Nanobiostimulant action of trigolic formulated zinc sulfide nanoparticles (ZnS-T NPs) on rice seeds by triggering antioxidant defense network and plant growth specific transcription factors.

Under a changing climate, nanotechnological interventions for climate resilience in crops are critical to maintaining food security. Prior research has documented the affirmative response of nano zinc sulfide (nZnS) on physiological traits of fungal-infested rice seeds. Here, we propose an application of trigolic formulated zinc sulfide nanoparticles (ZnS-T NPs) on rice seeds as nanobiostimulant to improve physiological parameters by triggering antioxidative defense system, whose mechanism was investigated at transcriptional level by differential expression of genes in germinated seedlings. Nanopriming of healthy rice seeds with ZnS-T NPs (50 µg/ml), considerably intensified the seed vitality factors, including germination percentage, seedling length, dry weight and overall vigor index. Differential activation of antioxidant enzymes, viz. SOD (35.47%), APX (33.80%) and CAT (45.94%), in ZnS-T NPs treated seedlings reduced the probability of redox imbalance and promoted the vitality of rice seedlings. In gene expression profiling by reverse transcription quantitative real time PCR (qRT-PCR), the notable up-regulation of target antioxidant genes (CuZn SOD, APX and CAT) and plant growth specific genes (CKX and GRF) in ZnS-T NPs treated rice seedlings substantiates their molecular role in stimulating both antioxidant defenses and plant growth mechanisms. The improved physiological quality parameters of ZnS-T NPs treated rice seeds under pot house conditions corresponded well with in vitro findings, which validated the beneficial boosted impact of ZnS-T NPs on rice seed development. Inclusively, the study on ZnS-T NPs offers fresh perspectives into biochemical and molecular reactions of rice, potentially positioning them as nanobiostimulant capable of eliciting broad-spectrum immune and growth-enhancing responses.

Transcriptomic analysis reveals particulate hexavalent chromium regulates key inflammatory pathways in human lung fibroblasts as a possible mechanism of carcinogenesis.

Hexavalent chromium [Cr(VI)] is considered a major environmental health concern and lung carcinogen. However, the exact mechanism by which Cr(VI) causes lung cancer in humans remains unclear. Since several reports have demonstrated a role for inflammation in Cr(VI) toxicity, the present study aimed to apply transcriptomics to examine the global mRNA expression in human lung fibroblasts after acute (24 h) or prolonged (72 and 120 h) exposure to 0.1, 0.2 and 0.3 µg/cm2 zinc chromate, with a particular emphasis on inflammatory pathways. The results showed Cr(VI) affected the expression of multiple genes and these effects varied according to Cr(VI) concentration and exposure time. Bioinformatic analysis of RNA-Seq data based on the Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and MetaCore databases revealed multiple inflammatory pathways were affected by Cr(VI) treatment. qRT-PCR data corroborated RNA-Seq findings. This study showed for the first time that Cr(VI) regulates key inflammatory pathways in human lung fibroblasts, providing novel insights into the mechanisms by which Cr(VI) causes lung cancer.

Activity of zinc oxide and zinc borate nanoparticles against resistant bacteria in an experimental lung cancer model.

