Modified Citrus Pectin (MCP) Confers a Renoprotective Effect on Early-Stage Nephropathy in Type-2 Diabetic Mice.

Diabetic nephropathy (DN) is a significant global health concern with a high morbidity rate. Accumulating evidence reveals that Galectin-3 (Gal-3), a ß-galactoside-binding lectin, is a biomarker in kidney diseases. Our study aimed to assess the advantageous impacts of modified citrus pectin (MCP) as an alternative therapeutic strategy for the initial and ongoing progression of DN in mice with type 2 diabetes mellitus (T2DM). The animal model has been split into four groups: control group, T2DM group (mice received intraperitoneal injections of nicotinamide (NA) and streptozotocin (STZ), T2DM+MCP group (mice received 100 mg/kg/day MCP following T2DM induction), and MCP group (mice received 100 mg/kg/day). After 4 weeks, kidney weight, blood glucose level, serum kidney function tests, histopathological structure alterations, oxidative stress, inflammation, apoptosis, and fibrosis parameters were determined in renal tissues. Our findings demonstrated that MCP treatment reduced blood glucose levels, renal histological damage, and restored kidney weight and kidney function tests. Additionally, MCP reduced malondialdehyde level and restored glutathione level, and catalase activity. MCP demonstrated a notable reduction in inflammatory and apoptosis mediators TNF-α, iNOS, TGF-ßRII and caspase-3. Overall, MCP could alleviate renal injury in an experimental model of DN by suppressing renal oxidative stress, inflammation, fibrosis, and apoptosis mediators.

First record of Apanteles hemara (N.) on Leucinodes orbonalis Guenée and biodiversity of Hymenoptera parasitoids on Brinjal.

The brinjal fruit and shoot borer (BFSB), Leucinodes orbonalis Guenée (Lepidoptera: Crambidae), is a very detrimental pest that causes significant economic losses to brinjal crop worldwide. Infested brinjal fruits were collected from vegetable fields located at the ICAR-Indian Agricultural Research Institute (ICAR-IARI), New Delhi, India, during two consecutive seasons (2021-2022). The larvae of the pest were brought to the laboratory and reared under controlled conditions of 25 ± 0.5 °C and 70 ± 5% relative humidity, for the emergence of parasitoids. In addition, the survey of Hymenoptera parasitoids in brinjal was conducted utilizing a sweep net and yellow pan trap over the course of two seasons. The results reveal that five parasitoid species were emerged from L. orbonalis viz., Apanteles hemara Nixon, 1965, Bracon greeni Ashmead 1896 (Hymenoptera: Braconidae), Goryphus nursei (Cameron, 1907), Trathala flavoorbitalis (Cameron, 1907) (Hymenoptera: Ichneumonidae) and Spalangia gemina Boucek 1963 (Hymenoptera: Spalangiidae). Out of these, A. hemara and S. gemina were documented as new occurrences in Delhi. Additionally, A. hemara was recorded for the first time as a parasite on L. orbonalis. Trathala flavoorbitalis was observed during both seasons and exhibited higher parasitism reaching 15.55% and 18.46% in July and August 2022, respectively. However, the average parasitism (%) recorded by A. hemara, B. greeni, G. nursei, T. flavoorbitalis and S. gemina was 3.10%, 1.76%, 1.10%, 9.28% and 1.20% respectively. Furthermore, the findings showed a significant (p ≤ 0.01) strongly positive correlation between fruit infestation (%) by L. orbonalis and parasitism (%). The survey indicates the presence of a broad group (19 families and 60 species) of Hymenoptera parasitoids in the brinjal crop ecosystem in Delhi which could be valuable in biological control. In light of these results, this study revealed that A. hemara and other parasitoids identified in this study alongside T. flavoorbitalis would be ideal biocontrol agents within the integrated pest management (IPM) program of BFSB in Delhi.

Comparing specific capacitance in rice husk-derived activated carbon through phosphoric acid and potassium hydroxide activation order variations.

