A nanoplatform based on allylthiopurine bio-MOF and glycosylated AIE PARP inhibitor for cancer synthetic lethal therapy.

A biological nanoplatform (Gal-ANI@ZnAP NPs) was constructed based on a prodrug-skeletal metal-organic framework (MOF) using purine nucleobase analogue prodrug 6-allylthiopurine as a bioactive ligand, and functionalized with AIE fluorescent PARP inhibitor glycoconjugate for visualization therapy and synthetic lethal cancer therapy. This nanoplatform could actively target cancer cells, selectively release drugs in response to esterase/pH, and visualize drug uptake. In vitro studies revealed that Gal-ANI@ZnAP NPs increased the synthetic lethality in cancer cells by inducing DNA repair failure with the simultaneous targeting of PARP and nucleotide metabolism, thereby exhibiting a significant cancer-killing effect. The study presents a novel strategy to construct an AIE nanoplatform using pharmaceutical molecules for drug uptake visualization and boosting synthetic lethality in cancer.

Mn(iii)-mediated carbon-centered radicals generate an enhanced immunotherapeutic effect.

A strategy for designing cancer therapeutic nanovaccines based on immunogenic cell death (ICD)-inducing therapeutic modalities is particularly attractive for optimal therapeutic efficacy. In this work, a highly effective cancer therapeutic nanovaccine (denoted as MPL@ICC) based on immunogenic photodynamic therapy (PDT) was rationally designed and fabricated. MPL@ICC was composed of a nanovehicle of MnO2 modified with a host-guest complex using amino pillar[6]arene and lactose-pyridine, a prodrug of isoniazid (INH), and chlorine e6 (Ce6). The nanovaccine exhibited excellent biosafety, good targeting ability to hepatoma cells and enrichment at tumor sites. Most importantly, it could modulate the tumor microenvironment (TME) to facilitate the existence of Mn(iii) and Mn(iii)-mediated carbon-centered radical generation with INH released from the prodrug in situ to further strengthen ICD. This is the first report on Mn(iii)-mediated generation of carbon-centered radicals for successful anti-tumor immunotherapy using ICD, which provides a novel strategy for designing highly efficient cancer therapeutic nanovaccines.

A Paramagnetic Metal-Organic Framework Enhances Mild Magnetic Hyperthermia Therapy by Downregulating Heat Shock Proteins and Promoting Ferroptosis via Aggravation of Two-Way Regulated Redox Dyshomeostasis.

Mild magnetic hyperthermia therapy (MMHT) holds great potential in treating deep-seated tumors, but its efficacy is impaired by the upregulation of heat shock proteins (HSPs) during the treatment process. Herein, Lac-FcMOF, a lactose derivative (Lac-NH2 ) modified paramagnetic metal-organic framework (FcMOF) with magnetic hyperthermia property and thermal stability, has been developed to enhance MMHT therapeutic efficacy. In vitro studies showed that Lac-FcMOF aggravates two-way regulated redox dyshomeostasis (RDH) via magnetothermal-accelerated ferricenium ions-mediated consumption of glutathione and ferrocene-catalyzed generation of ∙OH to induce oxidative damage and inhibit heat shock protein 70 (HSP70) synthesis, thus significantly enhancing the anti-cancer efficacy of MMHT. Aggravated RDH promotes glutathione peroxidase 4 inactivation and lipid peroxidation to promote ferroptosis, which further synergizes with MMHT. H22-tumor-bearing mice treated with Lac-FcMOF under alternating magnetic field (AMF) demonstrated a 90.4% inhibition of tumor growth. This work therefore provides a new strategy for the simple construction of a magnetic hyperthermia agent that enables efficient MMHT by downregulating HSPs and promoting ferroptosis through the aggravation of two-way regulated RDH.

A hyaluronic acid modified cuprous metal-organic complex for reversing multidrug resistance via redox dyshomeostasis.