BACKGROUND: Recent research indicates a prevalence of typical lung infections, such as pneumonia, in lung cancer patients. Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii stand out as antibiotic-resistant pathogens. Given this, there is a growing interest in alternative therapeutic avenues. Boron and zinc derivatives exhibit antimicrobial, antiviral, and antifungal properties. OBJECTIVES: This research aimed to establish the effectiveness of ZnO and ZB NPs in combating bacterial infections in lung cancer cell lines. METHODS: Initially, this study determined the minimal inhibitory concentration (MIC) and fractional inhibitory concentration (FIC) of zinc oxide nanoparticles (ZnO NPs) and zinc borate (ZB) on chosen benchmark strains. Subsequent steps involved gauging treatment success through a lung cancer-bacteria combined culture and immunohistochemical analysis. RESULTS: The inhibitory impact of ZnO NPs on bacteria was charted as follows: 0.97 µg/mL for K. pneumoniae 700603, 1.95 µg/mL for P. aeruginosa 27853, and 7.81 µg/mL for Acinetobacter baumannii 19,606. In comparison, the antibacterial influence of zinc borate was measured as 7.81 µg/mL for Klebsiella pneumoniae 700603 and 500 µg/mL for both P. aeruginosa 27853 and A.baumannii 19606. After 24 h, the cytotoxicity of ZnO NPs and ZB was analyzed using the MTT technique. The lowest cell viability was marked in the 500 µg/mL ZB NPs group, with a viability rate of 48.83% (P < 0.001). However, marked deviations appeared at ZB concentrations of 61.5 µg/mL (P < 0.05) and ZnO NPs at 125 µg/mL. CONCLUSION: A synergistic microbial inhibitory effect was observed when ZnO NP and ZB were combined against the bacteria under investigation.

CHRONIC EFFECTS OF CADMIUM CHLORIDE ON RAT EMBRYOGENESIS.

The purpose of this study was to analyze the effects of cadmium toxicity on rat embryogenesis when exposed to other heavy metal citrates. Despite the variety of scientific publications discussing the influence of cadmium on mammalian postnatal development, the effect of this metal on embryogenesis has not yet been sufficiently studied. In this experimental study, cadmium chloride was administered to experimental pregnant female Wistar rats at a daily dose of 1.0 mg/kg. Rats were allocated at random into groups receiving either cadmium chloride alone or additional zinc citrate, cerium citrate, or nanocomposite (based on iodine, sulfur, and selenium citrate). The control group received distilled water at an equivalent volume. In each group, operational intervention occurred at the 13th and 20th day of gestation to assess numbers of live fetuses, corpora lutea, pre-implantation losses, post-implantation losses, and total implantation losses. When cadmium chloride alone was administered, a pronounced embryotoxic effect was observed, manifested as a significant decrease in the number of live fetuses. Experimental groups which received cadmium chloride with zinc citrate, cerium citrate, or nanocomposite had an increased number of live fetuses and corpora lutea, as well as a decreased number of implantation losses, compared to the group which only received cadmium chloride. Each combination of cerium, zinc, and selenium nanocomposite citrates demonstrated a compensatory effect on all measures of embryogenesis impacted by cadmium embryotoxicity. Thus, administration of the citrates of cerium, zinc, and selenium nanocomposite reduces cadmium embryotoxicity and its accumulation in the body.

Photo-excitable zinc sulfide nanoparticles: A theranostic nanotool for cancer management.

OBJECTIVES: Zinc sulfide nanoparticles (ZnS NPs), as one of the quantum dots less than 10 nm, possess unique size-dependent autofluorescence. Excitation of their valence electrons by energy higher than the bandgap reveals the ZnS NPs' inherited photocatalysis with additive cytotoxic consequences of reactive oxygen species (ROS) release. Coupling the cytotoxicity of photoactivated ZnS NPs with their autofluorescence would be a novel theranostic modality, combating superficially accessible carcinoma. MATERIAL AND METHODS: After synthesizing and characterization of ZnS NPs, we verified their photocatalysis and electron donation upon UV excitation in degrading organic dye and DNA cleavage, respectively. We then tested the efficacy of UV-activated ZnS NPs to induce ROS-dependent apoptosis in squamous cell carcinoma and breast cancer cell lines. RESULTS: The energetic electron-hole pairs generated upon UV excitation of ZnS NPs with the consequent cascade of ROS release revealed potent apoptotic cancer cell deaths, compared with single treatment modalities of nonexcited nanoparticles and UV. Moreover, the inherited luminescence of ZnS NPs enabled visualization of their predominant intracytoplasmic uptake with tracking of their cellular response. CONCLUSION: The intensified luminescence and the fortified cytotoxicity of photoactivated ZnS NPs enhance their theranostic qualifications, boosting their antitumorigenic use.