This manuscript investigates the influence of the chemical activation step order and process parameters on the specific capacitance of activated carbon derived from rice husk. The chemical activation was performed either before or after the carbonization step, using phosphoric acid (H3PO4) and potassium hydroxide (KOH) as activating agents. For activation before carbonization, the carbonization process was conducted at various temperatures (600, 750, 850, and 1050 °C). On the other hand, for activation after carbonization, the effect of the volume of the chemical agent solution was studied, with 0, 6, 18, 21, 24, and 30 mL/g of phosphoric acid and 0, 18, 30, 45, 60, and 90 mL/g of 3.0 M KOH solution. The results revealed that in the case of chemical activation before carbonization, the optimum temperature for maximizing specific capacitance was determined to be 900 °C. Conversely, in the case of chemical activation after carbonization, the optimal volumes of the chemical agent solutions were found to be 30 mL/g for phosphoric acid (H3PO4) and 21 mL/g for potassium hydroxide (KOH). Moreover, it was observed that utilizing phosphoric acid treatment before the carbonization step leads to an 21% increase in specific capacitance, attributed to the retention of inorganic compounds, particularly silica (SiO2). Conversely, when rice husks were treated with KOH after the carbonization step, the specific capacitance was found to be doubled compared to treatment with KOH prior to the carbonization step due to embedding of SiO2 and KHCO3 inorganic constituents. This study provides valuable insights into the optimization of the chemical activation step order and process parameters for enhanced specific capacitance in rice husk-derived activated carbon. These findings contribute to the development of high-performance supercapacitors using rice husk as a sustainable and cost-effective precursor material.

Graphitized mango seed as an effective 3D anode in batch and continuous mode microbial fuel cells for sustainable wastewater treatment and power generation.

Herein, we explored the utilization of graphitized mango seeds as 3D-packed anodes in microbial fuel cells (MFCs) powered by sewage wastewater. Mango seeds were graphitized at different temperatures (800 °C, 900 °C, 1000 °C, and 1100 °C) and their effectiveness as anodes was evaluated. Surface morphology analysis indicated that the proposed anode was characterized by layered branches and micro-sized deep holes, facilitating enhanced biofilm formation and microorganism attachment. Maximum power densities achieved in the MFCs utilizing the mango seed-packed anodes graphitized at 1100 °C and 1000 °C were 2170.8 ± 90 and 1350.6 ± 125 mW m-2, respectively. Furthermore, the weight of the graphitized seed anode demonstrated a positive correlation with the generated power density and cell potential. Specifically, MFCs fabricated with 9 g and 6 g anodes achieved maximum power densities of 2170.8 ± 90 and 1800.5 ± 40 mW m-2, respectively. A continuous mode air cathode MFC employing the proposed graphitized mango anode prepared at 1100 °C and operated at a flow rate of 2 L h-1 generated a stable current density of approximately 12 A m-2 after 15 hours of operation, maintaining its stability for 75 hours. Furthermore, a chemical oxygen demand (COD) removal efficiency of 85% was achieved in an assembled continuous mode MFC. Considering that the proposed MFC was driven by sewage wastewater without the addition of external microorganisms, atmospheric oxygen was used as the electron acceptor through an air cathode mode, agricultural biomass waste was employed for the preparation of the anode, and a higher power density was achieved (2170.8 mW m-2) compared to reported values; it is evident that the proposed graphitized mango seed anode exhibits high efficiency for application in MFCs.

Synergistic advancements in sewage-driven microbial fuel cells: novel carbon nanotube cathodes and biomass-derived anodes for efficient renewable energy generation and wastewater treatment.

