The Effects of Coenzyme Q10 Supplementation on Glucose Metabolism, Lipid Profiles, Inflammation, and Oxidative Stress in Patients With Diabetic Nephropathy: A Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: Data on the effects of coenzyme Q10 (CoQ10) supplementation on glucose metabolism, lipid profiles, inflammation, and oxidative stress in subjects with diabetic nephropathy (DN) are scarce. This research was done to determine the effects of CoQ10 supplementation on metabolic status in subjects with DN. METHODS: This randomized double-blind placebo-controlled clinical trial was done in 50 subjects with DN. Participants were randomly assigned into two groups to intake either 100 mg/day CoQ10 supplements (n = 25) or placebo (n = 25) for 12 weeks. Fasting blood samples were obtained at first and after 12-week intervention to quantify metabolic profiles. RESULTS: After 12 weeks of treatment, compared with the placebo, CoQ10 supplementation resulted in significant decreases in serum insulin levels (-3.4 ± 6.8 vs +0.8 ± 6.4 µIU/mL, p = 0.02), homeostasis model of assessment-estimated insulin resistance (-1.0 ± 2.0 vs +0.2 ± 1.8, p = 0.03), homeostasis model of assessment-estimated B cell function (-12.3 ± 26.3 vs +3.5 ± 23.1, p = 0.02) and HbA1c (-1.1 ± 1.0 vs -0.1 ± 0.2%, p < 0.001), and a significant improvement in quantitative insulin sensitivity check index (+0.009 ± 0.01 vs -0.006 ± 0.01, p = 0.01). In addition, CoQ10 supplementation significantly decreased plasma malondialdehyde (MDA) (-0.6 ± 0.5 vs +0.5 ± 1.0 µmol/L, p < 0.001) and advanced glycation end products levels (AGEs) (-316.4 ± 380.9 vs +318.6 ± 732.0 AU, p < 0.001) compared with the placebo. Supplementation with CoQ10had no significant impacts on fasting plasma glucose (FPG), lipid profiles, and matrix metalloproteinase-2 (MMP-2) compared with the placebo. CONCLUSIONS: Taken together, our study demonstrated that CoQ10 supplementation for 12 weeks among DN patients had favorable effects on glucose metabolism, MDA, and AGEs levels, but unchanged FPG, lipid profiles, and MMP-2 concentrations.

The application of peroxidase mimetic nanozymes in cancer diagnosis and therapy.

In recent decades, scholarly investigations have predominantly centered on nanomaterials possessing enzyme-like characteristics, commonly referred to as nanozymes. These nanozymes have emerged as viable substitutes for natural enzymes, offering simplicity, stability, and superior performance across various applications. Inorganic nanoparticles have been extensively employed in the emulation of enzymatic activity found in natural systems. Nanoparticles have shown a strong ability to mimic a number of enzyme-like functions. These systems have made a lot of progress thanks to the huge growth in nanotechnology research and the unique properties of nanomaterials. Our presentation will center on the kinetics, processes, and applications of peroxidase-like nanozymes. In this discourse, we will explore the various characteristics that exert an influence on the catalytic activity of nanozymes, with a particular emphasis on the prevailing problems and prospective consequences. This paper presents a thorough examination of the latest advancements achieved in the domain of peroxidase mimetic nanozymes in the context of cancer diagnosis and treatment. The primary focus is on their use in catalytic cancer therapy, alongside chemotherapy, phototherapy, sonodynamic therapy, radiation, and immunotherapy. The primary objective of this work is to offer theoretical and technical assistance for the prospective advancement of anticancer medications based on nanozymes. Moreover, it is anticipated that this will foster the investigation of novel therapeutic strategies aimed at achieving efficacious tumor therapy.

Differential Effects of the Lateral Hypothalamus Lesion as an Origin of Orexin and Blockade of Orexin-1 Receptor in the Orbitofrontal Cortex and Anterior Cingulate Cortex on Their Neuronal Activity.