Improved Photodynamic Activity of Phthalocyanine by Adjusting the Chirality of Modified Amino Acids.

Herein, four zinc phthalocyanines (ZnPcs) with chiral lysine modification were synthesized. We found that the chirality of lysine and the chiral structure position strongly influence the properties of ZnPcs. Among the four ZnPcs, d-lysine-modified ZnPc through -NH2 on Cε [denoted N(ε)-d-lys-ZnPc] showed superior properties, including tumor enrichment, cancer cell uptake, and tumor retention capability, compared to the other three ZnPcs. Thus, chiral molecule modification is a simple and effective strategy to regulate the abovementioned properties to achieve a satisfactory antitumor outcome of drugs.

Efficacy of Zn-Aspartate in comparison with ZnSO4 and L-Aspartate in amelioration of drought stress in maize by modulating antioxidant defence; osmolyte accumulation and photosynthetic attributes.

Human population is exceeding beyond the carrying capacity of earth resources and stresses like water shortage faced by the plants is jeopardizing the food security. Current research study was aimed to investigate the potentials of Zn-Aspartate (Zn-Asp), Zn-Sulphate (ZnSO4) and L-Aspartate (L-Asp) to be used as osmolytes and role of various levels of these chemicals in combating drought stress in maize plants in Punjab, Pakistan. Study was performed on two plots corresponding to drought and controlled environments. The lamina of maize plants was sprinkled row wise with various treatments including No spray (NS), water sprinkle (WS), sprinkle with ZnSO4 0.25% and 0.50%, sprinkle with Zn-Asp 0.25% and 0.50% and Foliar sprinkle of L-Asp 0.5% and 1%, respectively. Role of major osmoprotectants and secondary metabolites was analyzed and positive changes were found in total soluble sugars (41.16), flavonoids (5387.74), tocopherol content (9089.18), ascorbic acid (645.27) and anthocyanin (14.84) conc. which assists in mitigating drought menace on maize. Shoot mineral ions (Ca, K, Zn, P, Mg and N) status of water stressed maize plants was also analyzed and it was found that application experimental dose enhanced their availability to crop. Physio-biochemical studies were performed on antioxidants enzymes like superoxide dismutase (SOD), peroxidase (POD), carotenoid content (CC), malondialdehyde, hydrogen peroxide, aspartate and free amino acid contents. The activity of SOD was increased by 28.5% and activity of POD was increased by 33.33% due to foliar applied 0.5% Zn-Asp under drought stress. Photosynthetic pigments (chlorophyll A, B and total chlorophyll content) analysis was also carried out in this study. It was found that conc. of different chlorophylls pigments increased (chl-A: 2.24, chl-B: 25.12, total chl: 24.30) which enhanced photosynthetic activity culminating into better growth and yield). The level of malondialdehyde and hydrogen peroxide decreased by 43.9% and 32.8% respectively on treatment with 0.5% Zn-Asp proving the efficacy of the treatment in drought amelioration. Study reveals that Zn-Asp induced modulations are far better than conventional sulphate salts in mitigating water scarce environment. Current study recommends the use of the Zn-Asp to meet the global food and agricultural challenges as compared to ZnSO4 and L-Asp due to its better drought amelioration properties. This research provides valuable informations which can used for future research and practical use in agriculture fields by indigenous and other people to enhance yield of maize to meet the food necessities of country.

Zinc Inhibits Cadherin 1 Expression Induced by 1α,25-Dihydroxyvitamin D3 in Colon Cancer Cells.