Microbial fuel cells (MFCs) offer a dual solution of generating electrical energy from organic pollutants-laden wastewater while treating it. This study focuses on enhancing MFC performance through innovative electrode design. Three-dimensional (3D) anodes, created from corncobs and mango seeds via controlled graphitization, achieved remarkable power densities. The newly developed electrode configurations were evaluated within sewage wastewater-driven MFCs without the introduction of external microorganisms or prior treatment of the wastewater. At 1,000°C and 1,100°C graphitization temperatures, corncob and mango seed anodes produced 1,963 and 2,171 mW/m2, respectively, nearly 20 times higher than conventional carbon cloth and paper anodes. An advanced cathode composed of an activated carbon-carbon nanotube composite was introduced, rivaling expensive platinum-based cathodes. By optimizing the thermal treatment temperature and carbon nanotube content of the proposed cathode, comparable or superior performance to standard Pt/C commercial cathodes was achieved. Specifically, MFCs assembled with corncob anode with the proposed and standard Pt/C cathodes reached power densities of 1,963.1 and 2,178.6 mW/m2, respectively. Similarly, when utilizing graphitized mango seeds at 1,100°C, power densities of 2,171 and 2,151 mW/m2 were achieved for the new and standard cathodes, respectively. Furthermore, in continuous operation with a flow rate of 2 L/h, impressive chemical oxygen demand (COD) removal rates of 77% and 85% were achieved with corncob and mango seed anodes, respectively. This work highlights the significance of electrode design for enhancing MFC efficiency in electricity generation and wastewater treatment.

Maternal immune activation and role of placenta in the prenatal programming of neurodevelopmental disorders.

Maternal infection during pregnancy, leading to maternal immune activation (mIA) and cytokine release, increases the offspring risk of developing a variety of neurodevelopmental disorders (NDDs), including schizophrenia. Animal models have provided evidence to support these mechanistic links, with placental inflammatory responses and dysregulation of placental function implicated. This leads to changes in fetal brain cytokine balance and altered epigenetic regulation of key neurodevelopmental pathways. The prenatal timing of such mIA-evoked changes, and the accompanying fetal developmental responses to an altered in utero environment, will determine the scope of the impacts on neurodevelopmental processes. Such dysregulation can impart enduring neuropathological changes, which manifest subsequently in the postnatal period as altered neurodevelopmental behaviours in the offspring. Hence, elucidation of the functional changes that occur at the molecular level in the placenta is vital in improving our understanding of the mechanisms that underlie the pathogenesis of NDDs. This has notable relevance to the recent COVID-19 pandemic, where inflammatory responses in the placenta to SARS-CoV-2 infection during pregnancy and NDDs in early childhood have been reported. This review presents an integrated overview of these collective topics and describes the possible contribution of prenatal programming through placental effects as an underlying mechanism that links to NDD risk, underpinned by altered epigenetic regulation of neurodevelopmental pathways.

Exploiting the power of UPLC in separation and simultaneous determination of pholcodine, guaiacol along with three specified guaiacol impurities.

Pholcodine and guaiacol are widely used together in pharmaceutical syrups for cough treatment. On the other hand, the Ultra Performance Liquid Chromatographic technique is characterized by having the power of increasing chromatographic efficiency and decreasing run time compared to the traditional High Performance Liquid Chromatographic one. In this work, this power was exploited for the simultaneous determination of pholcodine, guaiacol along with three guaiacol impurities, namely; guaiacol impurity A, guaiacol impurity B, and guaiacol impurity E. Good separation was achieved by employing Agilent Zorbax C8 column (50 × 2.1 mm) as the stationary phase, and acetonitrile: phosphate buffer pH 3.5 (40: 60, by volume) as a mobile phase. The proposed method was validated as per International Council for Harmonisation guidelines. Linear relationships, at ranges of 50-1000 µg mL-1 for pholcodine and 5-100 µg mL-1 for guaiacol and the three related impurities, were established. Finally, the proposed method was applied for pholcodine and guaiacol determination in Coughpent® syrup and compared favorably to the reported one.

Maternal Immune Activation Induces Adolescent Cognitive Deficits Preceded by Developmental Perturbations in Cortical Reelin Signalling.