Multidrug resistance (MDR) which is often related to the overexpression of P-glycoprotein (P-gp) in drug-resistant cancer cells has been a major problem faced by current cancer chemotherapy. Reversing P-gp-related MDR by disrupting tumor redox homeostasis that regulates the expression of P-gp is a promising strategy. In this work, a hyaluronic acid (HA) modified nanoscale cuprous metal-organic complex (HA-CuTT) was developed to reverse P-gp-related MDR via two-way regulated redox dyshomeostasis, which was achieved by both Cu+-catalyzed generation of •OH and disulfide bonds-mediated depletion of glutathione (GSH). In vitro studies reveal that the DOX-loaded complex (HA-CuTT@DOX) has excellent targeting ability to HepG2-ADR cells due to the modification of HA and effectively induces redox dyshomeostasis in HepG2-ADR cells. Moreover, HA-CuTT@DOX can cause mitochondrial damage, decrease ATP level, and downregulate the P-gp expression, thereby leading to the reversal of MDR and the increased drug accumulation in HepG2-ADR cells. Importantly, in vivo experimental results show that it can achieve effective inhibition (89.6 %) of tumor growth in nude mice bearing HepG2-ADR cells. This is the first work to reverse P-gp-related MDR via two-way regulated redox dyshomeostasis based on a HA modified nanoscale cuprous metal-organic complex, providing a new therapeutic paradigm for effective treatment of MDR-related cancer.

Supramolecular nanoprodrug based on a chloride channel blocker and glycosylated pillar[5]arenes for targeted chemoresistance cancer therapy.

A supramolecular nanoprodrug (DOX@GP5⊃Pro-NFA) was constructed based on the host-guest complexation of chloride channel blocker prodrug (Pro-NFA) and glycosylated pillar[5]arene (GP5), which could target tumor cells via galactose and release DOX/NFA responsively under esterase stimulation. In vitro studies revealed that this supramolecular nanoprodrug can overcome drug resistance through inhibiting chloride channels as well as inhibiting the migration of HepG2/ADR cells. This strategy can therefore achieve enhanced potency in chemotherapy through reverse chemoresistance.

YTHDF2 controls hexavalent chromium-induced mitophagy through modulating Hif1α and Bnip3 decay via the m6A/mRNA pathway in spermatogonial stem cells/progenitors.

Spermatogonial stem cells (SSCs) are the basis of spermatogenesis, and SSC homeostasis is essential for lifelong male fertility. Currently, environmental pollution remains one of the factors affecting human reproductive health. Chromium is a prevalent metal element, and excessive exposure to hexavalent chromium (Cr (VI)) can cause male reproductive disorders. Nevertheless, the toxic effects of Cr (VI) on SSCs and the underlying mechanisms remain incompletely understood. Here, we showed that Cr (VI) exposure triggered mitophagy in mouse SSCs/progenitors in a time-dependent manner. Concurrently, Cr (VI) treatment caused reactive oxygen species (ROS) accumulation and activated the HIF1α-mediated BNIP3 expression to trigger mitophagy. In addition, Cr (VI) exposure significantly decreased the level of m6A modification. Further, we identified that YTHDF2 regulated the stability of Bnip3 and Hif1α mRNAs in an m6A-dependent manner, which was involved in Cr (VI)-induced mitophagy. Collectively, our study not only expands the mechanisms for Cr (VI)-caused male reproductive toxicity, but also provides pharmacological targets for prevention and treatment of Cr (VI)-induced male fertility impairment.

A supramolecular nano-delivery system based on AIE PARP inhibitor prodrug and glycosylated pillar[5]arene for drug-resistance therapy.

A supramolecular nano-delivery system GP5⊃Pro-ANI based on the host-guest complex of glycosylated pillar[5]arene (GP5) and an amide linked fluorescent PARP inhibitor (4-amino-1,8-naphthimide, ANI) was constructed. The PARP inhibitor ANI, capable of inhibiting the ability of DNA damage repair, was modified into an AIE prodrug (Pro-ANI), which allows for the visualization of real-time cancer cellular drug uptake tracing and selective drug release. In vitro studies revealed that the DOX-loaded GP5⊃Pro-ANI achieved targeted drug delivery and dual-drug synergistic chemotherapy for DNA repair interference and tumor DNA collapse aggravation, which enhanced the chemosensitivity and overcame tumor drug resistance and migration. This strategy paves a new avenue for utilizing PARP inhibitors to construct AIE supramolecular nano-delivery systems for drug uptake visualization and synergistic chemotherapy.