BACKGROUND: Zinc is a mineral that is essential for biological molecules, such as transcription factors, and is involved in the maintenance of intestinal homeostasis. Vitamin D signaling is mediated by vitamin D receptor (VDR) activated by 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] and is also important in intestinal functions, such as calcium absorption and epithelial barrier maintenance. However, the crosstalk between vitamin D signaling and zinc signaling in intestinal cells remains poorly understood. MATERIALS AND METHODS: Colon cancer SW480 and HCT116 cells were treated with zinc chloride (ZnCl2) with/without 1,25(OH)2D3 Expression of zinc-inducible genes [metallothionein 1A (MT1A) and MT2A] and VDR target genes [cytochrome P450 family 24 subfamily A member 1 (CYP24A1), transient receptor potential cation channel subfamily V member 6 (TRPV6) and cadherin 1 (CDH1)] was examined. RESULTS: Treatment of cells with ZnCl2 effectively induced MT1A and MT2A mRNA expression, and interestingly suppressed mRNA expression of CDH1, which was induced by 1,25(OH)2D3 in both cell lines. ZnCl2 also reduced the CDH1 protein level in HCT116 cells. CONCLUSION: Zinc signaling suppresses VDR-induced expression of CDH1.

Photodynamic Therapy with Zinc Phthalocyanine Inhibits the Stemness and Development of Colorectal Cancer: Time to Overcome the Challenging Barriers?

Photodynamic therapy (PDT) is a light-based cancer therapy approach that has shown promising results in treating various malignancies. Growing evidence indicates that cancer stem cells (CSCs) are implicated in tumor recurrence, metastasis, and cancer therapy resistance in colorectal cancer (CRC); thus, targeting these cells can ameliorate the prognosis of affected patients. Based on our bioinformatics results, SOX2 overexpression is significantly associated with inferior disease-specific survival and worsened the progression-free interval of CRC patients. Our results demonstrate that zinc phthalocyanine (ZnPc)-PDT with 12 J/cm2 or 24 J/cm2 irradiation can substantially decrease tumor migration via downregulating MMP9 and ROCK1 and inhibit the clonogenicity of SW480 cells via downregulating CD44 and SOX2. Despite inhibiting clonogenicity, ZnPc-PDT with 12 J/cm2 irradiation fails to downregulate CD44 expression in SW480 cells. Our results indicate that ZnPc-PDT with 12 J/cm2 or 24 J/cm2 irradiation can substantially reduce the cell viability of SW480 cells and stimulate autophagy in the tumoral cells. Moreover, our results show that ZnPc-PDT with 12 J/cm2 or 24 J/cm2 irradiation can substantially arrest the cell cycle at the sub-G1 level, stimulate the intrinsic apoptosis pathway via upregulating caspase-3 and caspase-9 and downregulating Bcl-2. Indeed, our bioinformatics results show considerable interactions between the studied CSC-related genes with the studied migration- and apoptosis-related genes. Collectively, the current study highlights the potential role of ZnPc-PDT in inhibiting stemness and CRC development, which can ameliorate the prognosis of CRC patients.

Antioxidant support to ameliorate the oxaliplatin-dependent microglial alteration: morphological and molecular study.

Oxaliplatin is a third-generation chemotherapy drug mainly used for colorectal cancer treatment. However, it is also known to trigger neuropathy whose underlying neurobiological mechanisms are still under investigation and currently available treatments show limited efficacy. It is now established that neurons are not the only cell type involved in chronic pain and that glial cells, mainly astrocytes and microglia, are involved in the initiation and maintenance of neuropathy. Among all the pathogenetic factors involved in neuropathic pain, an oxaliplatin-dependent oxidative stress plays a predominant role. In our study, the antioxidant properties of magnesium (Mg), manganese (Mn) and zinc (Zn) salts were evaluated in order to counteract microglial activation induced by oxaliplatin. The antioxidant efficacy of these metals was evaluated by the means of molecular and morphological assays on the BV-2 microglial cell line. Our data clearly show that Mg, Mn and Zn are able to prevent oxaliplatin-dependent microglial alterations by reducing both oxidative and endoplasmic reticulum stress.

ZnS@BSA Nanoclusters Potentiate Efficacy of Cancer Immunotherapy.