Exposure to maternal immune activation (MIA) in utero significantly elevates the risk of developing schizophrenia and other neurodevelopmental disorders. To understand the biological mechanisms underlying the link between MIA and increased risk, preclinical animal models have focussed on specific signalling pathways in the brain that mediate symptoms associated with neurodevelopmental disorders such as cognitive dysfunction. Reelin signalling in multiple brain regions is involved in neuronal migration, synaptic plasticity and long-term potentiation, and has been implicated in cognitive deficits. However, how regulation of Reelin expression is affected by MIA across cortical development and associated cognitive functions remains largely unclear. Using a MIA rat model, here we demonstrate cognitive deficits in adolescent object-location memory in MIA offspring and reductions in Reln expression prenatally and in the adult prefrontal cortex. Further, developmental disturbances in gene/protein expression and DNA methylation of downstream signalling components occurred subsequent to MIA-induced Reelin dysregulation and prior to cognitive deficits. We propose that MIA-induced dysregulation of Reelin signalling contributes to the emergence of prefrontal cortex-mediated cognitive deficits through altered NMDA receptor function, resulting in inefficient long-term potentiation. Our data suggest a developmental window during which attenuation of Reelin signalling may provide a possible therapeutic target.

Kinetic analysis of p-rGO/n-TiO2 nanocomposite generated by hydrothermal technique for simultaneous photocatalytic water splitting and degradation of methylene blue dye.

In this study, the nanocomposites of reduced graphene oxide/TiO2 (rGO/TiO2 with different percentages) have been synthesized using a modified Hummers' method followed by hydrothermal treatment. The morphology and bonding structure of the prepared samples have been characterized by Fourier-transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray diffractometry (XRD), and X-ray photoelectron spectroscopy (XPS). The photo-characteristic aspects of the prepared samples have been indicated by photoluminescence (PL) emission spectroscopy and ultraviolet-visible diffuse reflection spectroscopy (DRS). The photocatalytic performance of rGO/TiO2 demonstrated that it is an effective photocatalyst for methylene blue (MB) dye decomposition through illumination by a mercury lamp. Within 60 min of continuous irradiation, the nanocomposite-induced MB decomposition reached a rate of over 99%. Different MB concentrations and optimal percent loadings in catalysts have been investigated. Furthermore, the results showed that as the amount of catalyst increased, the decomposition of MB enhanced. Finally, the loading percentage of rGO with TiO2 has been studied, and an empirical equation relating the reaction rate constant until the mass of the photocatalyst and dye concentration has been proposed. The results showed that the prepared nanocomposites had good photocatalytic activity toward water splitting and photo-decomposition of MB.

Maternal behaviours and adult offspring behavioural deficits are predicted by maternal TNFα concentration in a rat model of neurodevelopmental disorders.

Exposure to inflammatory stressors during fetal development is a major risk factor for neurodevelopmental disorders (NDDs) in adult offspring. Maternal immune activation (MIA), induced by infection, causes an acute increase in pro-inflammatory cytokines which can increase the risk for NDDs directly by inducing placental and fetal brain inflammation, or indirectly through affecting maternal care behaviours thereby affecting postnatal brain development. Which of these two potential mechanisms dominates in increasing offspring risk for NDDs remains unclear. Here, we show that acute systemic maternal inflammation induced by the viral mimetic polyinosinic:polycytidylic acid (poly I:C) on gestational day 15 of rat pregnancy affects offspring and maternal behaviour, offspring cognition, and expression of NDD-relevant genes in the offspring brain. Dams exposed to poly I:C elicited an acute increase in the pro-inflammatory cytokine tumour necrosis factor (TNF; referred to here as TNFα), which predicted disruption of key maternal care behaviours. Offspring of poly I:C-treated dams showed early behavioural and adult cognitive deficits correlated to the maternal TNFα response, but, importantly, not with altered maternal care. We also found interacting effects of sex and treatment on GABAergic gene expression and DNA methylation in these offspring in a brain region-specific manner, including increased parvalbumin expression in the female adolescent frontal cortex. We conclude that the MIA-induced elevation of TNFα in the maternal compartment affects fetal neurodevelopment leading to altered offspring behaviour and cognition. Our results suggest that a focus on prenatal pathways affecting fetal neurodevelopment would provide greater insights into the mechanisms underpinning the TNFα-mediated genesis of altered offspring behaviour and cognition following maternal inflammation.

