e.g. normative, burden-of-disease, care cascade, cost and policy impact studies) essential for informing several phases of the health planning cycle (e.g. surveillance, prioritization, resource mobilization and policy development). Examples of the use of health examination survey data in the World Health Organization (WHO) European Region (i.e. Finland, Italy, Malta and the United Kingdom of Great Britain and Northern Ireland) and the WHO Region of the Americas (i.e. Chile, Mexico, Peru and the United States of America) are presented, and reasons why health provider-led data cannot replace health examination survey data are discussed (e.g. underestimation of morbidity and susceptibility to bias). In addition, the importance of having nationally representative random samples of the general population is highlighted and we argue that health examination surveys make a critical contribution to external quality control for a country's health system by increasing the transparency and accountability of health spending. Finally, we consider future technological advances that can improve survey fieldwork and suggest ways of ensuring health examination surveys are sustainable in low-resource settings.

The Solar Magnetic Hump, Heliopause, and the Very Local Interstellar Medium

The magnetic hump was observed from 2020.4 to ∼2022 by Burlaga et al. who offered the hypothesis that it originated at the Sun during the declining phase of the solar cycle. Voyager 1 observed intermittency of 1 hr increments of the magnetic field from 2013 through 2019, as well as in the magnetic hump that began at the jump pf2 at 2020.4 and ended at ∼2022. Throughout this interval, the intermittency in the components of B and the magnitude B was described by the Tsallis distribution (q-Gaussian distribution). The q-Gaussian distributions have been observed throughout the solar wind and heliosheath. However, there was little or no intermittency in the 1 hr increments of the magnetic field observed by Voyager 1 from ∼2022.0 through day 270, 2023. During this interval Voyager 1 observed intermittency with a Gaussian distribution, which is associated with Boltzmann–Gibbs statistics. The boundary between these two regions, at ∼2022.0, coincides with the heliopause predicted by Fisk & Gloeckler. Alternatively, the Voyager 1 observations might be a solar cycle effect.

Anti-Müllerian hormone as a promising novel biomarker for litter size in Romanov sheep.

Anti-Müllerian hormone (AMH) is a hormone produced by growing preantral and antral follicles of the ovary. AMH is accepted as an important biomarker for fertility and superovulation parameters in livestock species. This study aimed to evaluate changes in serum AMH level in the oestrous cycle, repeatability of AMH, the effect of age on serum AMH level and the effects of AMH on litter size in Romanov sheep. In the study, a total of 36 Romanov sheep were used as animal material. First blood samples (0th day) were collected from 36 ewes to evaluate AMH and progesterone levels. Second blood samples were collected randomly from 20 ewes 9 days after first sampling to compare AMH levels at two different periods of the oestrous cycle in Romanov ewes. The ewes were categorized into three groups as low, medium and high AMH based on their first AMH levels. Results indicated that serum AMH level did not change during the oestrous and dioestrous phases of the oestrous cycle and two random time points of the oestrous cycle (p > .05). Pearson correlation analysis revealed that there is a high (r = .95) and significant (p < .001) correlation between AMH levels at the 0th (AMH-1) and 9th (AMH-2) days. The effect of AMH level on litter size was found to be significant. Litter size was significantly higher in the high AMH group than in the low AMH group (p < .05). In addition, the age of ewes did not affect serum AMH levels (p > .05). ROC analysis indicates that AMH cut-off value >320 pg/mL with 70% sensitivity and 100% specificity can be used for litter size in Romanov ewes. In conclusion, AMH is highly repeatable and its serum AMH level did not change during the oestrous cycle in Romanov sheep. In addition, AMH affects litter size and can be reliably used as a marker for litter size in Romanov sheep.

Zygotic Exposure to Venlafaxine Disrupts the Circadian Locomotor Activity Behaviour in Zebrafish Larvae.

