The roles of organic amendments and plant treatments in soil polychlorinated biphenyl dissipation under oxic and sequential anoxic-oxic conditions.

Understanding polychlorinated biphenyl (PCB) degradation in sequential anaerobic-aerobic remediation is crucial for effective remediation strategies. In this study, microcosm and greenhouse experiments were conducted to dissect the effects of organic amendments (carbon-based) and plant treatments (ryegrass) on soil PCB dissipation under oxic and sequential anoxic-oxic conditions. We analyzed the soil bacterial community in greenhouse experiments using high-throughput sequencing to explore plant-pollutant-microbe interactions. Microcosm results showed that organic amendments alone did not facilitate aerobic PCB removal, but significantly accelerated PCB dechlorination under anoxic conditions altering the profiles of PCB congeners. In standard greenhouses, plant treatments substantially increased PCB dissipation to 50.8 ± 3.9%, while organic amendments aided phytoremediation by promoting plant growth, increasing PCB removal to 65.9 ± 3.2%. In sequential anaerobic-aerobic greenhouses, plant growth was inhibited by flooding treatment while flooding stress was markedly alleviated by organic amendments. Plant treatments alone during sequential treatments did not lead to PCB dissipation; however, dissipation was significantly promoted following organic amendments, achieving a removal of 41.2 ± 5.7%. This PCB removal was primarily due to anaerobic dechlorination during flooding (27.8 ± 0.5% removal), rather than from plant growth stimulation in subsequent planting phase. Co-occurrence network and functional prediction analyses revealed that organic amendments recruited specific bacterial clusters with distinct functions under different conditions, especially stimulating plant-microbe interactions and xenobiotics biodegradation pathways in planted systems. The findings provide valuable guidance for the design of practical remediation strategies under various remedy scenarios, such as in arable or paddy fields.

Emerging Trends in Dissolving-Microneedle Technology for Antimicrobial Skin-Infection Therapies.

Skin and soft-tissue infections require significant consideration because of their prolonged treatment duration and propensity to rapidly progress, resulting in severe complications. The primary challenge in their treatment stems from the involvement of drug-resistant microorganisms that can form impermeable biofilms, as well as the possibility of infection extending deep into tissues, thereby complicating drug delivery. Dissolving microneedle patches are an innovative transdermal drug-delivery system that effectively enhances drug penetration through the stratum corneum barrier, thereby increasing drug concentration at the site of infection. They offer highly efficient, safe, and patient-friendly alternatives to conventional topical formulations. This comprehensive review focuses on recent advances and emerging trends in dissolving-microneedle technology for antimicrobial skin-infection therapy. Conventional antibiotic microneedles are compared with those based on emerging antimicrobial agents, such as quorum-sensing inhibitors, antimicrobial peptides, and antimicrobial-matrix materials. The review also highlights the potential of innovative microneedles incorporating chemodynamic, nanoenzyme antimicrobial, photodynamic, and photothermal antibacterial therapies. This review explores the advantages of various antimicrobial therapies and emphasizes the potential of their combined application to improve the efficacy of microneedles. Finally, this review analyzes the druggability of different antimicrobial microneedles and discusses possible future developments.

Nutritional status and neurodevelopmental levels in infants at high risk of cerebral palsy.

Importance: Nutrition is associated with neurodevelopment. Infants at high risk of cerebral palsy (CP) usually suffer from undernutrition, yet the relationship between nutritional status and neurodevelopmental levels is unclear. Objective: To describe the nutritional status characteristics of infants at high risk of CP, and to explore the relationship between neurodevelopmental levels and nutritional status. Methods: This single-center cross-sectional study enrolled infants at high risk of CP, with corrected age from 0 days to 12 months. Weight and height were measured and calculated into z-scores, which were used to classify the nutritional status based on the World Health Organization growth charts and American Society for Parenteral and Enteral Nutrition standards. The Bayley Scales of Infant and Toddler Development were used to evaluate the developmental levels of gross motor, fine motor, cognition, receptive communication, and expressive communication. Results: A total of 479 infants at high risk of CP were recruited, with 43.4% classified as undernutrition. Compared to those with normal neurodevelopment, the odds of moderate and severe undernutrition were about 1.8 and 3.9 times higher in gross motor delay, 2.2 and 3.1 times higher in fine motor delay, 2.5 and 9.4 times higher in cognition delay, 2.2 and 3.9 times higher in receptive communication delay, and 3.0 and 5.6 times higher in expressive communication delay. There were significant positive correlations between nutritional status and neurodevelopmental levels (P < 0.001). Interpretation: Undernutrition and neurodevelopmental delays are prevalent among infants at high risk of CP. Worse nutritional status was correlated with lower neurodevelopmental levels.

