Albendazole sulfoxide (ABZSO), the pharmacologically active metabolite of albendazole, exhibits favorable tissue distribution but its pharmaceutical application is constrained by poor aqueous solubility. In this study, an optimized binary solid dispersion (SD) of ABZSO was prepared by the fusion method using poloxamers P188 and P407 at an 8:1 ratio, with a drug-to-carrier ratio of 1:3. The optimized formulation achieved rapid drug release, with a cumulative dissolution of 99.39% within minutes, and increased the apparent solubility of ABZSO to 105 mg·L-1. Solid-state characterization by differential scanning calorimetry, X-ray diffraction, Fourier-transform infrared spectroscopy, and scanning electron microscopy demonstrated that ABZSO was present in a partially amorphous, mixed-phase state, with residual crystallinity semi-quantitatively estimated as 21.80% and 32.33% as determined by DSC and XRD, respectively. The optimized formulation showed acceptable batch-to-batch reproducibility and maintained acceptable short-term dissolution performance under stress conditions, although further optimization of long-term physical stability remains necessary. In a goat pharmacokinetic study, the ABZSO-SD significantly enhanced systemic exposure and achieved a relative oral bioavailability of 120.55% compared with the laboratory-prepared suspension (P < 0.01). Overall, these findings demonstrate that the optimized ABZSO-SD formulation effectively improves the solubility, dissolution performance, and oral absorption of ABZSO, providing a potential formulation strategy for enhancing ABZSO bioavailability in ruminants.

The global spread of multidrug-resistant (MDR) bacteria prompts the exploration of innovative antimicrobial strategies. Phage lysins—peptidoglycan hydrolases known for species-specific activity and low resistance potential—offer promising alternatives to conventional antibiotics. However, their typically narrow spectrum limits broad therapeutic application. To overcome this limitation, we leveraged the wide distribution of streptococcal mobilizable prophage (SMphage) families across Streptococcus species as a strategy to discover lysins with inherent broad-spectrum potential. Within these conserved prophages, we expressed PlyNJ3, an SMphage-derived endolysin homolog identified in S. suis, and evaluated its therapeutic efficacy in infection models. PlyNJ3 exhibited potent lytic activity against a broad panel of streptococci, including diverse S. suis clinical isolates (15 serotypes), 83.3

Methuosis represents a novel cell death modality characterized by catastrophic cytoplasmic vacuolization in normal and malignant cells. However, the critical role and the underlying mechanism of cytoskeleton and plasma membrane damage in methuotic cells are largely unknown. We found that cytoskeleton protein F-actin, α-tubulin, β-tubulin and filamin A/B were disrupted in a reversible-dependent manner. In addition, RhoA-ROCK1 signaling pathway mediated cytoskeleton disruption in methuotic cells. Excessive cytoplasmic vacuolization triggered cellular plasma membrane damage and the release of damage associated molecular patterns (DAMPs), including lactate dehydrogenase (LDH), adenosine triphosphate (ATP) and calreticulin (CRT). Furthermore, at the end phase of methuotic cells, plasma membrane was damaged independent of pore-forming protein phosphorylation mixed lineage kinase domain-like (p-MLKL) and gasdermin D (GSDMD). Endosomal sorting complex required for transport (ESCRT)-III especially its subunit charged multivesicular body protein 3 (CHMP3) and charged multivesicular body protein 5 (CHMP5) negatively regulated excessive vacuolization-induced plasma membrane damage in cells undergoing methuosis. The critical role and potential mechanism of cytoskeleton and plasma membrane damage in methuotic cells are known, which would facilitate the employment of methuosis in life science and pharmacology.