Glyconanoparticles with Activatable Near-Infrared Probes for Tumor-Cell Imaging and Targeted Drug Delivery.

Background: Multifunctional nanocarriers based on tumor targeting and intracellular monitoring have received much attention and been a subject of intensive study by researchers in recent years. In this study, we report multifunctional glyconanoparticles with activatable near-infrared probes for tumor imaging and targeted drug delivery. Methods: Disulfide-functionalized dicyanomethylene-4H-pyran (DCM-SS-NH2) and amino-functionalized lactose were modified and loaded onto the surfaces of polydopamine nanoparticles (NPs) by Michael addition or Schiff-base reaction as GSH stimulation-responsive fluorescent probes and tumor-targeting moieties, respectively. Doxorubicin (DOX), a model anticancer drug, was loaded onto polydopamine through π-π interactions directly to prepare multifunctional PLDD (PDA@Lac/DCM/DOX) NPs. Results: Experimental results showed that PLDD NPs had been successfully prepared. DCM, the fluorescence of which was quenched in PLDD NPs, was able to restore red fluorescence in a solution with a GSH concentration of 5 mM. The amount of DOX released from PLDD NPs was 44% over 72 hours in a weak-acid environment (pH 5). The results of CLSM and flow cytometry indicated that the PLDD NPs had good HepG2-targeting ability due to the special recognition between lactose derivative of NPs and overexpressed asialoglycoprotein receptors on HepG2 cell membrane. More importantly, the disulfide bond of DCM-SS-NH2 was broken by the high concentration of GSH inside cancer cells, activating the near-infrared fluorescence probe DCM for cancer-cell imaging. MTT assays indicated that PLDD NPs exhibited higher anticancer efficiency for HepG2 cells and had reduced side effects on normal cells compared with free DOX. Conclusion: The fluorescence of modified DCM loaded onto PLDD NPs is able to be restored in the high-concentration GSH environment within cancer cells, while improving the effectiveness of chemotherapy with reduced side effects. It provides a good example of integration of tumor imaging and targeted drug delivery.

Polyamines protect boar sperm from oxidative stress in vitro.

Sperm are susceptible to excessive reactive oxygen species (ROS). Spermine and spermidine are secreted in large amounts by the prostate and potent natural free radical scavengers and protect cells against redox disorder. Thus, we used boar sperm as a model to study the polyamines uptake and elucidate whether polyamines protected sperm from ROS stress. Seven mature and fertile Duroc boars (aged 15 to 30 mo) were used in this study. In experiment 1, spermine and spermidine (3.6 ± 0.3 and 3.3 ± 0.2 mmol/L, respectively) were abundant in seminal plasma, and the content of polyamine decreased (P < 0.05) after preservation at 17 °C for 7 d or incubation at 37 °C for 6 h. In experiment 2, using labeling of spermine or spermidine by conjugation with fluorescein isothiocyanate and ultra-high-performance liquid chromatography, we found that the accumulation of spermine or spermidine in sperm was inhibited by quinidine and dl-tetrahydropalmatine (THP, organic cation transporters [OCT] inhibitors, P < 0.05), but not mildronate and l-carnitine (organic cation/carnitine transporter [OCTN] inhibitors, P > 0.05). In experiment 3, the addition of spermine or spermidine (0.5 mmol/L) in the extender resulted in higher motility, plasma membrane and acrosome integrity, and lower ROS level after preservation in vitro at 17 °C for 7 d (P < 0.05). In experiment 4, in the condition of oxidative stress (treatment with H2O2 at 37 °C for 2 h), the addition of spermine (1 mmol/L) or spermidine (0.5 mmol/L) in extender increased activities of glutathione peroxidase, glutathione reductase, and glutathione S-transferase; reduced glutathione and oxidized glutathione ratio (P < 0.05); and alleviate oxidative stress-induced lipid peroxidation, DNA damage, mitochondrial membrane potential (ΔΨm) decline, adenosine triphosphate depletion, and intracellular calcium concentration ([Ca2+]i) overload (P < 0.05), thereby improving boar sperm motility, the integrity of plasma membrane and acrosome (P < 0.05) in vitro. These data suggest that spermine and spermidine alleviate oxidative stress via the antioxidant capacity, thereby improving the efficacy of boar semen preservation.