TRPML1 ameliorates seizures-related neuronal injury by regulating autophagy and lysosomal biogenesis via Ca2+/TFEB signaling pathway.

Alterations in autophagy have been observed in epilepsy, although their exact etiopathogenesis remains elusive. Transient Receptor Potential Mucolipin Protein 1 (TRPML1) is an ion channel protein that regulates autophagy and lysosome biogenesis. To explore the role of TRPML1 in seizures-induced neuronal injury and the potential mechanisms involved, an hyperexcitable neuronal model induced by Mg2+-free solution was used for the study. Our results revealed that TRPML1 expression was upregulated after seizures, which was accompanied by intracellular ROS accumulation, mitochondrial damage, and neuronal apoptosis. Activation of TRPML1 by ML-SA1 diminished intracellular ROS, restored mitochondrial function, and subsequently alleviated neuronal apoptosis. Conversely, inhibition of TRPML1 had the opposite effect. Further examination revealed that the accumulation of ROS and damaged mitochondria was associated with interrupted mitophagy flux and enlarged defective lysosomes, which were attenuated by TRPML1 activation. Mechanistically, TRPML1 activation allows more Ca2+ to permeate from the lysosome into the cytoplasm, resulting in the dephosphorylation of TFEB and its nuclear translocation. This process further enhances autophagy initiation and lysosomal biogenesis. Additionally, the expression of TRPML1 is positively regulated by WTAP-mediated m6A modification. Our findings highlighted crucial roles of TRPML1 and autophagy in seizures-induced neuronal injury, which provides a new target for epilepsy treatment.

State-of-the-art strategies to enhance the mechanical properties of microneedles.

Microneedles (MNs) have gained increasing attention in the biomedical field, owing to their notable advantages over injectable and transdermal preparations. The mechanical properties of MNs are the key to determine whether MNs can puncture the skin for efficient drug delivery and therapeutic purposes. However, there is still lacking of a systemic summary on how to improve the mechanical properties of MNs. Herein, this review mainly analyzes the key factors affecting the mechanical properties of MNs from the theoretical point of view and puts forward improvement approaches. First, we analyzed the major stresses exerted on the MNs during skin puncture and described general methods to evaluate the mechanical properties of MNs. We then provided detail examples to elucidate how the physicochemical properties of single polymer, formulation compositions, and geometric parameters affected the mechanical properties of MNs. Overall, the mechanical strength of MNs can be enhanced by tuning the crosslinking density, crystallinity degree, and molecular weight of single polymer, introducing polysaccharides and nano-microparticles as reinforcers to form complex with polymer, and optimizing the geometric parameters of MNs. Therefore, this review will provide critical guidance on how to fabricate MNs with robust mechanical strength for successful transdermal drug delivery.

The changes of fungal community and flavor substances in Yunnan-style sausages: A comparative analysis of different drying methods.

