Zinc-Carnosine Metallodrug Network as Dual Metabolism Inhibitor Overcoming Metabolic Reprogramming for Efficient Cancer Therapy.

The targeting of tumor metabolism as a novel strategy for cancer therapy has attracted tremendous attention. Herein, we develop a dual metabolism inhibitor, Zn-carnosine metallodrug network nanoparticles (Zn-Car MNs), which exhibits good Cu-depletion and Cu-responsive drug release, causing potent inhibition of both OXPHOS and glycolysis. Notably, Zn-Car MNs can decrease the activity of cytochrome c oxidase and the content of NAD+, so as to reduce ATP production in cancer cells. Thereby, energy deprivation, together with the depolarized mitochondrial membrane potential and increased oxidative stress, results in apoptosis of cancer cells. In result, Zn-Car MNs exerted more efficient metabolism-targeted therapy than the classic copper chelator, tetrathiomolybdate (TM), in both breast cancer (sensitive to copper depletion) and colon cancer (less sensitive to copper depletion) models. The efficacy and therapy of Zn-Car MNs suggest the possibility to overcome the drug resistance caused by metabolic reprogramming in tumors and has potential clinical relevance.

MicroRNA-10 Family Promotes Renal Fibrosis through the VASH-1/Smad3 Pathway.

Renal fibrosis (RF) stands as a pivotal pathological process in the advanced stages of chronic kidney disease (CKD), and impeding its progression is paramount for delaying the advancement of CKD. The miR-10 family, inclusive of miR-10a and miR-10b, has been implicated in the development of various fibrotic diseases. Nevertheless, the precise role of miR-10 in the development of RF remains enigmatic. In this study, we utilized both an in vivo model involving unilateral ureteral obstruction (UUO) in mice and an in vitro model employing TGF-ß1 stimulation in HK-2 cells to unravel the mechanism underlying the involvement of miR-10a/b in RF. The findings revealed heightened expression of miR-10a and miR-10b in the kidneys of UUO mice, accompanied by a substantial increase in p-Smad3 and renal fibrosis-related proteins. Conversely, the deletion of these two genes led to a notable reduction in p-Smad3 levels and the alleviation of RF in mouse kidneys. In the in vitro model of TGF-ß1-stimulated HK-2 cells, the co-overexpression of miR-10a and miR-10b fostered the phosphorylation of Smad3 and RF, while the inhibition of miR-10a and miR-10b resulted in a decrease in p-Smad3 levels and RF. Further research revealed that miR-10a and miR-10b, through binding to the 3'UTR region of Vasohibin-1 (VASH-1), suppressed the expression of VASH-1, thereby promoting the elevation of p-Smad3 and exacerbating the progression of RF. The miR-10 family may play a pivotal role in RF.

Diastereodivergent Desymmetric Annulation to Access Spirooxindoles: Chemical Probes for Mitosis.

Spirooxindoles have emerged as promising architectures for engineering biologically active compounds. The diastereodivergent construction of unique scaffolds of this type with full control of continuous chiral centers including an all-carbon quaternary stereogenic center is yet to be developed. Here, we report an unprecedented diastereodivergent desymmetric [3 + 3] annulation of oxabicyclic alkenes with enals enabled by N-heterocyclic carbene (NHC)/Rh cooperative catalysis, leading to a series of enantiomerically enriched spirooxindole lactones with excellent enantioselectivities (up to >99% ee) and diastereoselectivities (up to >95:5 dr). The combined catalyst system comprises a rhodium complex that controls the configuration at the electrophilic carbon and an NHC catalyst that controls the configuration at the nucleophilic oxindole-containing carbon; thus, four stereoisomers of the spirooxindole products can be readily obtained simply by switching the configurations of the two chiral catalysts. Transformations of the chiral spirooxindoles delivered synthetically useful compounds. Importantly, those chiral spirooxindoles arrested mammalian cells in mitosis and exhibited potent antiproliferative activities against HeLa cells. Significantly, both absolute and relative configurations exert prominent effects on the bioactivities, underscoring great importance of catalytic asymmetric diastereodivergent synthesis beyond creating useful tools for the exploration of structure-activity relationships.