Boar semen preservation and artificial insemination are widely used in the pig industry. Although preservation in vitro prolongs sperm lifespan, reactive oxidative species (ROS) also accumulate in sperm with the increased preservation period. ROS over-accumulation would impair motility, the integrity of plasma membrane and acrosome, mitochondrial function, and eventually lead to infertility. Spermine and spermidine are secreted in large amounts by the prostate and are potent natural free radical scavengers. Thus, we used boar sperm as a model to study the polyamines uptake and elucidate whether polyamines protected sperm from ROS stress. We found for the first time that organic cation transporters mediated polyamines uptake in sperm cells, and that extracellular polyamines decreased during preservation in vitro. The addition of polyamines increased the activities of glutathione-related antioxidant enzymes and reduced glutathione and oxidized glutathione ratio, and alleviate oxidative stress-induced mitochondrial dysfunction, lipid peroxidation, and DNA damage, thereby maintaining sperm quality in vitro. These data suggest that spermine and spermidine alleviate oxidative stress, thereby improving the efficacy of boar semen preservation.

Pillar[5]arene-based supramolecular photosensitizer for enhanced hypoxic-tumor therapeutic effectiveness.

A galactose-targeting supramolecular photosensitizer system DOX@GP5⊃NBSPD was constructed based on a host-guest inclusion complex. The supramolecular system could achieve efficient delivery of DOX/NBS and selective release under GSH stimulation. In vitro studies revealed that this supramolecular DOX/NBS co-delivery system exhibited high ROS production and excellent cancer cell damage capability in a hypoxic environment. This strategy can therefore achieve enhanced hypoxic-tumor therapeutic effectiveness by chemo-photodynamic combination.

Melatonin Attenuates Chromium (VI)-Induced Spermatogonial Stem Cell/Progenitor Mitophagy by Restoration of METTL3-Mediated RNA N6-Methyladenosine Modification.

Spermatogonial stem cells (SSCs) are the basis of spermatogenesis, and any damage to SSCs may result in spermatogenic disorder and male infertility. Chromium (Cr) (VI) is a proven toxin, mutagen, and carcinogen, perpetually detrimental to environmental organisms due to its intricate and enduring detoxification process in vivo. Despite this, the deleterious effects of Cr (VI) on SSCs and the underlying mechanisms remain poorly understood. In this study, we identified that Cr (VI) impaired male reproductive system in mouse testes and induced mitochondrial dynamic imbalance and mitophagy in SSCs/progenitors. Cr (VI) also downregulated the RNA N6-methyladenosine (m6A) modification levels in mitochondrial dynamic balance and mitophagy genes in SSCs/progenitors. Inspiringly, the toxic effects of Cr (VI) could be relieved by melatonin pretreatment. Melatonin alleviated Cr (VI)-induced damage to male reproductive system and autophagy in mouse testes. Melatonin also attenuated Cr (VI)-induced cell viability loss and reactive oxygen species (ROS) generation, as well as mitochondrial dynamic disorders and mitophagy in SSCs/progenitors. The protective roles of melatonin against Cr (VI)-induced mitophagy were exerted by restoration of METTL3-mediated RNA m6A modification and activation of mitochondrial fusion proteins MFN2 and OPA1, as well as inhibition of the mitophagy BNIP3/NIX receptor pathway. Thus, our study provides novel insights into the molecular mechanisms for RNA m6A modification underlying the gene regulatory network responsible for mitochondrial dynamic balance, and also lays new experimental groundwork for treatment of Cr (VI)-induced damage to male fertility.