Ionophore polyether antibiotics (IPAs) exhibit remarkable therapeutic potential in combating parasitic diseases and cancer, yet their clinical utility is significantly hampered by severe hepatotoxicity. Despite widespread documentation of IPAs-induced hepatotoxicity, the precise molecular mechanisms underlying this phenomenon remain elusive. This study elucidates the role of ferroptosis in IPAs-induced liver injury and delineates the associated regulatory pathways. Through comprehensive in vitro (HepG2 cells) and in vivo (mice) investigations, we demonstrate that IPAs, particularly the highly toxic maduramicin (Mad), induce hepatocyte ferroptosis. Mechanistic studies employing lipid reactive oxygen species (ROS) quantification, intracellular Fe2+ assays, and Western blot analysis revealed that IPAs-induced ferroptosis occurs through an autophagy-dependent pathway. Surface plasmon resonance (SPR) and molecular docking analyses confirmed direct binding and regulation of transcription factor EB (TFEB) by maduramicin. This interaction activates TFEB, subsequently mediating nuclear receptor coactivator 4 (NCOA4)-regulated lysosomal degradation processes that culminate in ferroptosis-mediated hepatotoxicity. Importantly, our findings extend beyond maduramicin, as other IPAs including monensin and salinomycin similarly targeted TFEB, triggering hepatocyte ferroptosis. Crucially, adeno-associated virus serotype 8 (AAV8)-mediated TFEB knockdown in mice conferred protection against IPAs-induced liver injury and attenuated hepatocyte ferroptosis. These findings establish TFEB-mediated NCOA4-dependent ferritinophagy and ferroptosis as central mechanisms in IPAs-induced hepatotoxicity, thereby identifying TFEB as a promising therapeutic target for mitigating IPAs-induced liver damage. This study provides critical insights into the molecular mechanisms of IPAs-induced liver injury and offers a novel strategy for therapeutic intervention.

Methuosis, a novel cell death phenotype, is characterized by accumulation of cytoplasmic vacuolization upon external stimulus. Methuosis plays a critical role in maduramicin-induced cardiotoxicity despite the underlying mechanism is largely unknown. Herein, we aimed to investigate the origin and intracellular trafficking of cytoplasmic vacuoles, as well as the molecular mechanism of methuosis caused by maduramicin (1 & mu;g/mL) in myocardial cells. H9c2 cells and broiler chicken were used and were exposed to maduramicin at doses of 1 & mu;g/mL in vitro and 5 ppm-30 ppm in vivo. Morphological observation and dextran-Alexa Fluor 488 tracer experiment showed that endosomal compartments swelling and excessive macropinocytosis contributed to madurdamcininduced methuosis. Cell counting kit-8 assay and morphology indicated pharmacological inhibition of macropinocytosis largely prevent H9c2 cells from maduramicin-triggered methuosis. In addition, late endosomal marker Rab7 and lysosomal associated membrane protein 1 (LAMP1) increased in a time-dependent manner after maduramicin treatment, and the recycling endosome marker Rab11 and ADP-ribosylation factor 6 (Arf6) were decreased by maduramicin. Vacuolar-H+-ATPase (V-ATPase) was activated by maduramicin, and pharmacological inhibition and genetic knockdown V0 subunit of V-ATPase restore endosomal-lysosomal trafficking and prevent H9c2 cells methuosis. Animal experiment showed that severe cardiac injury included the increase of creatine kinase (CK) and creatine kinase-MB (CK-MB), and vacuolar degeneration resembled methuosis in vivo after maduramicin treatment. Taken together, these findings demonstrate that targeting the inhibition of VATPase V0 subunit will prevent myocardial cells methuosis by restoring endosomal-lysosomal trafficking.