Noninvasive Imaging of Tumor Glycolysis and Chemotherapeutic Resistance via De Novo Design of Molecular Afterglow Scaffold.

Chemotherapeutic resistance poses a significant challenge in cancer treatment, resulting in the reduced efficacy of standard chemotherapeutic agents. Abnormal metabolism, particularly increased anaerobic glycolysis, has been identified as a major contributing factor to chemotherapeutic resistance. To address this issue, noninvasive imaging techniques capable of visualizing tumor glycolysis are crucial. However, the currently available methods (such as PET, MRI, and fluorescence) possess limitations in terms of sensitivity, safety, dynamic imaging capability, and autofluorescence. Here, we present the de novo design of a unique afterglow molecular scaffold based on hemicyanine and rhodamine dyes, which holds promise for low-background optical imaging. In contrast to previous designs, this scaffold exhibits responsive "OFF-ON" afterglow signals through spirocyclization, thus enabling simultaneous control of photodynamic effects and luminescence efficacy. This leads to a larger dynamic range, broader detection range, higher signal enhancement ratio, and higher sensitivity. Furthermore, the integration of multiple functionalities simplifies probe design, eliminates the need for spectral overlap, and enhances reliability. Moreover, we have expanded the applications of this afterglow molecular scaffold by developing various probes for different molecular targets. Notably, we developed a water-soluble pH-responsive afterglow nanoprobe for visualizing glycolysis in living mice. This nanoprobe monitors the effects of glycolytic inhibitors or oxidative phosphorylation inhibitors on tumor glycolysis, providing a valuable tool for evaluating the tumor cell sensitivity to these inhibitors. Therefore, the new afterglow molecular scaffold presents a promising approach for understanding tumor metabolism, monitoring chemotherapeutic resistance, and guiding precision medicine in the future.

Dynamic crotonylation of EB1 by TIP60 ensures accurate spindle positioning in mitosis.

Spindle position control is essential for cell fate determination and organogenesis. Early studies indicate the essential role of the evolutionarily conserved Gαi/LGN/NuMA network in spindle positioning. However, the regulatory mechanisms that couple astral microtubules dynamics to the spindle orientation remain elusive. Here we delineated a new mitosis-specific crotonylation-regulated astral microtubule-EB1-NuMA interaction in mitosis. EB1 is a substrate of TIP60, and TIP60-dependent crotonylation of EB1 tunes accurate spindle positioning in mitosis. Mechanistically, TIP60 crotonylation of EB1 at Lys66 forms a dynamic link between accurate attachment of astral microtubules to the lateral cell cortex defined by NuMA-LGN and fine tune of spindle positioning. Real-time imaging of chromosome movements in HeLa cells expressing genetically encoded crotonylated EB1 revealed the importance of crotonylation dynamics for accurate control of spindle orientation during metaphase-anaphase transition. These findings delineate a general signaling cascade that integrates protein crotonylation with accurate spindle positioning for chromosome stability in mitosis.

Cognitive protection of sinomenine in type 2 diabetes mellitus through regulating the EGF/Nrf2/HO-1 signaling, the microbiota-gut-brain axis, and hippocampal neuron ferroptosis.

Recent years have witnessed a growing research interest in traditional Chinese medicine as a neuroprotective nutrient in the management of diabetic cognitive dysfunction. However, the underlying molecular mechanisms of sinomenine in mediating ferroptosis of hippocampal neurons have been poorly understood. This study sought to decipher the potential effect and molecular mechanism of sinomenine in the cognitive dysfunction following type 2 diabetes mellitus (T2DM). Multi-omics analysis was conducted to identify the microbiota-gut-brain axis in T2DM patient samples obtained from the publicly available database. In HT-22 cells, erastin was utilized to create a ferroptosis model, and streptozotocin was injected intraperitoneally to create a rat model of DM. It was noted that intestinal flora imbalance occurred in patients with T2DM-associated cognitive dysfunction. Sinomenine could reduce Erastin-induced hippocampus neuronal ferroptosis by increasing EGF expression. EGF protected hippocampal neurons against ferroptosis by activating the Nrf2/HO-1 signaling pathway. Furthermore, in vivo results confirmed that sinomenine blocked ferroptosis of hippocampal neurons and alleviated cognitive dysfunction in T2DM rats. Collectively, these results suggest that sinomenine confers neuroprotective effects by curtailing hippocampal neuron ferroptosis via the EGF/Nrf2/HO-1 signaling and microbiota-gut-brain axis. It may be a candidate for the treatment of diabetic cognitive dysfunction.