The impacts of race and regimens on the efficacy and safety of paclitaxel and platinum combination treatment for patients with advanced non-small cell lung cancer.

PURPOSE: Paclitaxel-platinum chemotherapy is the first-line treatment for advanced non-small cell lung cancer (NSCLC) patients. This study quantitatively evaluated the factors influencing the efficacy and safety of the paclitaxel-platinum regimen to provide the necessary reference for the development of clinical practice and clinical trials. METHODS: A literature search was performed using public databases. The parametric survival function was used to analyze the overall survival (OS) time course of patients treated with the paclitaxel-platinum regimen. The random effects model in the single-arm meta-analysis was used to analyze the objective response rate (ORR) and the incidence of grade 3-4 adverse events (AEs) under the predefined subgroups according to race and the regimen. RESULTS: A total of 31 studies consisting of 3365 participants were included in the analysis. Race was the most important determinant of efficacy and safety in the paclitaxel-platinum regimen, with the median survival time and ORR in East Asians and non-East Asians being 12.2 months (95% CI: 10.5-14.4 months) and 37% (95% CI: 32-41%) and 8.4 months (95% CI: 6.5-11.0 months) and 28% (95% CI: 25-32%), respectively. The incidence of grade 3-4 AEs such as leukopenia and neutropenia was about three times higher in East Asians compared to non-East Asians. CONCLUSIONS: The efficacy and safety of the paclitaxel-platinum regimen can vary between East Asian and non-East Asian populations and between different treatment schedules. The results of this study can provide a reliable and precise external control for the future evaluation of new treatment options for advanced NSCLC.

Association of serum CTRP9 levels with cardiac autonomic neuropathy in patients with type 2 diabetes mellitus.

AIMS: Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes and is associated with adipokines. The C1q tumor necrosis factor-related protein 9 (CTRP9) is a newly discovered adipokine. This study aimed to evaluate the association of serum CTRP9 levels with the prevalence and severity of CAN in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: We enrolled 262 patients (aged ≥18 years) with type 2 diabetes mellitus into this study. Standard cardiovascular autonomic reflex tests (CARTs) were used to assess CAN and patients were divided into three groups accordingly: a non-CAN group, an early CAN group, and a definite CAN group. Serum CTRP9 levels were measured by enzyme-linked immunosorbent assay, and the tertiles were calculated. RESULTS: Serum CTRP9 levels decreased significantly in the early CAN and definite CAN groups (P < 0.05). The percentage of definite CAN was the highest at the minimum tertile of serum CTRP9 level (T1; P < 0.05). Additionally, serum CTRP9 levels were negatively correlated with age, DM duration, hemoglobin A1c (HbA1c), and fasting plasma glucose (FPG) while positively correlated with high-density lipoprotein cholesterol (HDL; P < 0.05). The level of CTRP9 was also significantly associated with the four indexes of CARTs (P < 0.05). Furthermore, CTRP9 was a protective factor for definite CAN (P < 0.05). Compared with the maximum tertile (T3) of the serum CTRP9 levels, a decreased level of serum CTRP9 in T1 significantly increased the prevalence ratio of definite CAN in patients with type 2 diabetes mellitus (P < 0.05). CONCLUSION: Serum CTRP9 levels were independently associated with definite CAN. CTRP9 represents a reliable biomarker for exploring CAN in patients with type 2 diabetes mellitus.

Metformin improves boar sperm quality via 5'-AMP-activated protein kinase-mediated energy metabolism in vitro.