Carbon Nanofibers-Sheathed Graphite Rod Anode and Hydrophobic Cathode for Improved Performance Industrial Wastewater-Driven Microbial Fuel Cells.

Carbon nanofiber-decorated graphite rods are introduced as effective and low-cost anodes for industrial wastewater-driven microbial fuel cells. Carbon nanofiber deposition on the surface of the graphite rods could be performed by the electrospinning of polyacrylonitrile/N,N-Dimethylformamide solution using the rod as nanofiber collector, which was calcined under inert atmosphere. The experimental results indicated that at 10 min electrospinning time, the proposed graphite anode demonstrates very good performance compared to the commercial anodes. Typically, the generated power density from sugarcane industry wastewater-driven air cathode microbial fuel cells were 13 ± 0.3, 23 ± 0.7, 43 ± 1.3, and 185 ± 7.4 mW/m2 using carbon paper, carbon felt, carbon cloth, and graphite rod coated by 10-min electrospinning time carbon nanofibers anodes, respectively. The distinct performance of the proposed anode came from creating 3D carbon nanofiber layer filled with the biocatalyst. Moreover, to annihilate the internal cell resistance, a membrane-less cell was assembled by utilizing a poly(vinylidene fluoride) electrospun nanofiber layer-coated cathode. This novel strategy inspired a highly hydrophobic layer on the cathode surface, preventing water leakage to avoid utilizing the membrane. However, in both anode and cathode modifications, the electrospinning time should be optimized. The best results were obtained at 5 and 10 min for the cathode and anode, respectively.

Chronic developmental hypoxia alters mitochondrial oxidative capacity and reactive oxygen species production in the fetal rat heart in a sex-dependent manner.

Insufficient oxygen supply (hypoxia) during fetal development leads to cardiac remodeling and a predisposition to cardiovascular disease in later life. Previous work has shown hypoxia causes oxidative stress in the fetal heart and alters the activity and expression of mitochondrial proteins in a sex-dependent manner. However, the functional effects of these modifications on mitochondrial respiration remain unknown. Furthermore, while maternal antioxidant treatments are emerging as a promising new strategy to protect the hypoxic fetus, whether these treatments convey similar protection to cardiac mitochondria in the male or female fetus has not been investigated. Therefore, using an established rat model, we measured the sex-dependent effects of gestational hypoxia and maternal melatonin treatment on fetal cardiac mitochondrial respiration, reactive oxygen species (ROS) production, and lipid peroxidation. Pregnant Wistar rats were subjected to normoxia or hypoxia (13% oxygen) during gestational days (GDs) 6-20 (term ~22 days) with or without melatonin treatment (5 µg/ml in maternal drinking water). On GD 20, mitochondrial aerobic respiration and H2 O2 production were measured in fetal heart tissue, together with lipid peroxidation and citrate synthase (CS) activity. Gestational hypoxia reduced maternal body weight gain (p < .01) and increased placental weight (p < .05) but had no effect on fetal weight or litter size. Cardiac mitochondria from male but not female fetuses of hypoxic pregnancy had reduced respiratory capacity at Complex II (CII) (p < .05), and an increase in H2 O2 production/O2 consumption (p < .05) without any changes in lipid peroxidation. CS activity was also unchanged in both sexes. Despite maternal melatonin treatment increasing maternal and fetal plasma melatonin concentration (p < .001), melatonin treatment had no effect on any of the mitochondrial parameters investigated. To conclude, we show that gestational hypoxia leads to ROS generation from the mitochondrial electron transport chain and affects fetal cardiac mitochondrial respiration in a sex-dependent manner. We also show that maternal melatonin treatment had no effect on these relationships, which has implications for the development of future therapies for hypoxic pregnancies.