Although immunotherapy such as immune checkpoint inhibitors has shown promising efficacy in cancer treatment, the responsiveness among patients is relatively limited. Activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase/interferon gene stimulator (cGAS/STING) signaling pathway to upregulate innate immunity has become an emerging strategy for enhancing tumor immunotherapy. Herein, ZnS@BSA (bovine serum albumin) nanoclusters synthesized via a self-assembly approach are reported, where the released zinc ions under acidic tumor microenvironment significantly enhance cGAS/STING signals. Meanwhile, intracellular zinc ions can produce reactive oxygen species, which is further facilitated by the generated H2 S gas from ZnS@BSA via specifically inhibiting catalase in hepatocellular carcinoma cells. It is found that the nanoclusters activate the cGAS/STING signals in mice, which promotes the infiltration of CD8+ T cells at the tumor site and cross-presentation of dendritic cells, leading to an improved immunotherapy efficacy against hepatocellular carcinoma.

Regeneration of Bone Defects in a Rabbit Femoral Osteonecrosis Model Using 3D-Printed Poly (Epsilon-Caprolactone)/Nanoparticulate Willemite Composite Scaffolds.

Steroid-associated osteonecrosis (SAON) is a chronic disease that leads to the destruction and collapse of bone near the joint that is subjected to weight bearing, ultimately resulting in a loss of hip and knee function. Zn2+ ions, as an essential trace element, have functional roles in improving the immunophysiological cellular environment, accelerating bone regeneration, and inhibiting biofilm formation. In this study, we reconstruct SAON lesions with a three-dimensional (3D)-a printed composite made of poly (epsilon-caprolactone) (PCL) and nanoparticulate Willemite (npW). Rabbit bone marrow stem cells were used to evaluate the cytocompatibility and osteogenic differentiation capability of the PCL/npW composite scaffolds. The 2-month bone regeneration was assessed by a Micro-computed tomography (micro-CT) scan and the expression of bone regeneration proteins by Western blot. Compared with the neat PCL group, PCL/npW scaffolds exhibited significantly increased cytocompatibility and osteogenic activity. This finding reveals a new concept for the design of a 3D-printed PCL/npW composite-based bone substitute for the early treatment of osteonecrosis defects.

Effects of electroporation on anticancer activity of 5-FU and newly synthesized zinc(II) complex in chemotherapy-resistance human brain tumor cells.

Zn(II) complex of Schiff base derived from the condensation of 4-aminopyrimidine-2(1H)-one with salicylaldehyde was prepared and characterized by various physico-chemical and spectral methods for structure determination. The cytotoxic activity of the Zn(II) complex was investigated in comparison with 5-fluorouracil (5-FU) against two different human brain tumor cell lines (T98G and U118), while primer human dermal fibroblast cells (HDF) was used as control for biocompatibility. Then, the effectiveness of electroporation (EP) on cytotoxic activities of these compounds has been examined. The cytotoxicities of the 5-FU and new Zn(II) complex, alone or in combination with electroporation, were determined by MTT assay. The Zn(II) complex showed good cytotoxicity against T98G and U118 brain tumor cell lines with IC50 = 282.47 and 297.91 µM respectively, while it was safe on HDF healthy cells with IC50 = 826.72 µM. The 5-FU exhibited less cytotoxicity compared to the Zn(II) complex against T98G (IC50 = 382.35 µM) and U118 (IC50 = 396.56 µM) tumor cell lines. The combined application of Zn (II) + EP decreased the IC50 value by 5.96-fold in T98G cells and 4.76-fold in U118 cells. EP showed a similar effect in its combined application with 5-FU, resulting in a decrease of the IC50 value of 4.22-fold in the T98G cells and 3.84-fold in the U118 cells. In a conclusion, the Zn(II) complex exhibited an anticancer potential against both brain tumor cell lines (T98G and U118) and EP greatly increased the cytotoxicity of Zn(II) complex and 5-FU on these chemotherapy-resistant cells.