Sperm are specialized cells that require adenosine triphosphate (ATP) to support their function. Maintaining sperm energy homeostasis in vitro is vitally important to improve the efficacy of boar sperm preservation. Metformin can activate 5'-AMP-activated protein kinase (AMPK) to improve metabolic flexibility and maintain energy homeostasis. Thus, the aim of the present study was to investigate whether metformin can improve boar sperm quality through AMPK mediation of energy metabolism. Sperm motility parameters, membrane integrity, acrosome integrity, mitochondrial membrane potential (ΔΨ m), ATP content, glucose uptake, and lactate efflux were analyzed. Localization and expression levels of AMPK and phospho-Thr 172-AMPK (p-AMPK) were also detected by immunofluorescence and western blotting. We found that metformin treatment significantly increased sperm motility parameters, ΔΨ m, and ATP content during storage at 17 °C. Moreover, results showed that AMPK was localized at the acrosomal region, connecting piece, and midpiece of sperm and p-AMPK was distributed at the post-acrosomal region, connecting piece, and midpiece. When sperm were incubated with metformin for 4 h at 37 °C, sperm motility parameters, ΔΨ m, ATP content, p-AMPK, glucose uptake, and lactate efflux all significantly increased, whereas the addition of Compound C treatment, an inhibitor of AMPK, counteracted these positive effects. Together, our results suggest that metformin promotes AMPK activation, which contributes to the maintenance of energy hemostasis and mitochondrial activity, thereby maintaining boar sperm functionality and improving the efficacy of semen preservation.

PAMAM-cRGD mediating efficient siRNA delivery to spermatogonial stem cells.

BACKGROUND: Spermatogonial stem cells (SSCs) are the cornerstone of sperm production and thus perpetual male fertility. In clinics, transplantation of patient's own SSCs into testes is a promising technique to restore fertility when male germ cells have been depleted by gonadotoxic therapies. Auto-transplantation of genetically modified SSCs even has the potential to treat male infertility caused by genetic mutations. However, SSCs are refractory to transfection approaches. Poly(amidoamine) (PAMAM) dendrimers have the unique three-dimensional architecture, surface charge, and high density of surface groups that are suitable for ligand attachment, thereby facilitating target delivery. The goal of this study was to elucidate whether PAMAM dendrimers can efficiently deliver short interfering RNAs (siRNAs) to SSCs. METHODS AND RESULTS: We introduced cyclic arginine-glycine-aspartic acid (cRGD) peptides to the fifth generation of PAMAM dendrimers (G5) to generate PAMAM-cRGD dendrimers (G5-cRGD). The characterization of G5-cRGD was detected by Fourier transform infrared spectroscope (FTIR), transmission electron microscope (TEM), and the Cell Counting Kit-8 (CCK-8) assay. Confocal microscopy and flow cytometry were used to evaluate the delivery efficiency of siRNA by G5-cRGD to SSCs. The results showed that G5-cRGD encompassing siRNA could self-assemble into spherical structures with nanoscale size and possess high transfection efficiency, excellent endosomal escape ability, and low cytotoxicity, superior to a commercial transfection reagent Lipofectamine® 2000. Moreover, we demonstrated that G5-cRGD efficiently delivered siRNAs and triggered gene silencing. CONCLUSIONS: This study thus provides a promising nanovector for siRNA delivery in SSCs, facilitating the future clinical application of SSC auto-transplantation with genetically modified cells with a hope to cure male infertility that is caused by genetic disorders.

Glycogen Synthase Kinase-3 Regulates Sperm Motility and Acrosome Reaction via Affecting Energy Metabolism in Goats.