Characterization of lipopeptide produced by Bacillus altitudinis Q7 and inhibitory effect on Alternaria alternata.

This study identified the antifungal metabolites produced by Bacillus altitudinis Q7 against Alternaria alternata and investigated the antifungal activity and antifungal action. Lipopeptide, the important secondary metabolites were identified by Fourier transform infrared (FTIR) and liquid chromatography-mass spectrometry as lichenysin. The antifungal activity of lipopeptide on A. alternata was determined by microdilution technique, and its minimum inhibitory concentration was 1.2 mg/ml. Stability test showed that lipopeptide had excellent temperature and pH resistance. To investigate whether lichenysin acted on the cell membrane and changed its permeability, the ultra-violet absorption of protein and nucleic acid were measured using a colorimetric method. The antifungal metabolites produced by B. altitudinis Q7 was lichenysin, which showed stable antifungal activity in the extreme environments. Lichenysin could inhibit A. alternata by altering the permeability of cell membrane, leading to the outflow of proteins and nucleic acids from the cytoplasm. This research suggests the lipopeptide from B. altitudinis Q7 is a potential biological control agent against A. alternata.

MicroRNA-10 Family Promotes the Epithelial-to-Mesenchymal Transition in Renal Fibrosis by the PTEN/Akt Pathway.

Renal fibrosis (RF) is a common reason for renal failure, and epithelial-mesenchymal transition (EMT) is a vital mechanism that promotes the development of RF. It is known that microRNA-10 (miR-10) plays an important role in cancer EMT; however, whether it takes part in the EMT process of RF remains unclear. Therefore, we established an in vivo model of unilateral ureteral obstruction (UUO), and an in vitro model using TGF-ß1, to investigate whether and how miR-10a and miR-10b take part in the EMT of RF. In addition, the combinatorial effects of miR-10a and miR-10b were assessed. We discovered that miR-10a and miR-10b are overexpressed in UUO mice, and miR-10a, miR-10b, and miRs-10a/10b knockout attenuated RF and EMT in UUO-treated mouse kidneys. Moreover, miR-10a and miR-10b overexpression combinatorially promoted RF and EMT in TGF-ß1-treated HK-2 cells. Inhibiting miR-10a and miR-10b attenuated RF and EMT induced by TGF-ß1. Mechanistically, miR-10a and miR-10b suppressed PTEN expression by binding to its mRNA3'-UTR and promoting the Akt pathway. Moreover, PTEN overexpression reduced miR-10a and miR-10b effects on Akt phosphorylation (p-Akt), RF, and EMT in HK-2 cells treated with TGF-ß1. Taken together, miR-10a and miR-10b act combinatorially to negatively regulate PTEN, thereby activating the Akt pathway and promoting the EMT process, which exacerbates RF progression.

Synergistic Effect of PVDF-Coated PCL-TCP Scaffolds and Pulsed Electromagnetic Field on Osteogenesis.

Bone exhibits piezoelectric properties. Thus, electrical stimulations such as pulsed electromagnetic fields (PEMFs) and stimuli-responsive piezoelectric properties of scaffolds have been investigated separately to evaluate their efficacy in supporting osteogenesis. However, current understanding of cells responding under the combined influence of PEMF and piezoelectric properties in scaffolds is still lacking. Therefore, in this study, we fabricated piezoelectric scaffolds by functionalization of polycaprolactone-tricalcium phosphate (PCL-TCP) films with a polyvinylidene fluoride (PVDF) coating that is self-polarized by a modified breath-figure technique. The osteoinductive properties of these PVDF-coated PCL-TCP films on MC3T3-E1 cells were studied under the stimulation of PEMF. Piezoelectric and ferroelectric characterization demonstrated that scaffolds with piezoelectric coefficient d33 = -1.2 pC/N were obtained at a powder dissolution temperature of 100 °C and coating relative humidity (RH) of 56%. DNA quantification showed that cell proliferation was significantly enhanced by PEMF as low as 0.6 mT and 50 Hz. Hydroxyapatite staining showed that cell mineralization was significantly enhanced by incorporation of PVDF coating. Gene expression study showed that the combination of PEMF and PVDF coating promoted late osteogenic gene expression marker most significantly. Collectively, our results suggest that the synergistic effects of PEMF and piezoelectric scaffolds on osteogenesis provide a promising alternative strategy for electrically augmented osteoinduction. The piezoelectric response of PVDF by PEMF, which could provide mechanical strain, is particularly interesting as it could deliver local mechanical stimulation to osteogenic cells using PEMF.