[目的]建立一种绵羊组织中地昔尼尔及其代谢产物2,4,6-三氨基-5-氯基嘧啶质量浓度的超高效液相色谱-串联质谱(UPLC-MS/MS)检测方法.[方法]对采集的绵羊肌肉、脂肪、肝脏、肾脏组织进行前处理,以乙腈和七氟丁酸水溶液为流动相,利用Acquity UPLC Beh C18色谱柱进行梯度洗脱;流速为0.15 mL/min,柱温为30 ℃,进样量为5 μL.在正离子扫描模式下通过多离子反应监测采集数据,采用外标法测定地昔尼尔及其代谢产物浓度,并考察该检测方法的线性范围、检测限、定量限、回收率、批内与批间精密度、准确度和稳定性.[结果]建立的检测方法灵敏度高,检测限为10,μg/kg,定量限为20 μg/kg,地昔尼尔和2,4,6-三氨基-5-氰基嘧啶的添加浓度为20～1 000 μg/kg,标准曲线的线性关系良好,相关系数均≥0.99.将地昔尼尔和2,4,6-三氨基-5-氰基嘧啶以高、中、低、定量限4个水平分别添加到各空白组织中,测得地昔尼尔和2,4,6-三氨基-5-氰基嘧啶的回收率为70％～110％,批内和批间变异系数均＜15％.在考察的条件下,地昔尼尔和2,4,6-三氨基-5-氰基嘧在各组织中的稳定性良好.[结论]建立的UPLC-MS/MS检测方法专属性强、重复性好、灵敏度高,可适用于地昔尼尔乳剂在绵羊组织内的药物代谢动力学和残留研究.

Objective To study the efficacy of DZ1462, a novel sodium-phosphate transporter inhibitor, on rat hyperphosphatemia models established by 5/6 nephrectomy.Methods Totally 156 rats were randomly selected into four groups. Rats fed a normal diet were control group, named as group Ⅰ (n=6); rats fed a normal diet after 5/6 nephrectomy were named as group Ⅱ (n=60); rats fed a high phosphate diet after 5/6 nephrectomy were named as group Ⅲ (n=60); rats fed a high phosphate diet after sham surgery were named as group Ⅳ (n=30). The molding cycle was 10 weeks. Serum Pi was detected and the number of animal deaths was recorded every two weeks. Hematoxylin-eosin (HE) staining was performed to observe the change in kidney pathology, and to screen animal models with high phosphorus blood syndrome. Totally 18 model rats that met the inclusion criteria (all of group Ⅲ) were selected and randomly assigned to three groups: the model control group recorded as the G2 group; the DZ1462 administration group (30 mg/kg, tid, 21 d) recorded as the G3 group; the Sevelamer administration group (250 mg/kg, tid, 21 d) recorded as the G4 group. In addition, the normal control group was set as the G1 group. Serum phosphate levels were measured using a kit.Results In the 8th and 10th weeks, compared to group Ⅰ, serum phosphorus in group Ⅲ showed a significant difference (P < 0.01). The kidneys in group Ⅲ had obvious glomerular sclerosis, renal tubular atrophy, degeneration, interstitial inflammation, fibrosis, and calcification. Similarly to chronic kidney disease accompanied by hyperphosphatemia, the animal model was established successfully. At each time point, the serum phosphorus inhibition rate of the G3 group was significantly higher than that of the G4 group (P < 0.05).Conclusion DZ1462, as a novel small-molecule inhibitor of intestinal sodium and phosphorus transporter, can effectively inhibit intestinal phosphorus ion absorption in rat hyperphosphatemia model, and is expected to become a potential drug for the clinical treatment of hyperphosphatemia.

Chloroquine was once thought to be a promising treatment for COVID-19 but it quickly failed due to its inefficiency and association with increased mortality. Further, comorbidities such as hypertension may have contributed this failure. The safety and toxicity of chloroquine at doses required for treating SARS-CoV-2 infection in hypertensive patients remain unknown. Herein, to investigate these effects, we performed a safety evaluation of chloroquine at the approved dose (63 mg/kg) and at a high dose (126 mg/kg) in hypertensive rats. We found that chloroquine increased the mortality of hypertensive rats to 18.2% and 100%, respectively, after 7 days. During the chloroquine exposure period, the bodyweight, feed, and water consumption of hypertensive rats were decreased significantly. In addition, we show that chloroquine induces prolongation of QTc interval, elevation of LDH and CK, and histopathological damage of the myocardium in hypertensive rats. Ocular toxicity was observed in hypertensive rats in the form of hemorrhage in the eyes and retinal damage. Furthermore, we also observed intestinal toxicity in hypertensive rats, which presented as thinning intestinal walls with hemorrhagic contents, and histopathological changes of the jejunum. Hepatotoxicity was also evidenced by elevated ALT, and vacuolization of hepatocytes was also observed. Nephrotoxicity was observed only in high dose chloroquine-treated hypertensive rats, presenting as alterations of urinalysis and renal function. Immune alterations were also found in high-dose chloroquine-treated hypertensive rats with elevation of serum IL-10, IL-1β and GRO, and moderate damage to the spleen. In summary, this study partially explains the reason for the failure of chloroquine as a COVID-19 therapy, and underlines the importance of safety evaluation and medical supervision of chloroquine to avoid patient harm, especially to those with hypertension.