Zinc-containing Mohs' paste affects blood flow and angiogenesis suppression.

PURPOSE: Mohs' paste, which is composed of zinc chloride and zinc oxide starch, is used for hemostasis of superficial malignancy in the clinical setting. We investigated the concentration of intramuscular zinc in mice after Mohs' paste application and evaluated its relationship with angiogenesis from the perspective of blood flow levels within 24 h. METHODS: Male C57BL/6JJmsSlc mice were administered single dose of Mohs' paste at 25%, 50%, and 75% after unilateral hind limb surgery, and glycerin, a viscosity modifier, was administered to the control group (0%). Hind limb blood flow levels were measured with a laser Doppler perfusion imaging system (n = 6). The amounts of intramuscular zinc and vascular endothelial growth factor-A (VEGF-A) expression were analyzed using inductively coupled plasma mass spectrometry (ICP-MS) and western blotting, respectively (n = 5 or 3). RESULTS: Blood flow levels were significantly decreased in the 50% group after 8 h, and significantly decreased in the 25% and 50% groups after 24 h. Intramuscular zinc was significantly increased in the 50% and 75% groups after 8 h. Western blotting showed that VEGF-A levels were significantly increased in the 25% and 50% groups after 8 h. Based on analytical experiments and biological investigation, we predicated the pharmacological effect of Mohs' paste and found over 50% of it is critical in the blood flow and angiogenesis suppression after more than 8 h of its application. CONCLUSIONS: The results suggest that the mechanism of blood flow suppression is independent of VEGF-A levels and might suppress future angiogenesis. Our findings support that of previous studies, in which Mohs' paste was expected to induce hemostasis and suppress angiogenesis. It is an excellent ointment that facilitates hemostasis by suppressing blood flow regardless of angiogenesis, and may be apt for situations where hemostasis is required in the clinical setting.

Knockdown of Mitogen-Activated Protein Kinase Kinase 3 Negatively Regulates Hepatitis A Virus Replication.

Zinc chloride is known to be effective in combatting hepatitis A virus (HAV) infection, and zinc ions seem to be especially involved in Toll-like receptor (TLR) signaling pathways. In the present study, we examined this involvement in human hepatoma cell lines using a human TLR signaling target RT-PCR array. We also observed that zinc chloride inhibited mitogen-activated protein kinase kinase 3 (MAP2K3) expression, which could downregulate HAV replication in human hepatocytes. It is possible that zinc chloride may inhibit HAV replication in association with its inhibition of MAP2K3. In that regard, this study set out to determine whether MAP2K3 could be considered a modulating factor in the development of the HAV pathogen-associated molecular pattern (PAMP) and its triggering of interferon-ß production. Because MAP2K3 seems to play a role in antiviral immunity against HAV infection, it is a promising target for drug development. The inhibition of MAP2K3 may also prevent HAV patients from developing a severe hepatitis A infection.

P62/SQSTM1/Keap1/NRF2 Axis Reduces Cancer Cells Death-Sensitivity in Response to Zn(II)-Curcumin Complex.

The hyperactivation of nuclear factor erythroid 2 p45-related factor 2 (NRF2), frequently found in many tumor types, can be responsible for cancer resistance to therapies and poor patient prognosis. Curcumin has been shown to activate NRF2 that has cytotprotective or protumorigenic roles according to tumor stage. The present study aimed at investigating whether the zinc-curcumin Zn(II)-curc compound, which we previously showed to display anticancer effects through multiple mechanisms, could induce NRF2 activation and to explore the underlying molecular mechanisms. Biochemical studies showed that Zn(II)-curc treatment increased the NRF2 protein levels along with its targets, heme oxygenase-1 (HO-1) and p62/SQSTM1, while markedly reduced the levels of Keap1 (Kelch-like ECH-associated protein 1), the NRF2 inhibitor, in the cancer cell lines analyzed. The silencing of either NRF2 or p62/SQSTM1 with specific siRNA demonstrated the crosstalk between the two molecules and that the knockdown of either molecule increased the cancer cell sensitivity to Zn(II)-curc-induced cell death. This suggests that the crosstalk between p62/SQSTM1 and NRF2 could be therapeutically exploited to increase cancer patient response to therapies.

