Combination of monensin and erlotinib synergistically inhibited the growth and cancer stem cell properties of triple-negative breast cancer by simultaneously inhibiting EGFR and PI3K signaling pathways.

BACKGROUND: Cancer stem cells (CSCs) in triple-negative breast cancer (TNBC) are recognized as a highly challenging subset of cells, renowned for their heightened propensity for relapse and unfavorable prognosis. Monensin, an ionophoric antibiotic, has been reported to exhibit significant therapeutic efficacy against various cancers, especially CSCs. Erlotinib is classified as one of the EGFR-TKIs and has been previously identified as a promising therapeutic target for TNBC. Our research aims to assess the effectiveness of combination of monensin and erlotinib as a potential treatment strategy for TNBC. METHODS: The combination of monensin and erlotinib was assessed for its potential anticancer activity through various in vitro assays, including cytotoxicity assay, colony formation assay, wound healing assay, transwell assay, mammosphere formation assay, and proportion of CSCs assay. Additionally, an in vivo study using tumor-bearing nude mice was conducted to evaluate the inhibitory effect of the monensin and erlotinib combination on tumor growth. RESULTS: The results indicated that combination of monensin with erlotinib synergistically inhibited cell proliferation, the migration rate, the invasion ability and decreased the CSCs proportion, and CSC markers SOX2 and CD133 in vivo and in vitro. Furthermore, the primary proteins involved in the signaling pathways of the EGFR/ERK and PI3K/AKT are simultaneously inhibited by the combination treatment of monensin and erlotinib in vivo and in vitro. CONCLUSIONS: The simultaneous inhibition of the EGFR/ERK and PI3K/AKT/mTOR signaling pathways by the combination of monensin and erlotinib exhibited a synergistic effect on suppressing tumor proliferation and cancer cell stemness in TNBC.

The relationship between dietary selenium intake and telomere length among diabetes.

Se is an indispensable trace element for the human body, and telomere length is considered a marker of biological ageing. Previous studies have shown that dietary Se intake is associated with telomere length. However, the relationship between Se intake and telomere length in patients with diabetes has not been well studied. Therefore, this study aimed to investigate the relationship between dietary Se intake and telomere length in patients with diabetes. We extracted 878 participants with diabetes from the National Health and Nutrition Examination Survey database for 1990-2002. Dietary Se intake was assessed using the 24 h dietary recall method, and telomere length was measured using quantitative PCR. Generalised linear models were constructed to assess the relationship between dietary Se intake and telomere length. After controlling for the confounders, 1 µg increase in dietary Se intake in female patients with diabetes, and telomere length increased by 1·84 base pairs (ß = 1·84 (95 % CI: 0·15, 3·53)), there was a line relationship between dietary Se intake and telomere length in female patients with diabetes and telomere length increased with increasing dietary Se intake within the range of 0-250 µg. The study demonstrates that dietary Se intake is significantly associated with telomere length only in the female population with diabetes in the USA. However, further prospective studies are required to confirm this finding.

Overactive Bladder during Pregnancy: A Prospective Longitudinal Study.

Background and Objectives: Overactive bladder (OAB) is a serious urination-related symptom of unknown pathogenesis that affects one's everyday activities. The objective of this study was to examine how OAB prevalence, symptom severity, and degree of distress caused by OAB symptoms evolved throughout the course of pregnancy. Materials and Methods: A total of 659 pregnant women were recruited from 2015 to 2020, and were evaluated through the International Consultation on Incontinence Questionnaire-Overactive Bladder (ICIQ-OAB) on OAB symptoms, administered in the early, middle, and late stages of pregnancy. Results: Generalized estimating equation analysis revealed that the odds of OAB occurring in the middle and late stages of pregnancy were 1.90 and 2.33 times higher, respectively, than in early pregnancy. The corresponding odds for OAB-wet were 1.63 and 2.07 higher, respectively, and the odds of OAB-dry occurring during late pregnancy were 0.80 higher than during early pregnancy. Symptoms were more severe by 0.07 and 0.21 points (on a 4-point scale) in the middle and late stages of pregnancy, respectively, than in early pregnancy; distress was greater by 0.13 and 0.27 points (on a 10-point scale) in the middle and late stages of pregnancy, respectively, than in early pregnancy. The prevalence of OAB, OAB-dry, and OAB-wet was significantly higher in early pregnancy than pre-pregnancy. Conclusions: The prevalence of OAB and OAB-wet increased over the course of pregnancy, but the prevalence of OAB-dry decreased. Furthermore, symptom severity and degree of distress increased over time.