Hyperactivation and acrosome reaction of sperm are pre-requisite steps for fertilization. However, the hyperactivation and acrosome reaction are critically controlled through the phosphorylation of specific proteins. Glycogen synthase kinase-3 (GSK3), a serine/threonine kinase with two different isoforms (α and ß), is involved in biochemical signaling pathways. This study was aimed to investigate whether the GSK3α/ß is present in goat sperm and its regulatory role in sperm motility and acrosome reaction. GSK3α/ß was detected with immunofluorescence and Western blotting. Sperm motility, membrane integrity, acrosome reaction, mitochondrial membrane potential, phospho-Ser21-GSK3α and phospho-Ser9-GSK3ß were analyzed. The ATP production and activities of lactate dehydrogenase (LDH), malate dehydrogenase (MDH), and succinate dehydrogenase (SDH) were measured. It was observed that the GSK3α/ß was expressed in goat sperm, especially in the peri-acrosomal, mid-piece and principal piece of the tail. The abundance of GSK3α/ß in sperm was increased during transit along the epididymis. Addition of either 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or CHIR99021 significantly increased the sperm motility patterns and GSK3α/ß phosphorylation. Interestingly, the adenosine triphosphate (ATP) production, activities of LDH, MDH and SDH were observed to be increased in the CHIR99021 treatment. The results suggested that GSK3α/ß regulates sperm motility and acrosome reaction via phospho-ser21-GSK3α and phospho-ser9-GSK3ß that involved in the regulation of sperm energy metabolism.

A Hypericin Delivery System Based on Polydopamine Coated Cerium Oxide Nanorods for Targeted Photodynamic Therapy.

Photodynamic therapy (PDT) as a non-aggressive therapy with fewer side effects has unique advantages over traditional treatments. However, PDT still has certain limitations in clinical applications, mainly because most photosensitizers utilized in PDT are hydrophobic compounds, which will self-aggregate in the aqueous phase and cause undesirable effects. In order to resolve this, we utilized the self-polymerization of dopamine molecules under alkaline conditions to coat cerium oxide nanorods (CeONR) with a dense polydopamine (PDA) film. Thereafter, thiolated galactose (Gal-SH) and hypericin (Hyp) were modified and loaded onto the surface to construct CeONR@PDA-Gal/Hyp, respectively, which can be used for targeted photodynamic therapy of human hepatoma HepG2 cells. CeONR@PDA-Gal/Hyp was characterized by transmission electron microscope (TEM), Zeta potential, Ultraviolet-visible (UV-Vis), and fluorescence spectroscopy, respectively. This hypericin delivery system possesses good biocompatibility and specific targeting ability, where the galactose units on the surface of CeONR@PDA-Gal/Hyp can specifically recognize the asialo-glycoprotein receptors (ASGP-R), which overexpress on HepG2 cell membrane. Furthermore, Hyp will detach from the surface of CeONR@PDA-Gal/Hyp after the nanorods enter cancer cells, and shows excellent PDT effect under the irradiation of light with a wavelength of 590 nm. Our work exemplifies a novel targeted delivery of hydrophobic photosensitizers for cancer treatment.

Melatonin protects rabbit spermatozoa from cryo-damage via decreasing oxidative stress.

Mammalian spermatozoa are highly susceptible to reactive oxygen species (ROS) stress. The aim of the present study was to investigate whether and how melatonin protects rabbit spermatozoa against ROS stress during cryopreservation. Semen was diluted with Tris-citrate-glucose extender in presence of different concentrations of melatonin. It was observed that addition of 0.1 mM melatonin significantly improved spermatozoa motility, membrane integrity, acrosome integrity, mitochondrial membrane potential as well as AMP-activated protein kinase (AMPK) phosphorylation. Meanwhile, the lipid peroxidation (LPO), ROS levels and apoptosis of post-thaw spermatozoa were reduced in presence of melatonin. Interestingly, when fresh spermatozoa were incubated with 100 µM H2O2, addition of 0.1 mM melatonin significantly decreased the oxidative damage compared to the H2O2 treatment, whereas addition of luzindole, an MT1 receptor inhibitor, decrease the effect of melatonin in spermatozoa. It was observed that the glutathione (GSH) content and activities of glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) were significantly increased with addition of melatonin during cryopreservation. In conclusion, addition of melatonin to the freezing extender protects rabbit spermatozoa against ROS attack by enhancing AMPK phosphorylation for increasing the antioxidative defense.

Construction of a biodegradable, versatile nanocarrier for optional combination cancer therapy.