Patients with underlying diseases and coronavirus disease 2019 (COVID-19) are at increased risk of death. Using the recommended anti-COVID-19 drug, chloroquine phosphate (CQ), to treat patients with severe cases and type 2 diabetes (T2D) could potentially cause harm. We aimed to understand the safety of CQ in patients with T2D by administrating the recommended dose (63 mg/kg twice daily for 7 days) and a high dose (126 mg/kg twice daily for 7 days) of CQ in T2D rats. We found that CQ increased the total mortality of the T2D rats from 27.3% to 72.7% in the recommended and high-dose groups during the whole period. CQ also induced hematotoxicity of T2D rats in the high-dose group; the hepatic enzymes in T2D rats were significantly elevated. CQ also changed the electrocardiograms, prolonged the QTc intervals, and produced urinary leukocytes and proteins in the T2D rats. Histopathological observations revealed that CQ caused severe damage to the rats' heart, jejunum, liver, kidneys, spleen, and retinas. Furthermore, CQ significantly decreased the serum IL-1β and IL-6 levels. In conclusion, the CQ dosage and regimen used to treat COVID-19 induced adverse effects in diabetic rats, suggesting the need to reevaluate the effective dose of CQ in humans.

Maduramicin ammonium (MAD) is one of the most frequently used anticoccidial agents in broiler chickens. However, the high toxicity and low solubility of MAD limit its clinical application. In this study, MAD-loaded nanostructured lipid carriers (MAD–NLCs) were prepared to overcome the defects of MAD by using highly soluble nanostructured lipid carriers (NLCs). The formulation was optimized via a three-level, three-factor Box–Behnken response surface method. Then, the optimal MAD–NLCs were evaluated according to their hydrodynamic diameter (HD), zeta potential (ZP), crystal structure, encapsulation efficiency (EE), drug loading (DL), in vitro release, and anticoccidial effect. The optimal MAD–NLCs had an HD of 153.6 ± 3.044 nm and a ZP of −41.4 ± 1.10 mV. The X-ray diffraction and Fourier-transform infrared spectroscopy results indicated that the MAD was encapsulated in the NLCs in an amorphous state. The EE and DL were 90.49 ± 1.05% and 2.34 ± 0.04%, respectively, which indicated that the MAD was efficiently encapsulated in the NLCs. In the in vitro study, the MAD–NLCs demonstrated a slow and sustained drug release behavior. Notably, MAD–NLCs had an excellent anticoccidial effect against Eimeria tenella in broiler chickens. In summary, MAD–NLCs have huge potential to form a new preparation administered via drinking water with a powerful anticoccidial effect.

过氧化氢又称双氧水(H2O2),为常用的消毒灭菌剂,且含氧高、氧化能力强、具有良好的消毒杀菌功能、不产生二次污染等优点,但其因稳定性差、储存条件要求高、8％以上的双氧水被列入危化品管理的特点,极大地限制了其应用.因此对其进行改造并解决稳定性,将能极大地提高其临床应用范围.本试验研究了一种稳定性过氧化氢的制备方法,并对其杀菌效果及稳定性进行考察.