This study aimed to investigate alterations in the fungal community and flavor substances in Yunnan-style sausages subjected to natural air-dried fermentation (NF), variable-temperature drying (VT), and constant-temperature drying (CT) and analyze the potential relationship between fungal community and flavor substances. The findings revealed that the NF group and VT group were more conducive to enhancing the accumulation of dominant fungi and characteristic flavor substances in Yunnan-style sausages. Glu, Ala, His, and Lys were identified as key taste substances based on their taste activity values (TAV ≥ 1). A total of 272 volatile compounds(VOCS) were detected in the sausage samples, while 28 key aroma compounds were screened based on the odor activity value (OAV ≥ 1). Multivariate statistical analysis showed that 12 key aroma compounds (VIP > 1) could be considered discriminative compounds, including (E,E)-2,4-nonadienal, nonanal, heptanal, benzaldehyde, Dodecanal, cyclohexanol, and hexyl-Benzene, etc. Furthermore, Wickerhamoomyces and Debaryomyces were positively correlated with most of the key flavor substances and physicochemical indices (|r| > 0.6, P < 0.05), which were potential flavor-contributing fungi in Yunnan-style sausages.

Biological Fate Tracking of Nitric Oxide-Propelled Microneedle Delivery System Using an Aggregation-Caused Quenching Probe.

Nanoparticle-loaded dissolving microneedles (DMNs) have attracted increasing attention due to their ability to provide high drug loading, adjustable drug release behavior, and enhanced therapeutic efficiency. However, such delivery systems still face unsatisfied drug delivery efficiency due to insufficient driving force to promote nanoparticle penetration and the lack of in vivo fate studies to guide formulation design. Herein, an aggregation-caused quenching (ACQ) probe (P4) was encapsulated in l-arginine (l-Arg)-based nanomicelles, which was further formulated into nitric oxide (NO)-propelled nanomicelle-integrated DMNs (P4/l-Arg NMs@DMNs) to investigate their biological fate. The P4 probe could emit intense fluorescence signals in intact nanomicelles, while quenching with the dissociation of nanomicelles, providing a "distinguishable" method for tracking the fate of nanomicelles at a different status. l-Arg was demonstrated to self-generate NO under the tumor microenvironment with excessive reactive oxygen species (ROS), providing a pneumatic force to promote the penetration of nanomicelles in both three-dimensional (3D)-cultured tumor cells and melanoma-bearing mice. Compared with passive microneedles (P4 NMs@DMNs) without a NO propellant, the P4/l-Arg NMs@DMNs possessed a good NO production performance and higher nanoparticle penetration capacity. In conclusion, this study offered an ACQ probe-based biological fate tracking approach to demonstrate the potential of NO-propelled nanoparticle-loaded DMNs in penetration enhancement for topical tumor therapy.

Antibacterial Agents and Adjuvants against Pseudomonas Aeruginosa Infections.

The development of narrow-spectrum antimicrobial agents is paramount for swiftly eradicating pathogenic bacteria, mitigating the onset of drug resistance, and preserving the homeostasis of bacterial microbiota in tissues. Owing to the limited affinity between the hydrophobic lipid bilayer interior of bacterial cells and most hydrophilic, polar peptides, the construction of a distinctive class of four-armed host-defense peptides/peptidomimetics (HDPs) is proposed with enhanced specificity and membrane perturbation capability against Pseudomonas aeruginosa by incorporating imidazole groups. These groups demonstrate substantial affinity for unsaturated phospholipids, which are predominantly expressed in the cell membrane of P. aeruginosa, thereby enabling HDPs to exhibit narrow-spectrum activity against this bacterium. Computational simulations and experimental investigations have corroborated that the imidazole-rich, four-armed peptidomimetics exhibit notable selectivity toward bacteria over mammalian cells. Among them, 4H10, characterized by its abundant and densely distributed imidazole groups, exhibits impressive activity against various clinically isolated P. aeruginosa strains. Moreover, 4H10 has demonstrated potential as an antibiotic adjuvant, enhancing doxycycline accumulation and exerting effects on intracellular targets by efficiently disrupting bacterial cell membranes. Consequently, the hydrogel composed of 4H10 and doxycycline emerged as a promising topical agent, significantly diminishing the skin P. aeruginosa burden by 97.1% within 2 days while inducing minimal local and systemic toxicity.

Chemodynamic Therapy of Glioblastoma Multiforme and Perspectives.