Maternal immune activation in rats induces dysfunction of placental leucine transport and alters fetal brain growth.

Maternal infection during pregnancy increases the offspring risk of developing a variety of neurodevelopmental disorders (NDDs), including schizophrenia. While the mechanisms remain unclear, dysregulation of placental function is implicated. We hypothesised that maternal infection, leading to maternal immune activation and stimulated cytokine production, alters placental and yolk sac amino acid transport, affecting fetal brain development and thus NDD risk. Using a rat model of maternal immune activation induced by the viral mimetic polyinosinic:polycytidylic acid (poly(I:C)), we investigated placental and yolk sac expression of system L amino acid transporter subtypes which transport several essential amino acids including branched-chain amino acids (BCAA), maternal and fetal BCAA concentration, placental 14C-leucine transport activity and associated impacts on fetal growth and development. Poly(I:C) treatment increased acutely maternal IL-6 and TNFα concentration, contrasting with IL-1ß. Transcriptional responses for these pro-inflammatory cytokines were found in placenta and yolk sac following poly(I:C) treatment. Placental and yolk sac weights were reduced by poly(I:C) treatment, yet fetal body weight was unaffected, while fetal brain weight was increased. Maternal plasma BCAA concentration was reduced 24 h post-poly(I:C) treatment, yet placental, but not yolk sac, BCAA concentration was increased. Placental and yolk sac gene expression of Slc7a5, Slc7a8 and Slc43a2 encoding LAT1, LAT2 and LAT4 transporter subtypes, respectively, was altered by poly(I:C) treatment. Placental 14C-leucine transport was significantly reduced 24 h post-treatment, contrasting with a significant increase 6 days following poly(I:C) treatment. Maternal immune activation induces dysregulated placental transport of amino acids affecting fetal brain development, and NDD risk potential in offspring.

El-Hattab-Alkuraya syndrome caused by biallelic WDR45B pathogenic variants: Further delineation of the phenotype and genotype.

Homozygous pathogenic variants in WDR45B were first identified in six subjects from three unrelated families with global development delay, refractory seizures, spastic quadriplegia, and brain malformations. Since the initial report in 2018, no further cases have been described. In this report, we present 12 additional individuals from seven unrelated families and their clinical, radiological, and molecular findings. Six different variants in WDR45B were identified, five of which are novel. Microcephaly and global developmental delay were observed in all subjects, and seizures and spastic quadriplegia in most. Common findings on brain imaging include cerebral atrophy, ex vacuo ventricular dilatation, brainstem volume loss, and symmetric under-opercularization. El-Hattab-Alkuraya syndrome is associated with a consistent phenotype characterized by early onset cerebral atrophy resulting in microcephaly, developmental delay, spastic quadriplegia, and seizures. The phenotype appears to be more severe among individuals with loss-of-function variants whereas those with missense variants were less severely affected suggesting a potential genotype-phenotype correlation in this disorder. A brain imaging pattern emerges which is consistent among individuals with loss-of-function variants and could potentially alert the neuroradiologists or clinician to consider WDR45B-related El-Hattab-Alkuraya syndrome.

H3PO4/KOH Activation Agent for High Performance Rice Husk Activated Carbon Electrode in Acidic Media Supercapacitors.