Holliday junction recognition protein interacts with and specifies the centromeric assembly of CENP-T.

The centromere is an evolutionarily conserved eukaryotic protein machinery essential for precision segregation of the parental genome into two daughter cells during mitosis. Centromere protein A (CENP-A) organizes the functional centromere via a constitutive centromere-associated network composing the CENP-T complex. However, how CENP-T assembles onto the centromere remains elusive. Here we show that CENP-T binds directly to Holliday junction recognition protein (HJURP), an evolutionarily conserved chaperone involved in loading CENP-A. The binding interface of HJURP was mapped to the C terminus of CENP-T. Depletion of HJURP by CRISPR-elicited knockout minimized recruitment of CENP-T to the centromere, indicating the importance of HJURP in CEPN-T loading. Our immunofluorescence analyses indicate that HJURP recruits CENP-T to the centromere in S/G2 phase during the cell division cycle. Significantly, the HJURP binding-deficient mutant CENP-T6L failed to locate to the centromere. Importantly, CENP-T insufficiency resulted in chromosome misalignment, in particular chromosomes 15 and 18. Taken together, these data define a novel molecular mechanism underlying the assembly of CENP-T onto the centromere by a temporally regulated HJURP-CENP-T interaction.

Inhibition of P2X7R in the amygdala ameliorates symptoms of neuropathic pain after spared nerve injury in rats.

The amygdala circuitry and P2X7 receptor (P2X7R) have both been shown to play important roles in the modulation of neuropathic pain (NP). However, little is known about the functional role of P2X7R in the amygdala for the regulation of NP. This study aims to evaluate the alleviative effect of intra-amygdala microinfusion of a pharmacological antagonist of P2X7R (A-438079) on NP and explore its possible mechanism of action. Male Sprague-Dawley rats were used to construct the animal model of NP through spared nerve injury (SNI). The SNI rats randomly received chronic bilateral microinjection of A-438079 (100 pmol/side) or saline into the amygdalae via cannulas. Mechanical paw withdrawal threshold (MWT) and thermal withdrawal duration (TWD) were measured by von Frey monofilaments. Besides, tail suspension test (TST), forced swimming test (FST), open field test (OFT) and sucrose preference test (SPT) were performed to assess depression- and anxiety-like behaviors. Immunofluorescence assay was employed to determine the levels of glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (IBA-1) and connexin 43 (Cx43) in the spinal cord. In addition, the change of growth associated protein 43 (GAP43) level in the spinal cord was assessed by Western blot. Our data showed that chronic treatment with A-438079 increased MWT and decreased TWD on days 11-21 post-SNI while decreased depression-like and anxiety-like behaviors. A-438079 administration significantly attenuated the elevated immunoreactivities of IBA-1 and GFAP in microglia and astrocytes after SNI. Furthermore, the decreased expression of GAP-43 in the spinal cord due to SNI was significantly attenuated by A-438079. However, when A-438079 and a pharmacological agonist (BzATP) of P2X7R were given simultaneously, all the effects caused by A-438079 alone were reversed. In brief, our study revealed the protective role of inhibiting P2X7R in the amygdala against symptoms associated with NP, possibly attributing to its inhibitory effects on spinal microglia and astrocytes.

MicroRNA-7a ameliorates neuropathic pain in a rat model of spinal nerve ligation via the neurofilament light polypeptide-dependent signal transducer and activator of transcription signaling pathway.