Introduction: Introduction: Several studies have demonstrated that orexins may regulate different forms of affective and cognitive processes during wakefulness. The Orbitofrontal Cortex (OFC) and Anterior Cingulate Cortex (ACC), as an essential part of the Prefrontal Cortex (PFC), have a crucial role in cognitive processes such as reward and decision-making. They also have a high amount of orexin receptor type 1 (OX1Rs). Methods: In the present study, we inhibited OX1Rs in this area after a 10-min baseline recording to find out the role of OX1Rs in the OFC neuron's firing rate. Next, we inhibited the lateral hypothalamus (LH) as the primary source of orexinergic neurons. Afterward, using a single-unit recording technique in rats, we detected the effects of the lateral hypothalamus on the firing rate and activity pattern of the ACC or OFC neurons. Results: Data showed that the blockade of OX1Rs in the OFC could excite 8 and inhibit 1 neuron(s) out of 11. In addition, the blockade of OX1Rs in the ACC could excite 6 and inhibit 3 neurons out of 10. LH inactivation excited 5 out of 12 neurons and inhibited 6 in the ACC. It also excited 8 and inhibited 6 neurons out of 14 in the OFC. These data suggest that the blockade of OX1Rs excites 72% of the neurons, but LH inactivation had a stimulating effect on only 50% of neurons in two main subregions of the PFC. Conclusion: Accordingly, PFC neurons may receive the orexinergic inputs from the LH and indirectly from other sources. Highlights: Blockade of orexin receptors 1 in ACC alter neural activity in this region.Blockade of orexin receptors 1 in OFC alter neural activity in this region.Lateral hypothalamus inhibition increase neural activity of only 50% neurons in ACC and OFC. Plain Language Summary: The discovery of the neuropeptide orexin/hypocretin in 1998 and subsequent research during the past 20 years revealed an important role for the lateral hypothalamus (LH) in driving the reward pathway, sleep and awake circuits, decision making and psychotic disorders. But our knowledge towards the function of this neurotransmitter on neural activity in specific areas of the brain is limited. In this study we decided to clear the specific role of orexin receptors placed in the two crucial areas of medial prefrontal cortex (mPFC) and the orexin projections from LH on neural firing rates in those regions. In the present study, we investigated the following items by using an in vivo extracellular single-unit recording technique in rats and our data shown that the effect of blocking of orexin receptors1 in mPFC caused a different results than inhibition of the origin of orexin projection in LH as a source of it.

A CB2 Receptor Agonist Reduces the Production of Inflammatory Mediators and Improves Locomotor Activity in Experimental Autoimmune Encephalomyelitis.

Background: Cannabinoids (CBs) have been found to regulate the immune system, affect innate and adaptive immune responses, and reduce inflammatory reactions. This study assessed the therapeutic effects of GW-405833 synthetic CB2 agonist on inflammatory factors as well as locomotor activity in experimental autoimmune encephalomyelitis (EAE). Methods: In this experimental study, 48 adult male C57BL/6 mice were randomly and equally assigned to eight groups. By injecting 250 mg of MOG35-55 peptide, EAE was induced. Every other day for 17 days after EAE onset, EAE-afflicted mice in groups 1-3 received an intraperitoneal injection of GW-405833 at a dose of 3, 10, and 30 mg/kg, respectively. Clinical status and locomotor activity, measured using the beam walking assay, were assessed every other day during the first 17 days after EAE onset. Mice were euthanized in day 17th of treatment and the serum levels of the IL-1ß, IL-12, CRP, and TNF-α proinflammatory cytokines as well as IL-4 and TGF-ß anti-inflammatory cytokines were measured by ELISA method. Results: Clinical manifestations of EAE in groups 2 and 3 were significantly milder than group 4 and locomotor activity in groups 1-3 was significantly better than group 4 in days 5-17 (p< 0.05). GW-405833 also significantly decreased the levels of IL-12, TNF-α, and CRP and significantly increased the levels of IL-4 and TGF-ß but had no significant effects on the level of IL-1ß. GW-405833 was not associated with significant side effects. Conclusion: The CB2 receptor agonist GW-405833, improves clinical conditions and reduces inflammation in mice with EAE.

Gamma-radiated immunosuppressed tumor xenograft mice can be a new ideal model in cancer research.

Tumor xenograft models can create a high capacity to study human tumors and discover efficient therapeutic approaches. Here, we aimed to develop the gamma-radiated immunosuppressed (GIS) mice as a new kind of tumor xenograft model for biomedical studies. First, 144 mice were divided into the control and treated groups exposed by a medical Cobalt-60 apparatus in 3, 4, and 5 Gy based on the system outputs. Then, 144 BALB/c mice were divided into four groups; healthy, xenograft, radiation, and radiation + xenograft groups. The animals in the xenograft and radiation + xenograft groups have subcutaneously received 3 × 106 MCF-7 cells 24 h post-radiation. On 3, 7, 14, and 21 days after cell injection, the animals were sacrificed. Then, the blood samples and the spleen and tumor tissues were removed for the cellular and molecular analyses. The whole-body gamma radiation had a high immunosuppressive effect on the BALB/c mice from 1 to 21 days post-radiation. The macroscopic and histopathological observations have proved that the created clusters' tumor structure resulted in the xenograft breast tumor. There was a significant increase in tumor size after cell injection until the end of the study. Except for Treg, the spleen level of CD4, CD8, CD19, and Ly6G was significantly decreased in Xen + Rad compared to the Xen alone group on 3 and 7 days. Unlike IL-4 and IL-10, the spleen level of TGF-ß, INF-γ, IL-12, and IL-17 was considerably decreased in the Xen + Rad than the Xen alone group on 3 and 7 days. The spleen expressions of the VEGF, Ki67, and Bax/Bcl-2 ratio were dramatically increased in the Xen + Rad group compared to the Xen alone on 3, 7, 14, and 21 days. Our results could confirm a new tumor xenograft model via an efficient immune-suppressive potential of the whole-body gamma radiation in mice.