Glioblastoma multiforme (GBM), a potential public health issue, is a huge challenge for the advanced scientific realm to solve. Chemodynamic therapy (CDT) based on the Fenton reaction emerged as a state-of-the-art therapeutic modality to treat GBM. However, crossing the blood-brain barrier (BBB) to reach the GBM is another endless marathon. In this review, the physiology of the BBB has been elaborated to understand the mechanism of crossing these potential barriers to treat GBM. Moreover, the designing of Fenton-based nanomaterials has been discussed for the production of reactive oxygen species in the tumor area to eradicate the cancer cells. For effective tumor targeting, biological nanomaterials that can cross the BBB via neurovascular transport channels have also been explored. To overcome the neurotoxicity caused by inorganic nanomaterials, the use of smart nanoagents having both enhanced biocompatibility and effective tumor targeting ability to enhance the efficiency of CDT are systematically summarized. Finally, the advancements in intelligent Fenton-based nanosystems for a multimodal therapeutic approach in addition to CDT are demonstrated. Hopefully, this systematic review will provide a better understanding of Fenton-based CDT and insight into GBM treatment.

Human epididymal protein 4 and its combined detection show good diagnostic value in lung cancer: A retrospective study.

OBJECTIVES: This study aimed to assess the diagnostic value of human epididymal protein 4 (HE4), a potential novel biomarker for lung cancer, and its combined detection with five other conventional biomarkers in lung cancer diagnosis and subtyping. METHODS: In this retrospective study, 115 lung cancer patients, 50 patients with benign pulmonary disease, and 50 healthy controls were included. Serum HE4, progastrin-releasing peptide (ProGRP), squamous cell carcinoma (SCC) antigen, cytokeratin-19 fragment (CYFRA21-1), neuron-specific enolase (NSE), and carcinoembryonic antigen (CEA) were analyzed using the electrochemiluminescence immunoassay and chemiluminescence immunoassay. The receiver operating characteristic curve was performed to analyze the diagnostic efficacy of individual biomarkers in identifying both lung cancer and its histologic subtypes. RESULTS: All six biomarkers showed significantly elevated levels in the lung cancer group compared to both benign pulmonary disease and control groups (P < 0.05). Among the biomarkers evaluated, HE4 exhibited the highest diagnostic performance for lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma with area under the curve (AUC) values of 0.921, 0.891, and 0.937, respectively. ProGRP was the optimal biomarker for small cell lung cancer with an AUC of 0.973. The combination of all six biomarkers yielded the largest AUCs in the diagnosis of lung cancer subtypes (0.937 for lung adenocarcinoma, 0.998 for lung squamous cell carcinoma, and 0.985 for small cell lung cancer). Furthermore, specific combinations, such as HE4 + CEA, HE4 + SCC, and ProGRP + HE4 + NSE, showed strong diagnostic performance in lung cancer. CONCLUSIONS: HE4 and its combined detection held substantial clinical significance in the diagnosis of lung cancer and its histologic subtyping, especially for lung adenocarcinoma and lung squamous cell carcinoma.

Epsilon-poly-l-lysine microneedle patch loaded with amorphous doxycycline nanoparticles for synergistic treatment of skin infection.

The development of antibiotic-loaded microneedles has been hindered for years by limited excipient options, restricted drug-loading space, poor microneedle formability, and short-term drug retention. Therefore, this study proposes a dissolving microneedle fabricated from the host-defense peptide ε-poly-l-lysine (EPL) as an antibacterial adjuvant system for delivering antibiotics. EPL serves not only as a major matrix material for the microneedle tips, but also as a broad-spectrum antibacterial agent that facilitates the intracellular accumulation of the antibiotic doxycycline (DOX) by increasing bacterial cell membrane permeability. Furthermore, the formation of physically crosslinked networks of EPL affords microneedle tips with improved formability, good mechanical properties, and amorphous nanoparticles (approximately 7.2 nm) of encapsulated DOX. As a result, a high total loading content of both antimicrobials up to 2319.1 µg/patch is achieved for efficient transdermal drug delivery. In a Pseudomonas aeruginosa-induced deep cutaneous infection model, the EPL microneedles demonstrates potent and long-term effects by synergistically enhancing antibiotic activities and prolonging drug retention in infected lesions, resulting in remarkable therapeutic efficacy with 99.91 % (3.04 log) reduction in skin bacterial burden after a single administration. Overall, our study highlights the distinct advantages of EPL microneedles and their potential in clinical antibacterial practice when loaded with amorphous DOX nanoparticles.