Neuropathic pain is a type of chronic pain induced by either central or peripheral nerve injury. MicroRNAs have been recently linked to many diseases, including neuropathic pain. However, the role of miR-7a in neuropathic pain still remains elusive. Thus, we aim to investigate the effects of miR-7a on neuropathic pain based on the spinal nerve ligation rat model. After establishment of spinal nerve ligation rat models, rats were infected with adeno-associated virus-neurofilament light polypeptide, adeno-associated virus-miR-7a or treated with metformin. The paw withdrawal threshold and paw withdrawal latency were assessed afterward, and the expression of miR-7a and neurofilament light polypeptide as well as their interaction was determined. Subsequently, miR-7a was overexpressed or silenced in dorsal root ganglion cells to investigate the role of miR-7a in neuropathic pain. Furthermore, the regulatory effect of neurofilament light polypeptide on neuropathic pain was detected using plasmid overexpressing neurofilament light polypeptide. Spinal nerve ligation rat model exhibited upregulation of neurofilament light polypeptide but downregulation of miR-7a. In addition, neurofilament light polypeptide accumulation or miR-7a inhibition decreased paw withdrawal threshold and paw withdrawal latency. Then, neurofilament light polypeptide accumulation or miR-7a inhibition was observed to increase the phosphorylation level of signal transducer and activator of transcription. miR-7a was found to directly target neurofilament light polypeptide and downregulate neurofilament light polypeptide. In addition, inhibiting the signal transducer and activator of transcription signaling pathway was also revealed to increase paw withdrawal threshold and paw withdrawal latency. Collectively, our study demonstrated that miR-7a ameliorated neuropathic pain via blocking the signal transducer and activator of transcription signaling pathway by repressing neurofilament light polypeptide. These findings, if taken further, can be of important clinical significance in treating patients with neuropathic pain.

The Natural Rotenoid Deguelin Ameliorates Diabetic Neuropathy by Decreasing Oxidative Stress and Plasma Glucose Levels in Rats via the Nrf2 Signalling Pathway.

BACKGROUND/AIMS: Deguelin is a natural rotenoid that shows anti-inflammatory and antimicrobial activities. Rotenoids prevent oxidative damage and potentiate natural antioxidant activity in diabetic conditions, suggesting utility in treating diabetes and its complications. Here, we evaluate the potential efficacy of deguelin against diabetic neuropathy (DN). METHODS: DN was induced by streptozotocin followed by daily treatment with deguelin (4, 6 or 8 mg/kg) for 14 days. Blood glucose was measured, neurobehavioral tests for nociception and motor coordination were performed, and neuron conduction velocities were analysed electrophysiologically. We also assessed (Na+-K+) ATPase activity, performed a reactive oxygen species assay, measured the levels of various markers of oxidative stress, and of hydrogen sulphide (H2S) in dorsal root ganglion (DRG) neurons, conducted immunoblotting studies for proteins and ELISA for inflammatory cytokines. RESULTS: Deguelin significantly suppressed mechanical and thermal hyperalgesia, as well as cold allodynia, and partially restored the conduction velocities of neurons in DN rats. Significantly decreased expression levels of capspase-3 in DRG neurons, and increased (Na+-K+) ATPase activity in sciatic nerves, were observed. In addition, deguelin decreased glucose levels, attenuated oxidative stress and neuroinflammation, and elevated levels of H2S, nuclear respiratory factor 2 (Nrf2) and heme oxygenase-1, suggesting a disease-attenuating effect of deguelin in DN rats. To shed light on the underlying mechanism of action of deguelin, insulin- and dimethyl fumarate (BG-12)-treated groups were also included. Insulin suppressed glucose levels and BG-12 produced effects on Nrf2 levels similar to 8 mg/kg deguelin, confirming involvement of the Nrf2 pathway in the beneficial effects of deguelin against DN. CONCLUSIONS: Deguelin attenuated DN by decreasing oxidative stress and plasma glucose levels via the Nrf2 signalling pathway.

MicroRNA-182 aggravates cerebral ischemia injury by targeting inhibitory member of the ASPP family (iASPP).