Probiotic supplementation improves the cognitive function and the anxiety-like behaviors in the stressed rats.

OBJECTIVES: Prenatal stresses increase incidence of neurodevelopmental disorders and influence cognitive abilities. Glucocorticoids are released in stress condition as endpoint activation of hypothalamus-pituitary-adrenal (HPA) axis. Evidence indicates a cross-talk between gut microbiota and brain function. This study assesses the effect of probiotic supplementation on behavioral functionand HPA axis action in stressed rats. MATERIALS AND METHODS: The young rats born from dams exposed to noise stress (ST) during third trimester of pregnancy were used. Two groups of stressed animals were received a two-week probiotic supplementation before (pre-ST) and after (post-ST) birth. The time and distance to find hidden platform in Morris water maze were evaluated as spatial memory. Also entry to open arms in elevated plus-maze was considered as anxiety-like behaviors. The serum level of corticosterone was measured as the HPA axis function. RESULTS: While the stressed rats decreased entries to open arms to one third compared to the controls (CON) the probiotic treatment increased the entries by two times. The ST rats required more time and distance to find the platform than did the CON animals. The pre- and post-ST rats significantly restored the impaired behavior almost near the CON ones. While the serum corticosterone concentration increased by 50% in the ST rats it was reduced to almost normal level in the pre- and post-ST rats. CONCLUSION: Our findings confirmed a link between the gut microbiome and probiotics with the behavioral functions and HPA axis. The probiotic treatment favorably affected the stress-dependent behavioral disorders and the interaction between HPA and gut-brain-microbiota axes.

Corrigendum: Does Severity of Alzheimer's Disease Contribute to Its Responsiveness to Modifying Gut Microbiota? A Double Blind Clinical Trial.

[This corrects the article DOI: 10.3389/fneur.2018.00662.].

Does Severity of Alzheimer's Disease Contribute to Its Responsiveness to Modifying Gut Microbiota? A Double Blind Clinical Trial.

Alzheimer's disease (AD) is associated with cognitive dysfunction. Evidence indicates that gut microbiota is altered in the AD and, hence, modifying the gut flora may affect the disease. In the previous clinical research we evaluated the effect of a probiotic combination on the cognitive abilities of AD patients. Since, in addition to pathological disorders, the AD is associated with changes in oxidant/antioxidant and inflammatory/anti-inflammatory biomarkers, the present work was designed to evaluate responsiveness of the inflammatory and oxidative biomarkers to the probiotic treatment. The control (CON) and probiotic (PRO) AD patients were treated for 12 weeks by the placebo and probiotic supplementation, respectively. The patients were cognitively assessed by Test Your Memory (TYM = 50 scores). Also serum concentrations of nitric oxide (NO), glutathione (GSH), total antioxidant capacity (TAC), malondialdehyde (MDA), 8-hydroxy-2' -deoxyguanosine (8-OHdG) and cytokines (TNF-a, IL-6, and IL-10) were measured. The cognitive test and the serum biomarkers were assessed pre- and post-treatment. According to TYM test 83.5% of the patients showed severe AD. The CON (12.86% ± 8.33) and PRO (-9.35% ± 16.83) groups not differently scored the cognitive test. Not pronounced change percent was found in the serum level of TNF-α (1.67% ± 1.33 vs. -0.15% ± 0.27), IL-6 (0.35% ± 0.17 vs. 2.18% ± 0.15), IL-10 (0.05% ± 0.10 vs. -0.70% ± 0.73), TAC (0.07% ± 0.07 and -0.06% ± 0.03), GSH (0.08% ± 0.05 and 0.04% ± 0.03) NO (0.11% ± 0.06 and 0.05% ± 0.09), MDA (-0.11% ± 0.03 and -0.17% ± 0.03), 8-OHdG (43.25% ± 3.01 and 42.70% ± 3.27) in the CON and PRO groups, respectively. We concluded that the cognitive and biochemical indications in the patients with severe AD are insensitive to the probiotic supplementation. Therefore, in addition to formulation and dosage of probiotic bacteria, severity of disease and time of administration deeply affects results of treatment.

Co-administration of MK-801 and morphine attenuates neuropathic pain in rat.