Proteomic changes of botulinum neurotoxin injection on muscle growth in children with spastic cerebral palsy.

PURPOSE: The study aims to explore the proteomic profile and specific target proteins associated with muscle growth in response to botulinum neurotoxin A (BoNT-A) treatment, in order to improve spasticity management in children with cerebral palsy (CP). EXPERIMENTAL DESIGN: A total of 54 participants provided 60 plasma samples for proteomic analysis. Among them, six children were sampled before and after receiving their first BoNT-A injection. In addition, 48 unrelated children were enrolled, among whom one group had never received BoNT-A injections and another group was sampled after their first BoNT-A injection. Differentially expressed proteins were identified using the data-independent acquisition (DIA) mass spectrometry approach. Gene Ontology (GO), protein-protein interaction network, and Kyoto Encyclopedia of Genes and Genome analysis were conducted to explore the function and relationship among differentially expressed proteins. The expression levels of target proteins were verified by quantitative real-time PCR and western blotting. RESULTS: Analysis identified significant differential expression of 90 proteins across two time points, including 48 upregulated and 42 downregulated proteins. The upregulated thioredoxin, α-actinin-1, and aggrecan, and the downregulated integrin beta-1 may affect the growth of muscles affected by spasticity 3 months after BoNT-A injection. This effect is potentially mediated through the activation or inhibition of PI3K-Akt, focal adhesion, and regulation of actin cytoskeleton signaling pathways. CONCLUSION AND CLINICAL RELEVANCE: BoNT-A injection could lead to a disruption of protein levels and signaling pathways, a condition subsequently associated with muscle growth. This finding might aid clinicians in optimizing the management of spasticity in children with CP.

Constraint-Induced Movement Therapy Promotes Myelin Remodeling and Motor Function by Mediating Sox2/Fyn Signals in Rats With Hemiplegic Cerebral Palsy.

OBJECTIVE: Hypoxic-ischemic brain injury in infants often leads to hemiplegic motor dysfunction. The mechanism of their motor dysfunction has been attributed to deficiencies of the transcription factor sex-determining region (SRY) box 2 (Sox2) or the non-receptor-type tyrosine kinase Fyn (involved in neuronal signal transduction), which causes a defect in myelin formation. Constraint-induced movement therapy (CIMT) following cerebral hypoxia-ischemia may stimulate myelin growth by regulating Sox2/Fyn, Ras homolog protein family A (RhoA), and rho-associated kinase 2 (ROCK2) expression levels. This study investigated how Sox2/Fyn regulates myelin remodeling following CIMT to improve motor function in rats with hemiplegic cerebral palsy (HCP). METHODS: To investigate the mechanism of Sox2 involvement in myelin growth and neural function in rats with HCP, Lentivirus (Lenti)-Sox2 adeno-associated virus and negative control-Lenti-Sox2 (LS) adeno-associated virus were injected into the lateral ventricle. The rats were divided into a control group and an HCP group with different interventions (CIMT, LS, or negative control-LS [NS] treatment), yielding the HCP, HCP plus CIMT (HCP + CIMT), HCP + LS, HCP + LS + CIMT, HCP + NS, and HCP + NS + CIMT groups. Front-limb suspension and RotaRod tests, Golgi-Cox staining, transmission electron microscopy, immunofluorescence staining, western blotting, and quantitative polymerase chain reaction experiments were used to analyze the motor function, dendrite/axon area, myelin ultrastructure, and levels of expression of oligodendrocytes and Sox2/Fyn/RhoA/ROCK2 in the motor cortex. RESULTS: The rats in the HCP + LS + CIMT group had better values for motor function, dendrite/axon area, myelin ultrastructure, oligodendrocytes, and Sox2/Fyn/RhoA/ROCK2 expression in the motor cortex than rats in the HCP and HCP + NS groups. The improvement of motor function and myelin remodeling, the expression of oligodendrocytes, and the expression of Sox2/Fyn/RhoA/ROCK2 in the HCP + LS group were similar to those in the HCP + CIMT group. CONCLUSION: CIMT might overcome RhoA/ROCK2 signaling by upregulating the transcription of Sox2 to Fyn in the brain to induce the maturation and differentiation of oligodendrocytes, thereby promoting myelin remodeling and improving motor function in rats with HCP. IMPACT: The pathway mediated by Sox2/Fyn could be a promising therapeutic target for HCP.