Fluorescent Nanohybrids from ZnS/CdSe Quantum Dots Functionalized with Triantennary, N-Hydroxy-p-(4-arylbutanamido)benzamide/Gallamide Dendrons That Act as Inhibitors of Histone Deacetylase for Lung Cancer.

N-Hydroxy-p-(4-arylbutanamido)benzamides (HABAB) belong to one class of histone deacetylase inhibitors (HDACi), which regulate deacetylation of lysine residue's amino group in histone, which results in chromatin constriction. In addition, transcriptional knockdown of the genetic loci possessing the suppressor genes of tumor occurs. A tripodal, HABAB-capped gallamide dendron possessing thiol anchoring unit was prepared by the click method. The resultant hydrophilic dendritic unit was easily attached on the outer layer of CdSe/ZnS (i.e., core/shell type) quantum dots by thiolate-Zn interaction, as supported via 1H NMR spectroscopic analysis of the conjugate with its original property of fluorescence. The resulting, water-miscible nanohybrid (nano-HTPB) which bore trivalent, peripheral HABABs as the HDACi was efficiently taken up by cells of lung cancer and transported into the nuclei of cells in 3 h, as confirmed by confocal microscopy analysis. The concentration levels of 50% inhibition (IC50) after 48 h incubation of the nano-HTPB for A549 and H1299 lung cancer cell lines were 14 and 18 nM, respectively, which were about 150-fold lower than those of the parent HTPB analogues. Nano-HTPB at 20 nM induced the knockdown of cell cycle at second growth/mitosis (i.e., G2/M) transition, which eventually led to apoptosis of lung cancer cells, demonstrating that the nano-HTPB was much more potent in inhibiting lung cancer cell growth in a synergistic manner than the parent HTPB analogues. In addition, the dendritic HABAB-capped nanohybrid, nano-HTPB, is more effective than the parent HTPB analogues both in vitro and in vivo. Furthermore, the nano-HTPB is more effective than the parent HTPB to increase the acetylation level of proteins related to histone and nonhistone like p53 and tubulin. Our results confirmed that covalent encapsulation of quantum dots with peripheral, triantennary HDACis represented a feasible strategy for synergistic drug delivery with enhanced biological effects.

Zinc chloride affects chondrogenesis via VEGF signaling.

Insulin mimetics, including zinc containing compounds, have previously been shown to influence chondrogenesis as it relates to healing of fractures in various preclinical models. However, the mechanism by which these compounds drive chondrogenic differentiation is yet undefined. Here, via next-generation sequencing (NGS) and in vitro functional validation, we show that Zinc Chloride (ZnCl2) induces expression of both chondrogenic genes (Sox9, Runx1, collagen) as well as genes associated with VEGF-mediated signal transduction, including VEGF receptors 1 and 2 and their ligands; VEGF-A and VEGF-B. Noticeably, although insulin was able to also induce expression of these pro-angiogenic and pro-chondrogenic genes, the impact of insulin on expression of VEGF receptor and ligand genes was marginal when compared to that of ZnCl2. Furthermore, while the VEGFR antagonist, Axitinib, was able to attenuate the pro-chondrogenic effects of both insulin and ZnCl2; a reduction in gene and protein expression was most profoundly observed when the antagonist was applied to cells treated with ZnCl2. Taken together, these data suggest an important role for the VEGF-mediated signal transduction pathways in the positive effects observed when applying zinc-based compounds as adjuvants for chondrogenesis-mediated fracture healing. In this regard, further mechanistic evaluation of ZnCl2 and other zinc-containing insulin mimetics may support rational design of therapies targeted for disease indications associated with impaired fracture healing.