旨在建立一种用于小鼠血浆中马度米星铵残留量的超高效液相色谱-串联质谱(UPLC-MS/MS)检测方法.在ICR小鼠血浆样品中加入内标,用乙腈提取,使用Acquity UPLC? BEH C18色谱柱(50 mm×2.1 mm,1.7μm)洗脱,内标法定量分析.方法学验证显示,待测物马度米星铵在1～400 ng·mL-1的浓度范围内,线性良好(R2≥0.99),回归方程为:y=1.697 37x+1.622 69,在小鼠血浆中回收率为82.87％～117.74％,日内和日间精密度为:0.99％～12.18％.结果表明:该方法特异性强、灵敏度高、重复性好,适用于小鼠血浆中马度米星铵浓度测定.

Background Halofuginone (HF)-loaded TPGS polymeric micelles (HTPM) were successfully fabricated using the thin-film hydration technique. HTPM via intravenous injection have been demonstrated to exert an excellent anticancer effect against triple-negative breast cancer (TNBC) cells and subcutaneous xenografts. In the present study, we further explored the potential treatment effect and mechanism of orally administered HTPM alone and in combination with surgical therapy on TNBC in subcutaneous and orthotopic mouse models. Methods Herein, the stability and in vitro release behavior of HTPM were first evaluated in the simulated gastrointestinal fluids. Caco-2 cell monolayers were then used to investigate the absorption and transport patterns of HF with/without encapsulation in TPGS polymeric micelles. Subsequently, the therapeutic effect of orally administered HTPM was checked on subcutaneous xenografts of TNBC in nude mice. Ultimately, orally administered HTPM, combined with surgical therapy, were utilized to treat orthotopic TNBC in nude mice. Results Our data confirmed that HTPM exhibited good stability and sustained release in the simulated gastrointestinal fluids. HF was authenticated to be a substrate of P-glycoprotein (P-gp), and its permeability across Caco-2 cell monolayers was markedly enhanced via heightening intracellular absorption and inhibiting P-gp efflux due to encapsulation in TPGS polymeric micelles. Compared with HF alone, HTPM showed stronger tumor-suppressing effects in subcutaneous xenografts of MDA-MB-231 cells when orally administered. Moreover, compared with HTPM or surgical therapy alone, peroral HTPM combined with partial surgical excision synergistically retarded the growth of orthotopic TNBC. Fundamentally, HTPM orally administered at the therapeutic dose did not cause any pathological injury, while HF alone led to weight loss and jejunal bleeding in the investigated mice. Conclusion Taken together, HTPM could be applied as a potential anticancer agent for TNBC by oral administration.

Triple-negative breast cancer (TNBC) is featured by aggression and metastasis and remains an unmet medical challenge due to high death rate. We aimed to repurpose maduramicin (MAD) as an effective drug against TNBC, and develop a nanoemulsion system to enhance anticancer efficacy of MAD. MDA-MB-231 and 4 T1 cells were used as in vitro model, and cell viability was determined by performing cell counting kit-8 and a colony-formation assay. Furthermore, MAD loaded nanoemulsion (MAD-NEs) was manufactured and characterized by a series of tests. The anticancer and anti-metastasis mechanism of MAD-NEs were assessed by performing cell cycle, apoptosis, wound-healing, transwell assay and Western blotting assays. Herein, MAD was firstly demonstrated to be an effective agent to suppress growth of TNBC cells. Subsequently, the optimized MAD-NEs were shown to have stability and high encapsulation efficiency, and could arrested cells in G0/G1 phase and induced apoptosis in TNBC cells. More importantly, MAD-NEs significantly impeded the metastasis of tumor cells, which was further demonstrated by the significant altered expression of epithelial-mesenchymal transition and extracellular matrix markers in vitro and in vivo. Moreover, compared to MAD, MAD-NEs exhibited higher efficacy in shrinking breast tumor size and repressing liver and lung metastasis in vivo, and showed excellent biocompatibility in tumor-bearing mice. The successfully prepared MAD-NEs are expected to be harnessed to suppress tumor growth, invasion and metastasis in the battle against malignant TNBC.