Dual engine-driven bionic microneedles for early intervention and prolonged treatment of Alzheimer's disease.

The microneedle (MN) delivery system presents an attractive administration route for patients with Alzheimer's disease (AD). However, the passive drug delivery mode and low drug loading of MNs often result in unsatisfactory therapeutic efficiency. To address these dilemmas, we developed dual engine-drive bionic MNs for robust AD treatment. Specifically, free rivastigmine (RVT) and RVT particles were co-loaded within the MNs to construct the valve and chambers of the guava, respectively, which can serve as an active engine to promote drug permeation by generating capillary force. K2CO3 and citric acid were introduced as a pneumatic engine into the MNs to promote the permeation of free RVT into deeper skin layers for early intervention in AD. Further, the RVT particles served as a drug depot to provide continuous drug release for prolonged AD treatment. Compared with free RVT-loaded MNs, the dual engine-driven bionic MNs showed an increase in drug loading, cumulative transdermal permeability, and normalized bioavailability of approximately 40%, 22%, and 49%, respectively. Pharmacodynamic studies further confirmed that the dual engine-driven bionic MNs were most effective in restoring memory and recognition functions in mice with short-term memory dysfunction. Therefore, the dual engine-driven bionic MNs hold great promise for highly efficient AD treatment.

The cerebral lymphatic drainage system and its implications in epilepsy.

The central nervous system has long been thought to lack a clearance system similar to the peripheral lymphatic system. Therefore, the clearance of metabolic waste in the central nervous system has been a subject of great interest in neuroscience. Recently, the cerebral lymphatic drainage system, including the parenchymal clearance system and the meningeal lymphatic network, has attracted considerable attention. It has been extensively studied in various neurological disorders. Solute accumulation and neuroinflammation after epilepsy impair the blood-brain barrier, affecting the exchange and clearance between cerebrospinal fluid and interstitial fluid. Restoring their normal function may improve the prognosis of epilepsy. However, few studies have focused on providing a comprehensive overview of the brain clearance system and its significance in epilepsy. Therefore, this review addressed the structural composition, functions, and methods used to assess the cerebral lymphatic system, as well as the neglected association with epilepsy, and provided a theoretical basis for therapeutic approaches in epilepsy.

Evaluating the safety and operability of asymmetric trapezoid and near-square side-port incision in cataract surgery.

PURPOSE: To compare the accuracy, safety, and consistency of asymmetric trapezoid and near-square side-port incision in cataract surgery. SETTING: Aier Eye Hospital of Wuhan University, Wuhan, Hubei Province, China. DESIGN: Prospective pilot study. METHODS: This study included patients who underwent phacoemulsification between January 2022 and August 2022. They were divided into Group A and Group B using the random number table method. Group A was given a near-square side-port incision and Group B was given an asymmetric trapezoid side-port incision. We contrasted the differences in incision length, width, and shape; surgical time; and postoperative intraocular pressure (IOP) between the 2 groups. RESULTS: 220 eyes of 220 patients were included. The mean external width of the incision in Group A was much smaller than that in Group B ( P < .01), and the consistency of the incision diameter in Group A was better than that in Group B. There was no statistically significant difference in incision length between the 2 groups ( P = .75). 1 day after surgery, there was no statistically significant difference in incision morphology between the 2 groups ( P = .72). The operating time for Group A was significantly shorter than that of Group B ( P < .01). There was no obvious incision leakage in both groups after surgery, and the IOP was generally elevated after surgery, but there was no significant statistical difference between the 2 groups ( P = .98). CONCLUSIONS: The present study suggests that a near-square side-port results in better consistency of incision width and shorter surgical time.