Maduramicin induces cardiotoxicity via Rac1 signaling-independent methuosis in H9c2 cells.

Maduramicin frequently induces severe cardiotoxicity in target and nontarget animals in clinic. Apoptotic and non-apoptotic cell death mediate its cardiotoxicity; however, the underlying non-apoptotic cell death induced by maduramicin remains unclear. In current study, a recently described non-apoptotic cell death "methuosis" caused by maduramicin was defined in mammalian cells. Rat myocardial cell H9c2 was used as an in vitro model, showing excessively cytoplasmic vacuolization upon maduramicin (0.0625-5 µg/mL) exposure for 24 h. Maduramicin-induced reversible cytoplasmic vacuolization of H9c2 cells in a time- and concentration-dependent manner. The vacuoles induced by maduramicin were phase lucent with single membrane and were not derived from the swelling of organelles such as mitochondria, endoplasmic reticulum, lysosome, and Golgi apparatus. Furthermore, maduramicin-induced cytoplasmic vacuoles are generated from micropinocytosis, which was demonstrated by internalization of extracellular fluid-phase marker Dextran-Alexa Fluor 488 into H9c2 cells. Intriguingly, these cytoplasmic vacuoles acquired some characteristics of late endosomes and lysosomes rather than early endosomes and autophagosomes. Vacuolar H+ -ATPase inhibitor bafilomycin A1 efficiently prevented the generation of cytoplasmic vacuoles and decreased the cytotoxicity of H9c2 cells triggered by maduramicin. Mechanism studying indicated that maduramicin activated H-Ras-Rac1 signaling pathway at both mRNA and protein levels. However, the pharmacological inhibition and siRNA knockdown of Rac1 rescued maduramicin-induced cytotoxicity of H9c2 cells but did not alleviate cytoplasmic vacuolization. Based on these findings, maduramicin induces methuosis in H9c2 cells via Rac-1 signaling-independent seriously cytoplasmic vacuolization.

Effect of maduramicin on crayfish (Procambius clarkii): Hematological parameters, oxidative stress, histopathological changes and stress response.

Maduramicin, an extensively used anticoccidial drug, has been introduced into environment due to poorly absorbed in the intestine of broiler chicken. To understand the potential ecological toxicity of maduramicin on aquatic organisms, acute and subacute toxicity, hemolymph biochemistry, histopathology and the expressions of drug metabolism and stress response genes of crayfish (Procambius clarkii) were investigated in this study. For the first time, the 96 h median lethal concentration (LC50) of maduramicin on crayfish was 67.03 mgL-1 with a 95% confidence interval (54.06-81.32 mgL-1). Then, the crayfish were exposed to 0.7 mgL-1 (1/100 LC50), 3.5 mgL-1 (1/20 LC50) and 7.0 mgL-1 (1/10 LC50) maduramicin for 28 days. Maduramicin significantly altered biochemical parameters including AST, ALT, CK, LDH and ALP of hemolymph in crayfish at several time points. The activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) of crayfish gills, hepatopancreas and abdominal muscle were significantly decreased or elevated by different concentrations of maduramicin treatment at varying time points. Furthermore, histopathological damage of crayfish gills, hepatopancreas and abdominal muscle were observed in a concentration-dependent manner. The expressions of metabolic and stress response genes (CYP450, GST, COX1, COX2, HSP70 and MT) in hepatopancreas of crayfish were significantly up-regulated by maduramicin (7.0 mgL-1) treatment for 8 h to 7 d, and returned to normal levels after the removal of maduramicin for 3-7 days. In conclusion, our findings demonstrated that environmental exposure of maduramicin threaten to the health of crayfish living in the areas nearby livestock farms or pharmaceutical factory. Crayfish exhibited resistance to the stress of maduramicin via activating drug metabolite and detoxification pathways.