H3PO4/KOH combined solution is proposed as a new effective activation agent for activated carbon production from rice husk. Several activated carbon samples were produced by using different volumes of the utilized acid and alkali individually, in addition to the combined solution. FTIR results indicated that the mixed agent partially decomposed the chemical compounds on the rice husk char surface, resulting in an increase in the surface area. Moreover, XRD and EDS analyses showed the presence of a considerable amount of amorphous silica. Electrochemical measurements concluded that the volume of the activation agent solution should be optimized for both single and mixed activation agents. Numerically, for 0.3 g treated rice husk char, the maximum specific capacitance was observed at 7, 10 and 14 mL of H3PO4, KOH (3 M) and mixed (1:1 by volume) activation agents, respectively; the determined specific capacitance values were 73.5, 124.2 and 241.3 F/g, respectively. A galvanostatic charging/discharging analysis showed an approximate symmetrical triangular shape with linear voltage versus time profile which indicates very good electrochemical performance as an electrode in the supercapacitors application. The stability of the proposed activated carbon was checked by performing a cyclic voltammetry measurement for 1000 cycles at 2 mV/s and for 30,000 cycles at 10 mV/s. The results indicate an excellent specific capacitance retention, as no losses were observed.

Melatonin enhances antioxidant defenses but could not ameliorate the reproductive disorders in induced hyperthyroidism model in male rats.

The present study was carried out to clarify the effect of different doses of melatonin on some reproductive hormones, serum total antioxidant, histopathological examination, lipid peroxidation, and antioxidant parameters in liver, kidney, heart, and testis tissues in induced-hyperthyroidism (HT) male rat model. A total of 75 mature male Wistar rats were equally allocated into five groups; control groups were daily I/P injected with distilled water containing 4 M ammonium hydroxide in methanol and 1% absolute ethanol; on hyperthyroidism model group, rats received daily I/P injection of L-thyroxine (0.2 mg/kg body weight). In melatonin-treated groups, rats were injected with the same dose of L-thyroxine followed by I/P injection of melatonin (1, 5, or 10 mg/kg, respectively) for 21 days. The hyperthyroidism group showed significant increase in serum thyroxine (T4), triiodothyronine (T3), and testosterone levels and a significant decrease in the levels of thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH), luteinizing hormone (LH), and serum total antioxidants capacity, with a significant decrease in superoxide dismutase (SOD) activity and glutathione reductase (GSH) content with a significant increase in malondialdehyde (MDA) concentration in all examined tissues. While, melatonin co-treatment to HT groups partially counteracted the effect of hyperthyroidism by decreasing serum T4 and T3 levels and increasing serum TSH. In addition, melatonin could decrease serum levels of FSH, LH, and testosterone, as well as it could increase serum total antioxidants capacity, SOD activity, and GSH content and decreased MDA concentration in all examined tissues. Additionally, melatonin could amend the histopathological alterations in the examined tissues of hyperthyroid rats but not the testicular tissue. It is concluded that melatonin has a protective role against the hyperthyroidism-induced oxidative damage but cannot ameliorate the reproductive disorders in male rat model.

Signaling Inhibitors Accelerate the Conversion of mouse iPS Cells into Cancer Stem Cells in the Tumor Microenvironment.

Cancer stem cells (CSCs) are a class of cancer cells characterized by self-renewal, differentiation and tumorigenic potential. We previously established a model of CSCs by culturing mouse induced pluripotent stem cells (miPSCs) for four weeks in the presence of a conditioned medium (CM) of cancer cell lines, which functioned as the tumor microenvironment. Based on this methodology of developing CSCs from miPSCs, we assessed the risk of 110 non-mutagenic chemical compounds, most of which are known as inhibitors of cytoplasmic signaling pathways, as potential carcinogens. We treated miPSCs with each compound for one week in the presence of a CM of Lewis lung carcinoma (LLC) cells. However, one-week period was too short for the CM to convert miPSCs into CSCs. Consequently, PDO325901 (MEK inhibitor), CHIR99021 (GSK-3ß inhibitor) and Dasatinib (Abl, Src and c-Kit inhibitor) were found to confer miPSCs with the CSC phenotype in one week. The tumor cells that survived exhibited stemness markers, spheroid formation and tumorigenesis in Balb/c nude mice. Hence, we concluded that the three signal inhibitors accelerated the conversion of miPSCs into CSCs. Similarly to our previous study, we found that the PI3K-Akt signaling pathway was upregulated in the CSCs. Herein, we focused on the expression of relative genes after the treatment with these three inhibitors. Our results demonstrated an increased expression of pik3ca, pik3cb, pik3r5 and pik3r1 genes indicating class IA PI3K as the responsible signaling pathway. Hence, AKT phosphorylation was found to be up-regulated in the obtained CSCs. Inhibition of Erk1/2, tyrosine kinase, and/or GSK-3ß was implied to be involved in the enhancement of the PI3K-AKT signaling pathway in the undifferentiated cells, resulting in the sustained stemness, and subsequent conversion of miPSCs into CSCs in the tumor microenvironment.