Ischemic stroke is one of the leading causes of death and disability globally and has been regarded as a major public health problem. MicroRNA 182 (miR-182) plays important roles in cellular differentiation, cell growth, cell apoptosis and metastasis. However, the role of miR-182 in the cerebral ischemia injury has never been investigated. In the present study, we demonstrate a crucial role of miR-182 in down-regulating inhibitory member of the ASPP family (iASPP) expression and promoting cerebral ischemia injury. MiR-182 also promotes NO and 3-NT production, and Caspase3 expression, while reduces SOD and MnSOD activities. Furthermore, the amplified cerebral ischemia injury induced by miR-182 is aggravated by inhibition of iASPP. In conclusion, miR-182 plays an aggressive role in the cerebral ischemia injury, and this is associated with inhibited iASPP expression.

Anticancer effect and mechanism of a Se-modified porphyrin Au(III) complex.

Au, Se and porphyrin are widely used components in the design of anticancer drugs, but their combination has never been referred to. In this work, a Se-modified porphyrin Au(III) complex, [AuTPP-Se]Cl, was designed and synthesized as a potential anticancer agent. This compound exhibits remarkable antiproliferative activity on all the six tested cancer cells. Its potency on HepG2 is even ten times higher than that of CDDP. The synergistic action among Au, Se and porphyrin components was validated. Mechanism study showed that both the induction of mitochondria-dependent apoptosis and the arrest of cell cycle contribute to the anticancer activity of [AuTPP-Se]Cl.

Metal-Organic Nanomaterials for Tumor Metabolic Blockade and Image to Increase Tumor Therapy.

The abnormal energy metabolism level of a tumor reduces the efficiency of chemotherapy. Metal-organic nanomaterials (MONs) with high drug loading efficiency, easy processes of synthesis, and controlled drug release have shown great potential in metabolic blocking and enhancement of tumor therapy. These metal-organic nanomedicines have been reported to modulate glycolysis or oxidative phosphorylation to provide monotherapy or combined therapies in tumorous treatments. In addition, the encapsulation or coordination of fluorescent dyes into MONs endowed them with the imaging ability of tumor metabolism. Herein, this Perspective summarizes the progress of MONs as therapeutic agents or imaging probes for application during tumor metabolic blocking or imaging, providing solid inspiration for biomedical applications of effective biomaterials. In addition, the current drawbacks of MONs for further biological applications in the future were discussed, giving stimulation of innovation and development in biomedical applications of MONs.

hUC-MSC-EV-miR-24 enhances the protective effect of dexmedetomidine preconditioning against myocardial ischemia-reperfusion injury through the KEAP1/Nrf2/HO-1 signaling.

The cardioprotective effect of microRNAs (miRNAs) on myocardial ischemic-reperfusion (I/R) injury has been documented. Here, we aim to decipher the mechanism of miR-24 delivered by human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSC-EVs) in myocardial I/R injury after dexmedetomidine (DEX) preconditioning. We collected and identified hUC-MSCs and extracted EVs, which were co-cultured with DEX-preconditioned hypoxia/reoxygenation (H/R) cardiomyocyte models or injected into I/R mouse models. The cardiomyocytes and myocardial injury were evaluated by molecular biology experiments. miR-24 was highly expressed in hUC-MSC-EVs. hUC-MSC-EVs could transfer miR-24 into cardiomyocytes where miR-24 augmented cell viability and inhibited cell apoptosis after DEX preconditioning. In the co-culture system of RAW264.7 macrophages with hUC-MSC-EVs, miR-24 promoted M2-type polarization of macrophages and reduced M1-type macrophage polarization. Mechanistically, miR-24 targeted KEAP1 and inhibited its expression, resulting in disruption of the Nrf2/HO-1 signaling. In vivo data confirmed that miR-24 delivered by hUC-MSC-EVs enhanced the suppressing effect of DEX preconditioning on inflammation and apoptosis in rats following myocardial I/R injury. Overall, miR-24 delivered by hUC-MSC-EVs can promote M2 polarization of macrophages and enhance the protective effect of DEX preconditioning on myocardial I/R injury by down-regulating the KEAP1/Nrf2/HO-1 signaling axis.