Urinary Incontinence Is Associated With Increased All-Cause Mortality in Older Nursing Home Residents: A Meta-Analysis.

PURPOSE: Urinary incontinence is a syndrome common in older adults, but it is not clear whether urinary incontinence is associated with the risk for mortality in elderly nursing home residents. METHODS: We conducted a systematic review and meta-analysis in PubMed, Cochrane, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science databases. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the included studies. The meta-analysis was summarized using a random-effects or fixed-effects model, and the heterogeneity among studies was examined using the I2 statistic. FINDINGS: Six cohort studies with 1,656 participants were included in the final analysis. The NOS score for each study was greater than 6. Urinary incontinence was significantly associated with a higher risk for mortality in nursing homes, with a hazard ratio (HR) of 1.20 (95% confidence interval [CI] 1.12-1.28, I2 = 41.6%). The significant association of urinary incontinence with increased mortality risk was observed in subgroup analysis according to region, status of dementia, and follow-up period, with a pooled HR of 2.02 (95% CI 1.32-3.11, I2 = 0%) for Asian countries, 1.18 (95% CI 1.11-1.26, I2 = 41.6%) for Western countries, 1.17 (95% CI 1.09-1.26, I2 = 0%) for patients with dementia, 1.35 (95% CI 1.13-1.60, I2 = 58.9%) for patients without dementia, 1.16 (95% CI 1.07-1.25, I2 = 43.2%) for studies with a follow-up period of 1 year, and 1.30 (95% CI 1.15-1.48, I2 = 24.5%) for studies with a follow-up period of more than 1 year. CONCLUSIONS: Urinary incontinence is associated with an increased risk for death among residents of care facilities. Therefore, it was necessary to screen the elderly dwelling in nursing homes who were experiencing or at risk for urinary incontinence with useful tools (e.g., overactive bladder symptom score, bladder control self-assessment questionnaire, three incontinence questions). In addition, early interventions strategies, such as weight loss, stopping smoking, pelvic floor muscle training, and medical and surgical treatments would contribute to decreasing the risk for urinary incontinence and preventing adverse outcomes in nursing home residents. CLINICAL RELEVANCE: In our study, we found that the elderly with urinary incontinence who resided in nursing homes had a higher risk for mortality than those without urinary incontinence. Therefore, urinary incontinence in the elderly residing in nursing homes is of particular concern. Early detection and intervention are important for the elderly with urinary incontinence, and caregivers should be made aware of this importance.

Suppressing Alpha-Hemolysin as Potential Target to Screen of Flavonoids to Combat Bacterial Coinfection.

The rapid emergence of bacterial coinfection caused by cytosolic bacteria has become a huge threat to public health worldwide. Past efforts have been devoted to discover the broad-spectrum antibiotics, while the emergence of antibiotic resistance encourages the development of antibacterial agents. In essence, bacterial virulence is a factor in antibiotic tolerance. However, the discovery and development of new antibacterial drugs and special antitoxin drugs is much more difficult in the antibiotic resistance era. Herein, we hypothesize that antitoxin hemolytic activity can serve as a screening principle to select antibacterial drugs to combat coinfection from natural products. Being the most abundant natural drug of plant origins, flavonoids were selected to assess the ability of antibacterial coinfections in this paper. Firstly, we note that four flavonoids, namely, baicalin, catechin, kaempferol, and quercetin, have previously exhibited antibacterial abilities. Then, we found that baicalin, kaempferol, and quercetin have better inhibitions of hemolytic activity of Hla than catechin. In addition, kaempferol and quercetin, have therapeutic effectivity for the coinfections of Staphylococcus aureus and Pseudomonas aeruginosa in vitro and in vivo. Finally, our results indicated that kaempferol and quercetin therapied the bacterial coinfection by inhibiting S. aureus α-hemolysin (Hla) and reduced the host inflammatory response. These results suggest that antitoxins may play a promising role as a potential target for screening flavonoids to combat bacterial coinfection.