The antidepressant venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, is commonly prescribed to treat major depressive disorder and is found at high concentrations in the aquatic environment. Concerns have been raised related to the health of aquatic organisms in response to this nontargeted pharmaceutical exposure. For instance, we previously demonstrated that exposure to venlafaxine perturbs neurodevelopment, leading to behavioural alterations in zebrafish (Danio rerio). We also observed disruption in serotonin expression in the pineal and raphe, regions critical in regulating circadian rhythms, leading us to hypothesize that zygotic exposure to venlafaxine disrupts the circadian locomotor rhythm in larval zebrafish. To test this, we microinjected zebrafish embryos with venlafaxine (1 or 10 ng) and recorded the locomotor activity in 5-day-old larvae over a 24-h period. Venlafaxine deposition reduced larval locomotor activity during the light phase, but not during the dark phase of the diurnal cycle. The melatonin levels were higher in the dark compared to during the light photoperiod and this was not affected by embryonic venlafaxine deposition. Venlafaxine exposure also did not affect the transcript abundance of clock genes, including clock1a, bmal2, cry1aand per2, which showed a clear day/night rhythmicity. A notable finding was that exposure to luzindole, a melatonin receptor antagonist, decreased the locomotor activity in the control group in light, whereas the activity was higher in larvae raised from the venlafaxine-deposited embryos. Overall, zygotic exposure to venlafaxine disrupts the locomotor activity of larval zebrafish fish during the day, demonstrating the capacity of antidepressants to disrupt the circadian rhythms in behaviour. Our results suggest that disruption in melatonin signalling may be playing a role in the venlafaxine impact on circadian behaviour, but further investigation is required to elucidate the possible mechanisms in larval zebrafish.

Resting Energy Expenditure, Metabolic and Sex Hormones in Two Phases of the Menstrual and Hormonal Contraceptive Cycles.

Resting energy expenditure (REE) may fluctuate during the menstrual cycle (MC), due to the physiological effects of estradiol (E2) and progesterone (P4). This study examined changes in REE and metabolic hormones (leptin, ghrelin, thyroid hormones), and dietary intake in two hormonally distinct groups, naturally menstruating women (NoOC) and women using monophasic combined oral contraceptives (COC). Measurements included REE by indirect calorimetry, body composition by bioimpedance, and blood samples for hormone analysis in the early follicular and mid-luteal phases of the MC in NoOC-group (n = 38) or the active and inactive phases of the COC cycle (COC, n = 19). Participants recorded their food intake for 3 days after measurements. A secondary analysis was completed for the NoOC-group without REE outliers (difference between measurements >1.5 × interquartile range, n = 4). In the NoOC-group, luteal phase REE was 40 kcal higher than follicular phase REE [95% confidence interval (CI): -2 kcal/d-82 kcal/d, d = 0.20, p = 0.061]. Leptin (d = 0.35, p < 0.001), T3 (d = 0.26, p = 0.05) and fat intake (d = 0.48, p = 0.027) were lower, and T4 (d = 0.21, p = 0.041) was higher in the luteal phase. After excluding outliers, REE was 44 kcal higher in the luteal phase than in the follicular phase (95% CI: 12 kcal/d-76 kcal/d, d = 0.22, p = 0.007). In the COC-group, the mean difference in REE was -2 kcal (95% CI-82 kcal/d-79 kcal/d) between active and inactive phases, while T3 was higher in the inactive phase (d = 0.01, p = 0.037). REE increases only slightly from the follicular to the luteal phase but remains unchanged between COC phases. Increases in T3, leptin, and fat intake during the luteal phase might echo metabolic fluctuations that parallel female sex hormones during the MC.

Unveiling the Complex Ecosystem of Breast Cancer: Crucial Insights for Patients and Doctors.

Breast cancer, a multifaceted disease, presents a dynamic ecosystem where the primary tumor interacts intricately with its microenvironment, circulatory system, and distant organs. Circulating tumor cells (CTCs) disseminate from the primary tumor to organs, such as the brain, lungs, liver, and bones, encountering various fates: cell death, cellular dormancy, or senescence. Dormant cells, characterized by reversible growth arrest at the G0/G1 phase of the cell cycle, pose a significant challenge as they evade conventional treatments and can later reawaken, leading to cancer relapse. The phenomenon of tumor dormancy is influenced by the tumor microenvironment, immune modulation, and cellular adaptations. Emerging evidence suggests that breast-conserving surgery coupled with radiation therapy offers superior survival benefits compared to mastectomy, potentially due to the 'breast homing phenomenon.' This hypothesis posits that residual breast tissue provides a niche for reactivated dormant cells, reducing distant metastasis. Immunotherapy and lifestyle modifications, including diet and exercise, show promise in managing dormant cells. Understanding the mechanisms of dormancy and developing targeted therapies are crucial for achieving long-term remission and potentially curing breast cancer.