ATF5-regulated Mitochondrial Unfolded Protein Response Attenuates Neuronal Damage in Epileptic Rat by Reducing Endoplasmic Reticulum Stress Through Mitochondrial ROS.

Endoplasmic reticulum (ER) dysfunction caused by excessive ER stress is a crucial mechanism underlying seizures-induced neuronal injury. Studies have shown that mitochondrial reactive oxygen species (ROS) are closely related to ER stress, and our previous study showed that activating transcription factor 5 (ATF5)-regulated mitochondrial unfolded protein response (mtUPR) modulated mitochondrial ROS generation in a hippocampal neuronal culture model of seizures. However, the effects of ATF5-regulated mtUPR on ER stress and the underlying mechanisms remain uncertain in epilepsy. In this study, ATF5 upregulation by lentivirus infection attenuated seizures-induced neuronal damage and apoptosis in a rat model of pilocarpine-induced epilepsy, whereas ATF5 downregulation by lentivirus infection had the opposite effects. ATF5 upregulation potentiated mtUPR by increasing the expression of mitochondrial chaperone heat shock protein 60 (HSP60) and caseinolytic protease proteolytic subunit (ClpP) and reducing mitochondrial ROS generation in pilocarpine-induced seizures in rats. Additionally, upregulation of ATF5 reduced the expression of glucose-regulated protein 78 (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP), suggesting suppression of ER stress; Moreover, ATF5 upregulation attenuated apoptosis-related proteins such as B-cell lymphoma-2 (BCL2) downregulation, BCL2-associated X (BAX) and cleaved-caspase-3 upregulation. However, ATF5 downregulation exerted the opposite effects. Furthermore, pretreatment with the mitochondria-targeted antioxidant mito-TEMPO attenuated the harmful effects of ATF5 downregulation on ER stress and neuronal apoptosis by reducing mitochondrial ROS generation. Overall, our study suggested that ATF5-regulated mtUPR exerted neuroprotective effects against pilocarpine-induced seizures in rats and the underlying mechanisms might involve mitochondrial ROS-mediated ER stress.

Combating multidrug resistance of breast cancer with ginsenoside Rh2-irrigated nano-in-thermogel.

The emergence of multidrug resistance (MDR) is the leading cause of mortality in patients with breast cancer. Overexpressed P-glycoprotein (P-gp) that can pump out chemotherapeutics from multidrug-resistant cancer cells is the main cause of chemotherapy failure. P-gp inhibitors are hence increasingly used to sensitize chemotherapy to breast cancer with MDR by reducing the efflux of drugs. However, representative P-gp inhibitors usually have severe side effects and the effect of their release behavior on chemotherapy are neglected in current studies. We constructed a nano-in-thermogel delivery system with the sequential release of ginsenoside Rh2 (GRh2) and a chemotherapeutic drug in the tumor microenvironment as a drug compounding "reservoir" to combat MDR in breast cancer. Briefly, paclitaxel (PTX) and GRh2 were encapsulated in solid lipid nanoparticles (SLNs) and dispersed in a poloxamer-based thermogel (SLNs-Gel). GRh2 was used as an innovative and safe P-gp inhibitor to lower P-gp expression and cellular adenosine triphosphate context, thereby sensitizing PTX-resistant breast cancer cells (MCF-7/PTX) to PTX. Pharmacodynamic and in vivo safety studies confirmed that intratumoral injection of SLNs-Gel significantly suppressed the proliferation of PTX-resistant breast cancer and alleviated the PTX-induced hematotoxicity. The GRh2-irrigated nano-in-thermogel delivery system shows great potential in combating multidrug-resistant cancer.