The Associated Regulatory Mechanisms of Zinc Lactate in Redox Balance and Mitochondrial Function of Intestinal Porcine Epithelial Cells.

Zinc lactate (ZnLA) is a new organic zinc salt which has antioxidant properties in mammals and can improve intestinal function. This study explored the effects of ZnLA and ZnSO4 on cell proliferation, Zn transport, antioxidant capacity, mitochondrial function, and their underlying molecular mechanisms in intestinal porcine epithelial cells (IPEC-J2). The results showed that addition of ZnLA promoted cell proliferation, inhibited cell apoptosis and IL-6 secretion, and upregulated the mRNA expression and concentration of MT-2B, ZNT-1, and CRIP, as well as affected the gene expression and activity of oxidation or antioxidant enzymes (e.g., CuZnSOD, CAT, and Gpx1, GSH-PX, LDH, and MDA), compared to ZnSO4 or control. Compared with the control, ZnLA treatment had no significant effect on mitochondrial membrane potential, whereas it markedly increased the mitochondrial basal OCR, nonmitochondrial respiratory capacity, and mitochondrial proton leakage and reduced spare respiratory capacity and mitochondrial reactive oxygen (ROS) production in IPEC-J2 cells. Furthermore, ZnLA treatment increased the protein expression of Nrf2 and phosphorylated AMPK, but reduced Keap1 and p62 protein expression and autophagy-related genes LC3B-1 and Beclin mRNA abundance. Under H2O2-induced oxidative stress conditions, ZnLA supplementation markedly reduced cell apoptosis and mitochondrial ROS levels in IPEC-J2 cells. Moreover, ZnLA administration increased the protein expression of Nrf2 and decreased the protein expression of caspase-3, Keap1, and p62 in H2O2-induced IPEC-J2 cells. In addition, when the activity of AMPK was inhibited by Compound C, ZnLA supplementation did not increase the protein expression of nuclear Nrf2, but when Compound C was removed, the activities of AMPK and Nfr2 were both increased by ZnLA treatment. Our results indicated that ZnLA could improve the antioxidant capacity and mitochondrial function in IPEC-J2 cells by activating the AMPK-Nrf2-p62 pathway under normal or oxidative stress conditions. Our novel finding also suggested that ZnLA, as a new feed additive for piglets, has the potential to be an alternative for ZnSO4.

Additive Effects of Zinc Chloride on the Suppression of Hepatitis A Virus Replication by Interferon in Human Hepatoma Huh7 Cells.

BACKGROUND/AIM: Hepatitis A virus (HAV) infection is still one of the serious health problems worldwide, despite the existence of effective vaccines for HAV. Zinc compounds have antiviral activities against various DNA and RNA viruses. Therefore, we investigated the effects of zinc compounds on the antiviral activity of interferon against HAV. MATERIALS AND METHODS: The effects of zinc compounds with or without interferon on HAV genotype IIIA HA11-1299 replication were examined in human hepatoma Huh7 cells. Cell viability was examined by the MTS assay. Inflammasome associated gene expression was examined by real-time reverse transcription-polymerase chain reaction. RESULTS: Both zinc sulfate and zinc chloride had an inhibitory effect on HAV replication. Zinc sulfate tended to enhance while zinc chloride significantly enhanced the anti-HAV effect induced by interferon-alpha-2a. Zinc chloride significantly up-regulated mitogen-activated protein kinase 12 (MAPK12) and down-regulated 6 related genes [baculoviral IAP repeat containing 3 (BIRC3), interleukin 1 beta (IL1B), proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1), prostaglandin-endoperoxide synthase 2 (PTGS2), PYD and CARD domain containing (PYCARD), and tumor necrosis factor (TNF)]. CONCLUSION: Zinc chloride inhibits HAV replication and has additive effects on the anti-HAV activities of interferon.