Catechol chitosan coated dual-loaded liposomes based on oxidation and saccharification mechanisms for enhancing skin anti-aging effects.

Skin aging has become a major urgent problem to be solved. Evidence reveals that oxidation and glycosylation are two dominant inducements of aging. Resveratrol (RES) with outstanding anti-oxidant effect and carnosine (CAR) with superb anti-glycation property were selected as two model drugs to evaluate the feasibility of their synergistic anti-aging effect. RES and CAR at the most desired mass ratio, supplying the most superior synergistic anti-aging effects were further encapsulated in liposomes (LP), which were separately coated with chitosan (CS) and catechol chitosan (Cat-CS) to increase the transdermal penetration. Their anti-aging efficacy was explored in human skin fibroblast (HSF) and human immortalized keratinocytes (HaCaT) cells, as well as the back skin of guinea pigs. Herein, RES and CAR at the mass ratio of 2:1 exhibited the most ideal synergistic anti-aging effect. The constructed liposomes have been shown to possess excellent fundamental properties and sustained-release properties. The aging-related indicator levels in the two cells and guinea pigs were obviously improved for the RES + CAR@Cat-CS-LP group. Additionally, skin appearance, tissue morphology, and collagen content were visibly improved, indicating its perfect anti-aging effect. In conclusion, RES + CAR@Cat-CS-LP is expected to be exploited as a potential anti-aging drug delivery system.

Targeting the PI3K/AKT signaling pathway with PNU120596 protects against LPS-induced acute lung injury.

OBJECTIVES: This study investigated the potential therapeutic benefits of PNU120596, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor (α7nAChR), in mitigating acute lung injury (ALI) induced by lipopolysaccharide (LPS) in a mouse model. Specifically, we sought to examine the impact of PNU120596 on the PI3K/AKT signaling pathway in the context of ALI. METHODS: ALI was induced in mice by LPS administration, and the protective effects of PNU120596 were assessed. Lung injury, lung function, and the inflammatory response were evaluated. Additionally, the activation of the PI3K/AKT signaling pathway was examined, along with the levels of inflammatory factors and oxidative stress markers. KEY FINDINGS: PNU120596 significantly ameliorated LPS-induced lung injury, improved lung function, and reduced the inflammatory response in the mouse model of ALI. Furthermore, we observed that PNU120596 inhibited the activation of the PI3K/AKT signaling pathway, which was associated with decreased levels of inflammatory factors and oxidative stress markers. CONCLUSIONS: PNU120596 exhibits promising therapeutic potential for the treatment of acute lung injury, potentially by targeting the PI3K/AKT signaling pathway. These findings suggest that modulation of the α7 nicotinic acetylcholine receptor with PNU120596 may offer a viable strategy for the management of ALI, warranting further investigation and potential clinical applications.

Multifunctional nanofibrous scaffolds for enhancing full-thickness wound healing loaded with Bletilla striata polysaccharides.

The considerable challenge of wound healing remains. In this study, we fabricated a novel multifunctional core-shell nanofibrous scaffold named EGF@BSP-CeO2/PLGA (EBCP), which is composed of Bletilla striata polysaccharide (BSP), Ceria nanozyme (CeO2) and epidermal growth factor (EGF) as the core and poly(lactic-co-glycolic acid) (PLGA) as the shell via an emulsion electrospinning technique. An increase in the BSP content within the scaffolds corresponded to improved wound healing performance. These scaffolds exhibited increased hydrophilicity and porosity and improved mechanical properties and anti-UV properties. EBCP exhibited sustained release, and the degradation rate was <4 % in PBS for 30 days. The superior biocompatibility was confirmed by the MTT assay, hemolysis, and H&E staining. In addition, the in vitro results revealed that, compared with the other groups, the EBCP group presented excellent antioxidant and antibacterial effects. More importantly, the in vivo results indicated that the wound closure rate of the EBCP group reached 94.0 % on day 10 in the presence of H2O2. The results demonstrated that EBCP could comprehensively regulate the wound microenvironment, possess hemostatic abilities, and significantly promote wound healing. In conclusion, the EBCP is promising for facilitating the treatment of infected wounds and represents a potential material for clinical applications.