Biomodulatory Effects of Molecular Delivery in Human T Cells Using 3D-Printed Acoustofluidic Devices

ObjectiveCell-based therapies have shown significant promise for treating many diseases, including cancer. Current cell therapy manufacturing processes primarily utilize viral transduction to insert genomic material into cells, which has limitations, including variable transduction efficiency and extended processing times. Non-viral transfection techniques are also limited by high variability or reduced molecular delivery efficiency. Novel 3D-printed acoustofluidic devices are in development to address these challenges by delivering biomolecules into cells within seconds via sonoporation. MethodsIn this study, we assessed biological parameters that influence the ultrasound-mediated delivery of fluorescent molecules (i.e., calcein and 150 kDa FITC-Dextran) to human T cells using flow cytometry and confocal imaging. ResultsLow cell plating densities (100,000 cells/mL) enhanced molecular delivery compared to higher cell plating densities (p < 0.001), even though cells were resuspended at equal concentrations for acoustofluidic processing. Additionally, cells in the S phase of the cell cycle had enhanced intracellular delivery compared to cells in the G2/M phase (p < 0.001) and G0/G1 phase (p < 0.01), while also maintaining higher viability compared to G0/G1 phase (p < 0.001). Furthermore, the calcium chelator (EGTA) decreased overall molecular delivery levels. Confocal imaging indicated that the actin cytoskeleton had important implications on plasma membrane recovery dynamics after sonoporation. In addition, confocal imaging indicates that acoustofluidic treatment can permeabilize the nuclear membrane, which could enable rapid intranuclear delivery of nucleic acids. ConclusionsThe results of this study demonstrate that a 3D-printed acoustofluidic device can enhance molecular delivery to human T cells, which may enable improved techniques for non-viral processing of cell therapies.

Extreme-ultraviolet Polarimetric Diagnostics of the Solar Corona: The Hanle Effect of Ne viii 770 Å

Magnetic fields are the primary driver of the plasma thermodynamics in the upper solar atmosphere, especially in the corona. However, magnetic field measurements in the solar corona are sporadic, thereby limiting us from the complete understanding of physical processes occurring in the coronal plasma. In this paper, we explore the diagnostic potential of a coronal emission line in the extreme-ultraviolet, i.e., Ne viii 770 Å, to probe the coronal magnetic fields. We utilize 3D “Magnetohydrodynamic Algorithm outside a Sphere” models as input to the FORWARD code to model polarization in the Ne viii line produced as a result of resonance scattering, and we interpret its modification due to collisions and the magnetic fields through the Hanle effect. The polarization maps are synthesized both on the disk and off the limb. The variation of this polarization signal through the different phases of Solar Cycle 24 and the beginning phase of Solar Cycle 25 is studied in order to understand the magnetic diagnostic properties of this line owing to different physical conditions in the solar atmosphere. The detectability of the linear polarization signatures of the Hanle effect significantly improves with increasing solar activity, consistent with the increase in the magnetic field strength and the intensity of the mean solar brightness at these wavelengths. We finally discuss the signal-to-noise ratio requirements by considering realistic instrument designs.

Therapeutic impacts of GNE‑477‑loaded H2O2 stimulus‑responsive dodecanoic acid‑phenylborate ester‑dextran polymeric micelles on osteosarcoma.

Osteosarcoma (OS) is a highly malignant primary bone neoplasm that is the leading cause of cancer‑associated death in young people. GNE‑477 belongs to the second generation of mTOR inhibitors and possesses promising potential in the treatment of OS but dose tolerance and drug toxicity limit its development and utilization. The present study aimed to prepare a novel H2O2 stimulus‑responsive dodecanoic acid (DA)‑phenylborate ester‑dextran (DA‑B‑DEX) polymeric micelle delivery system for GNE‑477 and evaluate its efficacy. The polymer micelles were characterized by morphology, size and critical micelle concentration. The GNE‑477 loaded DA‑B‑DEX (GNE‑477@DBD) tumor‑targeting drug delivery system was established and the release of GNE‑477 was measured. The cellular uptake of GNE‑477@DBD by three OS cell lines (MG‑63, U2OS and 143B cells) was analyzed utilizing a fluorescent tracer technique. The hydroxylated DA‑B was successfully grafted onto dextran at a grafting rate of 3%, suitable for forming amphiphilic micelles. Following exposure to H2O2, the DA‑B‑DEX micelles ruptured and released the drug rapidly, leading to increased uptake of GNE‑477@DBD by cells with sustained release of GNE‑477. The in vitro experiments, including MTT assay, flow cytometry, western blotting and RT‑qPCR, demonstrated that GNE‑477@DBD inhibited tumor cell viability, arrested cell cycle in G1 phase, induced apoptosis and blocked the PI3K/Akt/mTOR cascade response. In vivo, through the observation of mice tumor growth and the results of H&E staining, the GNE‑477@DBD group exhibited more positive therapeutic outcomes than the free drug group with almost no adverse effects on other organs. In conclusion, H2O2‑responsive DA‑B‑DEX presents a promising delivery system for hydrophobic anti‑tumor drugs for OS therapy.