Synthesis of Tilmicosin Nanostructured Lipid Carriers for Improved Oral Delivery in Broilers: Physiochemical Characterization and Cellular Permeation.

This study aimed to develop nanostructured lipid carriers (NLCs) for improved oral absorption of tilmicosin (TMS) in broilers. Thus, palmitic acid, lauric acid, and stearic acid were selected as solid lipids to formulate TMS-pNLCs, TMS-lNLCs, and TMS-sNLCs, respectively. They showed similar physicochemical properties and meanwhile possessed excellent storage and gastrointestinal stability. The TMS interacted with the lipid matrix and was encapsulated efficiently in NLCs in an amorphous structure. NLCs could enhance oral absorption of TMS compared to 10% tilmicosin phosphate solution in broilers, among which the TMS-sNLCs were the most efficient drug delivery carriers, with a relative oral bioavailability of 203.55%. NLCs could inhibit the efflux of P-glycoprotein (P-pg) toward TMS, which may be involved with improved oral absorption. Taken together, these types of solid lipids influenced the enhanced level of NLCs toward oral bioavailability of TMS, and the sNLCs proved to be the most promising oral delivery carriers of TMS.

Polymeric Micellar Delivery of Novel Microtubule Destabilizer and Hedgehog Signaling Inhibitor for Treating Chemoresistant Prostate Cancer.

Castration-resistant prostate cancer that has become resistant to docetaxel (DTX) represents one of the greatest clinical challenges in the management of this malignancy. There is an urgent need to develop novel therapeutic agents to overcome chemoresistance and improve the overall survival of patients. We have designed a novel microtubule destabilizer (2-(4-hydroxy-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (QW-296) and combined it with a newly synthesized hedgehog (Hh) signaling pathway inhibitor 2-chloro-N 1-[4-chloro-3-(2-pyridinyl)phenyl]-N 4,N 4- bis(2-pyridinylmethyl)-1,4-benzenedicarboxamide (MDB5) to treat taxane-resistant (TXR) prostate cancer. The combination of QW-296 and MDB5 exhibited stronger anticancer activity toward DU145-TXR and PC3-TXR cells and suppressed tumor colony formation when compared with single-drug treatment. Because these drugs are hydrophobic, we synthesized the mPEG-p(TMC-MBC) [methoxy-poly(ethylene glycol)-block-poly(trimethylene carbonate-co-2-methyl-2-benzoxycarbonyl-propylene carbonate)] copolymer, which could self-assemble into micelles with loading capacities of 8.13% ± 0.75% and 9.12% ± 0.69% for QW-296 and MDB5, respectively. Further, these micelles provided controlled the respective drug release of 58% and 42% release of QW-296 and MDB5 within 24 hours when dialyzed against PBS (pH 7.4). We established an orthotopic prostate tumor in nude mice using stably luciferase expressing PC3-TXR cells. There was maximum tumor growth inhibition in the group treated with the combination therapy of QW-296 and MDB5 in micelles compared with their monotherapies or combination therapy formulated in cosolvent. The overall findings suggest that combination therapy with QW-296 and MDB5 has great clinical potential to treat TXR prostate cancer, and copolymer mPEG-p(TMC-MBC) could serve as an effective delivery vehicle to boost therapeutic efficacy in vivo.

Transcriptome profile analysis reveals cardiotoxicity of maduramicin in primary chicken myocardial cells.