A novel model of liver cancer stem cells developed from induced pluripotent stem cells.

BACKGROUND: Liver cancer is the second most common cause of cancer-related death. Every type of tumours including liver cancer contains cancer stem cells (CSCs). To date, the molecular mechanism regulating the development of liver CSCs remains unknown. METHODS: In this study, we tried to generate a new model of liver CSCs by converting mouse induced pluripotent stem cells (miPSCs) with hepatocellular carcinoma (HCC) cell line Huh7 cells conditioned medium (CM). miPSCs treated with CM were injected into the liver of BALB/c nude mice. The developed tumours were then excised and analysed. RESULTS: The primary cultured cells from the malignant tumour possessed self-renewal capacity, differentiation potential and tumorigenicity in vivo, which were found rich in liver cancer-associated markers as well as CSC markers. CONCLUSIONS: We established a model of liver CSCs converting from miPS and showed different stages of stemness during conversion process. Our CSC model will be important to assess the molecular mechanisms necessary to develop liver CSCs and could help in defeating liver cancer.

Celecoxib Targeted Therapy Attenuates Mouse Colon Carcinogenesis through Modulation of Expression Patterns of Cancer Stem Cells.

This study was designated to explore the role of cancer stem cells (CSCs) during chemically induced mouse colon carcinogenesis (by 1,2- dimethylhydrazine dihydrochloride, DMH) with/or without the treatment with a targeted (anti-COX-2) therapeutic drug, celecoxib. Two experiments were conducted. The first, a short-term, 16-week mouse colon carcinogenesis bioassay, demonstrates the early stages of colon carcinogenesis. The other is a medium-term, 32-week mouse colon cancer experiment that mimics an end point of colon malignancy. Colon tumors were detected in animals after 32 weeks; histopathologically, they varied from benign hyperplastic polyps and adenomas to dysplastic polyps, adenocarcinomas, and invasive carcinomas. The overall colon tumor incidences, multiplicities, and volumes were obviously reduced when treated with celecoxib after DMH initiation. The immunohistochemical (IHC) labeling indexes (L1%) of the proliferating cell nuclear antigen (PCNA) were lower in the colonic epithelium in both experiments after treatment with celecoxib. Also, the IHC expression patterns of CD133 and CD44, known to associate CSCs, showed differential changes depending on the end-point stage of carcinogenesis and celecoxib treatment. Moreover, the biochemical aldehyde dehydrogenase-1 (ALDH-1) activity levels, a known CSC marker in colonic epithelia, were downregulated after 16 weeks but were upregulated after 32 weeks. Flow cytometric analysis showed that numbers of CD133 cells increased in the colonic epithelia of mice after 16 weeks, while the numbers of CD44 but not CD133 cells increased after 32 weeks. Treatment with celecoxib after DMH induced significant increase in apoptotic cell numbers by 47% after 16 weeks, but these numbers had not changed after 32 weeks compared with the corresponding group treated DMH only. Thus, the specific markers and CSC populations targeted by this drug may vary depending on the genetic and phenotypic stages of carcinogenesis. This drug could be useful during targeted therapy for colon cancer patients.