A novel biodegradable versatile nanocarrier (FA-CM) was fabricated based on the self-assembly of delaminated CoAl-layered double hydroxides (LDHs) and manganese dioxide (MnO2) for optional combination cancer therapy. Biodegradation, versatility, targeting, bioimaging, in vitro cytotoxicity and in vivo antitumor efficacy were evaluated. The results showed that FA-CM could not only be effectively degraded into Co2+, Al3+ and Mn2+ to overcome the long-term toxic side effects, but also successfully load any positive-charged, negative-charged, hydrophilic, and hydrophobic drug, meeting the critical requirement of versatile nanocarrier. Meanwhile, the presence of FA led to the higher uptake efficiency, cytotoxicity, and excellent fluorescence imaging of FA-CM toward cancerous cells. In particular, FA-CM exhibited glutathione and pH dual-response drug release, avoiding any premature leakage and side effects. The applicability of the FA-CM was determined by co-loading hydrophilic (doxorubicin (DOX)) and hydrophobic drug (paclitaxel (PTX)) for synergistic combination chemotherapy. In vitro cytotoxicity evaluation and a xenograft tumor model of hepatoma showed that this combination exhibited more efficient anticancer effects compared with either free drug alone or the corresponding cocktail solutions. Especially, the ratios of DOX and PTX loaded on FA-CM could be tuned as needed. A powerful approach is provided for the design and preparation of a biodegradable versatile nanocarrier with targeted ability and excellent biocompatibility, which can be potentially applied in clinical practice and medical imaging. STATEMENT OF SIGNIFICANCE: Drug delivery nanocarriers that can transport an effective dosage of drug molecules to targeted cells and tissues have been extensively designed to overcome the adverse side effects and low effectiveness of conventional chemotherapy. However, lack of biodegradability and versatility existing in majority of nanocarriers limit their further clinical applications. Thus, constructing a novel biodegradable versatile nanocarrier that can carry various types of drugs, is in urgent need and more suitable for commercial production and clinical use. In this study, we developed a novel biodegradable versatile nanocarrier (FA-CM) based on the self-assembly of delaminated CoAl-layered double hydroxides (LDHs) and manganese dioxide (MnO2) for optional combination cancer therapy. This work provides a new strategy for constructing versatile biodegradable platform for targeted drug delivery, which would have broad applications in cancer theranostics.

Quantitative comparison of drug efficacy in treating hot flashes in patients with breast cancer.

OBJECTIVE: This study aimed to quantitatively evaluate drug efficacy and identify relevant factors that affect the relief of hot flashes in patients with breast cancer. METHODS: A comprehensive literature search was performed using public databases. Randomized clinical studies on drug therapy for the treatment of hot flashes in patients with breast cancer were identified. A time-effect model was established, and crucial pharmacodynamic parameters, such as maximal efficacy (Emax) and onset time (ET50), were used to reflect the differences in efficacy among the drugs. RESULTS: Eighteen studies involving 5178 subjects were included. It was found that the baseline of hot flashes was an important factor for the Emax value of drugs. After correcting the baseline to the level of eight times per day, the Emax values of progesterone, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs), neuroleptic agents, tibolone, phytoestrogen, other types of drugs, and placebo were 8.3(95%CI 6.8, 9.9),5.1(95%CI 4.4, 5.7), 4.4(95%CI 3.6, 5.3), 4.0(95%CI 3.6, 4.3), 3.4(95%CI 2.4, 4.3), 2.5(95%CI 0.8, 4.2), and 2.7(95%CI 2.1, 3.3), respectively. The ET50 of all the drugs were approximately 2-2.5 weeks, which was obviously longer than that of the placebo (1.2 weeks). When compared with the previously reported efficacy characteristics in natural menopausal women, no significant difference was found between the two populations. CONCLUSIONS: Progesterone showed the highest efficacy, followed by SSRIs/SNRIs, neuroleptic agents, and tibolone, while phytoestrogen and other types of drugs showed no efficacy advantages. There is a significant association between the baseline of hot flashes and drug efficacy, while there was no significant difference between breast cancer patients and natural menopausal women.