Maduramicin, an excellent ionophore antibiotic, is extensively used to control coccidiosis in poultry. Numerous maduramicin intoxications have been reported in farm animal and human due to its relatively narrow safety range, with necrosis or degeneration of cardiac and skeletal muscles as hallmark. To date, the mechanisms of maduramicin-induced cardiotoxicity remain unclear in chicken and other animals. Maduramicin (5 µg/mL)-treated primary chicken myocardial cells were used for RNA sequencing (RNA-Seq) and bioinformatics analysis in this study. A total of 1442 differential expressed genes were identified. 810 genes were up-regulated and the rest 632 genes were down-regulated. Transcriptome analysis revealed that the cytokine-cytokine receptor interaction, apoptosis, calcium signal and cytoplasmic vacuolization pathways were significantly affected. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis showed that gene expression patterns were consistent with RNA-Seq analysis. Pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-α) and interleukin-8 (IL-8), apoptosis ratios, cleaved caspase-3, intracellular calcium level and Ca2+-ATPase activity were elevated after maduramicin (0.05, 0.5 and 5 µg/mL) treatment. Massive vacuole formation was found in the cytoplasm by morphology and transmission electron microscopy observation. Taken together, the results suggested that maduramicin exerted its cardiotoxicity by multiple molecular mechanisms in primary chicken myocardial cells.

Facile Preparation of Nanosilver Particles with Excellent Antimicrobial Activity via Release of Ionic Silver.

Nanosilver particles (SNPs) have been widely exploited in various fields, including the medical sciences due to their excellent inhibitory and bactericidal effects. It is of great importance to prepare SNPs using green synthesis that has environmentally acceptable solvent systems and eco-friendly reducing agents. In the current study, gallic acid was employed as both a reducing agent and a stabilizing agent to synthesize SNPs at mild ambient conditions. The image of transmission electron microscopy (TEM) showed that SNPs exhibited approximately spherical shape with the average diameter of 13.81±2.21 nm. The absorbance peak of obtained SNPs was sharp with the maximum wavelength of 400.5 nm by ultraviolet-visible (UV-vis) spectroscopy, suggesting the formation of small and highly monodispersed SNPs. The antimicrobial potential of the SNPs was evaluated against multiple common pathogenic microbes. The results indicated that the microbial sensitivity to the SNPs was found to vary depending on the microbial species. Among them, the gram-negative bacteria exhibited more sensitive toward SNPs than the gram-positive bacteria. In addition, the N-acetyl-L-cysteine (NAC), a silver ion chelator, pretreatment could protect the E. coli and P. aeruginosa from the SNPs inhibition, while the pretreatment of the L-ascorbic acid, an antioxidant against oxidative stress, did not significantly influence the antibacterial effects of the SNPs. These data suggested that the ionic silver release, but not reactive oxygen species (ROS), played a key role in the antimicrobial effect of the SNPs. To sum up, this study provides an environmentally friendly technique for facile synthesis of SNPs with excellent antibacterial potential.

D-dopachrome tautomerase is over-expressed in pancreatic ductal adenocarcinoma and acts cooperatively with macrophage migration inhibitory factor to promote cancer growth.

Previous studies have established the important role of MIF in the development of pancreatic ductal adenocarcinoma (PDAC) for both therapeutic and diagnostic perspectives, but little is known about the expression and function of D-dopachrome tautomerase (DDT), a functional homolog of MIF, in PDAC. In the present study, we demonstrated that DDT was over-expressed in PDAC tissues in a pattern correlated with MIF. In the pancreatic cancer cell lines, PANC-1, BXPC-3 and ASPC-1, both DDT and MIF were expressed and co-localized with each other in the endosomal compartments and plasma membrane. Knockdown of DDT and MIF in PANC-1 cells cooperatively inhibited ERK1/2 and AKT phosphorylation, increased p53 expression, and reduced cell proliferation, invasion and tumor formation. These effects were rescued by the re-expression of MIF or DDT, but not by the forced expression of the tautomerase-deficient mutants of DDT and MIF, P1G-DDT and P1G-MIF. Finally, we observed that 4-iodo-6-phenylpyrimidine (4-IPP), a covalent tautomerase inhibitor of both DDT and MIF, attenuated PANC-1 cell proliferation and colony formation in vitro and tumor growth in vivo. Thus, targeting the tautomerase sites of both MIF and DDT may offer more efficient therapeutic benefits to PDAC patients.