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.

As immune adjuvants assisting vaccines, nanoparticle delivery systems have been widely exploited. Squalene, the major ingredient of approved adjuvant MF59, has great potential in activating immune responses. In the current study, model antigen ovalbumin (OVA) was encapsulated into squalene-based nanostructured lipid carriers (NLCs), and the chitosan, a cationic polysaccharide, was used for modifying nanoparticles to develop a functionalized and cationic nanoparticle delivery system (OVA-csNLCs). Firstly, the optimal formulation of csNLCs was successfully screened out, and had hydrodynamic diameter of 235.80 ± 5.99 nm and zeta potential of 34.90 ± 6.95 mV. Then, the generated OVA-csNLCs had no significant difference in hydrodynamic diameter and exhibited lower zeta potential of 19.03 ± 0.31 mV and high encapsulation efficiency of 83.4%. Sucrose (10%, w/w) was selected as optimal lyoprotectant, exhibiting good stability of OVA-csNLCs in the form of freeze-dried powder. More importantly, the OVA-csNLCs effectively promoted OVA antigen uptake by macrophage, significantly enhanced the level of OVA-specific IgG, and induced a Th2-based immune response in vivo. Furthermore, mice immunization experiment demonstrated that OVA-csNLCs had well biocompatibility and facilitated spleen lymphocytes proliferation. Above findings indicate that chitosan modified squalene nanostructured lipid carriers show promise as antigen delivery system and an open adjuvant platform.

为探究硫酸铜和马度米星铵对水产动物的生态毒性,本研究以鲫鱼为模型,从急性毒性、亚急性毒性和遗传毒性3个方面研究硫酸铜和马度米星铵单一与联合暴露对鲫鱼的毒性效应.结果 表明,硫酸铜对鲫鱼96 h的半数致死浓度(50％ lethal concentration,LC50)为3.6 mg·L-1,硫酸铜和马度米星铵联合暴露时,硫酸铜对鲫鱼的96 h-LC50为1.4 mg· L-1,马度米星铵对鲫鱼的96 h-LC50为4.2 mg·L-1,硫酸铜对鲫鱼为高等毒性;硫酸铜和马度米星铵对鲫鱼的联合毒性表现为协同作用.染毒第7天,硫酸铜和马度米星铵均可影响过氧化氢酶(catalase,CAT)和谷胱甘肽过氧化物酶(glutathione peroxidase,GPx)的活性,随着剂量和染毒时间的增加,CAT和GPx的活性逐渐下降.硫酸铜和马度米星铵单一或联合暴露7d或21 d显著下调cat基因表达,对sod和gpx基因表达无显著影响.染毒后期,染毒组谷丙转氨酶(alanine aminotransferase,ALT)、谷草转氨酶(aspartate transaminase,AST)和碱性磷酸酶(alkaline phosphatase,ALP)活性及丙二醛(malondialdehyde,MDA)含量均高于对照组.硫酸铜和马度米星铵单一及联合染毒均能诱导鲫鱼红细胞产生微核,微核数与硫酸铜和马度米星铵的浓度呈正相关;随着硫酸铜和马度米星铵浓度的增加,肝细胞的脱氧核糖核酸(deoxyribonucleic acid,DNA)出现断裂,彗星尾部所占比例逐渐升高;高浓度联合染毒组红细胞微核率和肝细胞尾部DNA百分比显著高于单一染毒组.硫酸铜和马度米星铵联合暴露可导致鲫鱼血液毒性、肝细胞氧化损伤及遗传毒性的加和性,为评估Cu2+与马度米星铵复合污染对鲫鱼的生态毒性提供基础数据和理论依据.