CD4(+)CD25 (+) regulatory T cells are not required for mesenchymal stem cell function in fully MHC-mismatched mouse cardiac transplantation.

Although the immunomodulative properties of mesenchymal stem cells (MSCs) open up attractive possibilities in solid-organ transplantation, information concerning the optimal dose, route, timing of administration, major histocompatibility complex (MHC)-restriction and relevant mechanisms is currently lacking. Therefore, better characterization of MSC immunoregulatory activity and elucidation of its mechanisms are crucial. In this study, we confirmed that MSCs did not elicit proliferation by allogeneic CD4(+) T cells, suggesting that MSCs were not immunogenic. By using C57BL/6 mouse MSCs as donor-derived or recipient-derived or as third-party MSCs, we discovered that MSCs suppressed CD4(+) T cell proliferation and prolonged mouse cardiac allograft survival in a dose-dependent and non-MHC-restricted manner. We also found that intraperitoneal administration favored survival prolongation, although this prolongation was weaker than that via the intravenous route. Only infusion at earlier time points favored survival prolongation. Depletion of CD4(+)CD25(+) T cells did not affect the immunosuppression of MSCs on CD4(+) T cells. Moreover, MSCs did not induce regulatory T cells. The in vivo data revealed that MSCs did not increase the percentage of CD4(+)CD25(+) T cells and FoxP3 expression. More importantly, we demonstrated for the first time that depletion of CD4(+)CD25(+) T cells did not hinder MSC-induced survival prolongation, indicating that CD4(+)CD25(+) regulatory T cells were not essential for the prolongation of MSC-mediated allograft survival.

De Garengeot hernia: the ultrasound and computed tomographic findings in an 81-year-old woman.

The presence of appendix within a femoral hernia is a rare condition in an incarcerated femoral hernia. It has a characteristic groin mass, and the diagnosis of appendicitis is mainly made intraoperatively. A specific imaging appearance (ultrasonography, computed tomography [CT]) allows accurate prospective diagnosis. The recognition of this rare femoral hernia helps us to choose appropriate therapeutic approach. We report a case of an 81-year-old woman who present with painful and nonreducible groin mass. The ultrasonography and CT characteristic imaging features successfully diagnosed de Garengeot hernia. To our knowledge, this is the first description of a combination of CT and ultrasound in the preoperative diagnosis.

HuR and TIA1/TIAL1 are involved in regulation of alternative splicing of SIRT1 pre-mRNA.

SIRT1 is a pleiotropic protein that plays critical and multifunctional roles in metabolism, senescence, longevity, stress-responses, and cancer, and has become an important therapeutic target across a range of diseases. Recent research demonstrated that SIRT1 pre-mRNA undergoes alternative splicing to produce different isoforms, such as SIRT1 full-length and SIRT1-∆Exon8 variants. Previous studies revealed these SIRT1 mRNA splice variants convey different characteristics and functions to the protein, which may in turn explain the multifunctional roles of SIRT1. However, the mechanisms underlying the regulation of SIRT1 alternative splicing remain to be elucidated. Our objective is to search for new pathways that regulate of SIRT1 alternative splicing. Here we describe experiments showing that HuR and TIA1/TIAL1, two kinds of RNA-binding proteins, were involved in the regulation of alternative splicing of SIRT1 pre-mRNA under normal and stress circumstances: HuR increased SIRT1-∆Exon8 by promoting SIRT1 exon 8 exclusion, whereas TIA1/TIAL1 inhibition of the exon 8 exclusion led to a decrease in SIRT1-∆Exon8 mRNA levels. This study provides novel insight into how the alternative splicing of SIRT1 pre-mRNA is regulated, which has fundamental implications for understanding the critical and multifunctional roles of SIRT1.

New stenurothripid thrips from mid-Cretaceous Kachin amber (Thysanoptera, Stenurothripidae).

Hitherto, only two species of the thysanopteran suborder Terebrantia have been reported from mid-Cretaceous Kachin amber (Myanmar). This is here expanded through the discovery of two new genera and species, described and figured as Parallelothripsseparatusgen. et sp. nov. and Didymothripsabdominalisgen. et sp. nov., both of the family Stenurothripidae. Both taxa have key apomorphies of the Stenurothripidae, allowing for a confident assignment as to family. Both species have characteristic comb-like anteromarginal setae, which are discussed along with structural differences between the two sexes. Cycad pollen was found on the thrips' bodies, providing further evidence that Thysanoptera were pollinators of gymnosperms during the mid-Cretaceous.

Using halofuginone-silver thermosensitive nanohydrogels with antibacterial and anti-inflammatory properties for healing wounds infected with Staphylococcus aureus.

Contamination by pathogens, such as bacteria, can irritate a wound and prevent its healing, which may affect the physical fitness of the infected person. As such, the development of more novel nano-biomaterials able to cope with the inflammatory reaction to bacterial infection during the wound healing process to accelerate wound healing is required. Herein, a halofuginone­silver nano thermosensitive hydrogel (HTPM&AgNPs-gel) was prepared via a physical swelling method. HTPM&AgNPs-gel was characterized based on thermogravimetric analysis, differential scanning calorimetry, morphology, injectability, and rheological mechanics that reflected its exemplary nature. Moreover, HTPM&AgNPs-gel was further tested for its ability to facilitate healing of skin fibroblasts and exert antibacterial activity. Finally, HTPM&AgNPs-gel was tested for its capacity to accelerate general wound healing and treat bacterially induced wound damage. HTPM&AgNPs-gel appeared spherical under a transmission electron microscope and showed a grid structure under a scanning electron microscope. Additionally, HTPM&AgNPs-gel demonstrated excellent properties, including injectability, temperature-dependent swelling behavior, low loss at high temperatures, and appropriate rheological properties. Further, HTPM&AgNPs-gel was found to effectively promote healing of skin fibroblasts and inhibit the proliferation of Escherichia coli and Staphylococcus aureus. An evaluation of the wound healing efficacy demonstrated that HTPM&AgNPs-gel had a more pronounced ability to facilitate wound repair and antibacterial effects than HTPM-gel or AgNPs-gel alone, and exhibited ideal biocompatibility. Notably, HTPM&AgNPs-gel also inhibited inflammatory responses in the healing process. HTPM&AgNPs-gel exhibited antibacterial, anti-inflammatory, and scar repair features, which remarkably promoted wound healing. These findings indicated that HTPM&AgNPs-gel holds great clinical potential as a promising and valuable wound healing treatment.

Injectable nano-in situ-thermosensitive-hydrogels based on halofuginone and silver for postoperative treatment against triple-negative breast cancer.

Postoperative distant metastasis and high recurrence rate causes a dilemma in treating triple-negative breast cancer (TNBC) owing to its unforeseeable invasion into various organs or tissues. The wealth of nutrition provided by vascular may facilitate the proliferation and angiogenesis of cancer cells, which further enhance the rates of postoperative metastasis and recurrence. Chemotherapy, as a systemic postoperative adjuvant therapy, is generally applied to diminish recurrence and metastasis of TNBC. Herein, an halofuginone-silver nano thermosensitive hydrogel (HTPM&AgNPs-gel) was prepared via a physical swelling method. The in vitro anticancer efficacy of HTPM&AgNPs-gel was analyzed by investigating cell proliferation, migration, invasion, and angiogenesis capacity. Furthermore, the in vivo anti-cancer activity of HTPM&AgNPs-gel was further appraised through the tumor suppression, anti-metastatic, anti-angiogenic, and anti-inflammatory ability. The optimized HTPM&AgNPs-gel, a thermosensitive hydrogel, showed excellent properties, including syringeability, swelling behavior, and a sustained release effect without hemolysis. In addition, HTPM&AgNPs-gel was confirmed to effectively inhibit the proliferation, migration, invasion, and angiogenesis of MDA-MB-231 cells. An evaluation of the in vivo anti-tumor efficacy demonstrated that HTPM&AgNPs-gel showed a stronger tumor inhibition rate (68.17%) than did HTPM-gel or AgNPs-gel used alone and exhibited outstanding biocompatibility. Notably, HTPM&AgNPs-gel also inhibited lung metastasis induced by residual tumor tissue after surgery and further blocked angiogenesis-related inflammatory responses. Taken together, the suppression of inflammation by interdicting the blood vessels adjoining the tumor and inhibiting angiogenesis is a potential strategy to attenuate the recurrence and metastasis of TNBC. HTPM&AgNPs-gel is a promising anticancer agent for TNBC as a local postoperative treatment.