Background Halofuginone hydrobromide (HF) is a synthetic analogue of the naturally occurring quinazolinone alkaloid febrifugine, which has potential therapeutic effects against breast cancer, however, its poor water solubility greatly limits its pharmaceutical application. D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) is a water-soluble derivative of vitamin E, which can self-assemble to form polymeric micelles (PMs) for encapsulating insoluble anti-tumor drugs, thereby effectively enhancing their anti-cancer effects. Methods HF-loaded TPGS PMs (HTPMs) were manufactured using a thin-film hydration technique, followed by a series of characterizations, including the hydrodynamic diameter (HD), zeta potential (ZP), stability, drug loading (DL), encapsulation efficiency (EE), and in vitro drug release. The anti-cancer effects and potential mechanism of HTPMs were investigated in the breast cell lines MDA-MB-231 and MCF-7, and normal breast epithelial cell line Eph-ev. The breast cancer-bearing BALB/c nude mouse model was successfully established by subcutaneous injection of MDA-MB-231 cells and used to evaluate the in vivo therapeutic effect and safety of the HTPMs. Results The optimized HTPMs had an HD of 17.8±0.5 nm and ZP of 14.40±0.1 mV. These PMs exhibited DL of 12.94 ± 0.46% and EE of 90.6 ± 0.85%, along with excellent storage stability, dilution tolerance and sustained drug release in pH-dependent manner within 24 h compared to free HF. Additionally, the HTPMs had stronger inhibitory effects than free HF and paclitaxel against MDA-MB-231 triple-negative breast cancer cells, and little toxicity in normal breast epithelial Eph-ev cells. The HTPMs induced cell cycle arrest and apoptosis of MDA-MB-231 by disrupting the mitochondrial membrane potential and enhancing reactive oxygen species formation. Evaluation of in vivo anti-tumor efficacy demonstrated that HTPMs exerted a stronger tumor inhibition rate (68.17%) than free HF, and exhibited excellent biocompatibility. Conclusion The findings from this study indicate that HTPMs holds great clinical potential for treating triple-negative breast cancer.

Maduramicin (MAD) is widely introduced into aquatic environments and results in the contamination of fish products. Worryingly, the consumption of MAD-contaminated crayfish (Procambarus clarkii) may induce symptoms of Haff disease. In this study, to monitor this potential contamination and to understand the residue and elimination characteristics of MAD in edible tissues of crayfish, a sensitive and efficient ultra-performance liquid chromatography–tandem mass spectrometry method was developed, validated, and applied. After extraction with acetonitrile and purification by solid-phase extraction column, multiple-reaction monitoring mass spectrometry with positive ionization mode was used to determine MAD’s residues. The limits of detection and of quantification were 6 μg·kg−1 and 20 μg·kg−1, respectively. The fortified recoveries ranged from 74.2% to 110.4%, with relative standard deviation of 1.2% to 10.1%. Furthermore, MAD was completely eliminated after 3 and 5 days from abdominal muscle and hepatopancreas tissues of crayfish, respectively. The maximum residue limits (MRLs) of MAD respectively was 200 μg·kg−1 in muscle and 600 μg·kg−1 in the hepatopancreas, and its withdrawal time in both edible tissues was 25.8 °C·d. Collectively, the results of this study indicate the proposed method is an efficient tool to evaluate the public health risk associated with crayfish consumption.

犬乳腺肿瘤是兽医临床中犬最常见的肿瘤之一,严重威胁犬只健康.手术结合化学疗法是治疗犬乳腺肿瘤的主要方法,然而我国尚未批准用于兽医临床的抗犬乳腺肿瘤化学治疗药物.犬乳腺肿瘤与人乳腺肿瘤共享部分发病机制,科学合理的将人用抗乳腺癌药物转为犬用药物为解决宠物临床用药短缺带来新的途径.为加快犬乳腺肿瘤药物的研发,有必要对犬乳腺瘤相关药物进行综述.本文在概括犬乳腺肿瘤化疗用药现状的基础上,重点综述了近年来国内外抗犬乳腺肿瘤药物的研究进展,以期为犬乳腺肿瘤药物的创制提供思路与借鉴.