Antibiofilm activity of polyethylene glycol-quercetin nanoparticles-loaded gelatin-N,O-carboxymethyl chitosan composite nanogels against Staphylococcus epidermidis.

BACKGROUND: Biofilms, such as those from Staphylococcus epidermidis, are generally insensitive to traditional antimicrobial agents, making it difficult to inhibit their formation. Although quercetin has excellent antibiofilm effects, its clinical applications are limited by the lack of sustained and targeted release at the site of S. epidermidis infection. OBJECTIVES: Polyethylene glycol-quercetin nanoparticles (PQ-NPs)-loaded gelatin-N,O-carboxymethyl chitosan (N,O-CMCS) composite nanogels were prepared and assessed for the on-demand release potential for reducing S. epidermidis biofilm formation. METHODS: The formation mechanism, physicochemical characterization, and antibiofilm activity of PQ-nanogels against S. epidermidis were studied. RESULTS: Physicochemical characterization confirmed that PQ-nanogels had been prepared by the electrostatic interactions between gelatin and N,O-CMCS with sodium tripolyphosphate. The PQ-nanogels exhibited obvious pH and gelatinase-responsive to achieve on-demand release in the micro-environment (pH 5.5 and gelatinase) of S. epidermidis. In addition, PQ-nanogels had excellent antibiofilm activity, and the potential antibiofilm mechanism may enhance its antibiofilm activity by reducing its relative biofilm formation, surface hydrophobicity, exopolysaccharides production, and eDNA production. CONCLUSIONS: This study will guide the development of the dual responsiveness (pH and gelatinase) of nanogels to achieve on-demand release for reducing S. epidermidis biofilm formation.

Maduramicin-guided nanotherapy: A polymeric micelles for targeted drug delivery in canine mammary tumors.

Canine mammary tumors (CMT) can severely compromise the life quality of the affected dogs through local recurrence, distant metastases and ultimately succumb to death. Recently, more attention has been given to the potential antimetastatic effect of maduramicin (MAD) on breast cancer. However, its poor aqueous solubility and toxicity to normal tissues limit its clinical application. Therefore, to address the drawbacks of MAD and enhance its anticancer and antimetastatic effects, MAD-loaded TPGS polymeric micelles (MAD-TPGS) were prepared by a thin-film hydration technique. The optimized MAD-TPGS exhibited excellent size distribution, stability and improved water solubility. Cellular uptake assays showed that TPGS polymer micelles could enhance drug internalization. Moreover, TPGS synergistically improved the cytotoxicity of MAD by targeting mitochondrial organelles, improving reactive oxygen species levels and reducing the mitochondrial transmembrane potential. More importantly, MAD-TPGS significantly impeded the metastasis of tumor cells. In vivo results further confirmed that, in addition to exhibiting excellent biocompatibility, MAD-TPGS exhibited greater antitumor efficacy than free MAD. Interestingly, MAD-TPGS displayed superior suppression of CMT metastasis via tail vein injection compared to oral administration, indicating its suitability for intravenous delivery. Overall, MAD-TPGS could be applied as a potential antimetastatic cancer agent for CMT.