Partial peripheral nerve injury often leads to chronic pain states, including allodynia and hyperalgesia. The purpose of this study was to investigate the involvement of the N-methyl-D-aspartate and opioid receptors in the behavioural responses following chronic constriction nerve injury (CCI). The animals were injected a combination of MK-801 (0.3 mg/kg, 20 min before, and 6 h after the operation) and morphine (8 mg/kg, 30 min prior to the operation) and were tested for allodynia and hyperalgesia reactions at 0, 3, 7, 14, 21 and 28 days after CCI. Compound action potentials were also recorded from the injured nerve 2 weeks post-operation to indicate nerve injury state electrophysiologically. Our results indicate that the CCI model importantly influences the behavioural responses to both the thermal and mechanical stimulations. Also, the pre-emptive co-administration of MK-801 and morphine has suppressive effects on the cold allodynia but a slight alleviation on the mechano-allodynia and heat hyperalgesia.

Effect of Probiotic Supplementation on Cognitive Function and Metabolic Status in Alzheimer's Disease: A Randomized, Double-Blind and Controlled Trial.

Alzheimer's disease (AD) is associated with severe cognitive impairments as well as some metabolic defects. Scant studies in animal models indicate a link between probiotics and cognitive function. This randomized, double-blind, and controlled clinical trial was conducted among 60 AD patients to assess the effects of probiotic supplementation on cognitive function and metabolic status. The patients were randomly divided into two groups (n = 30 in each group) treating with either milk (control group) or a mixture of probiotics (probiotic group). The probiotic supplemented group took 200 ml/day probiotic milk containing Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum (2 × 109 CFU/g for each) for 12 weeks. Mini-mental state examination (MMSE) score was recorded in all subjects before and after the treatment. Pre- and post-treatment fasting blood samples were obtained to determine the related markers. After 12 weeks intervention, compared with the control group (-5.03% ± 3.00), the probiotic treated (+27.90% ± 8.07) patients showed a significant improvement in the MMSE score (P <0.001). In addition, changes in plasma malondialdehyde (-22.01% ± 4.84 vs. +2.67% ± 3.86 µmol/L, P <0.001), serum high-sensitivity C-reactive protein (-17.61% ± 3.70 vs. +45.26% ± 3.50 µg/mL, P <0.001), homeostasis model of assessment-estimated insulin resistance (+28.84% ± 13.34 vs. +76.95% ± 24.60, P = 0.002), Beta cell function (+3.45% ± 10.91 vs. +75.62% ± 23.18, P = 0.001), serum triglycerides (-20.29% ± 4.49 vs. -0.16% ± 5.24 mg/dL, P = 0.003), and quantitative insulin sensitivity check index (-1.83 ± 1.26 vs. -4.66 ± 1.70, P = 0.006) in the probiotic group were significantly varied compared to the control group. We found that the probiotic treatment had no considerable effect on other biomarkers of oxidative stress and inflammation, fasting plasma glucose, and other lipid profiles. Overall, the current study demonstrated that probiotic consumption for 12 weeks positively affects cognitive function and some metabolic statuses in the AD patients. CLINICAL TRIAL REGISTRATION: http://www.irct.ir/, IRCT201511305623N60.

Gabapentin enhances anti-nociceptive effects of morphine on heat, cold, and mechanical hyperalgesia in a rat model of neuropathic pain.

OBJECTIVES: Neuropathic pain is caused by lesions or diseases affecting the somatosensory system and often responds poorly to typical medications. In this study, we evaluated anti-nociceptive effects of morphine, gabapentin and their combination on heat hyperalgesia, cold and mechanical allodynia in chronic constriction injury (CCI) model of neuropathic pain in rats. MATERIALS AND METHODS: Morphine (2, 4 and 8 mg/kg) and gabapentin (5, 10 and 20 mg/kg) were administered either alone or in combination (morphine 2 mg/kg and gabapentin 5 mg/kg). RESULTS: Our results showed that morphine and gabapentin alone produce anti-nociceptive effects at higher doses (morphine 4 and 8 mg/kg and gabapentin 10 and 20 mg/kg) whereas their combination resulted in better analgesia at lower doses as compared to other treatment groups (morphine 2 mg/kg or gabapentin 5 mg/kg). CONCLUSION: These findings suggest that gabapentin potentiates the analgesic effects of morphine in the chronic constriction injury (CCI) model of neuropathic pain and combination of these drugs may be considered as a beneficial treatment for neuropathic pain.

Alterations in nitric oxide synthase-expressing neurons in the forebrain regions of rats after developmental exposure to organophosphates.

Several mechanisms have been addressed as contributors to the long lasting behavioral deficits after developmental exposure to organophosphate (OP) compounds. Here, the effects of developmental exposure to two common OP insecticides, chlorpyrifos (CPF) and diazinon (DZN), on nitric oxide synthase (NOS)-expressing neurons in the rat forebrain are reported. A daily dose of 1mg/kg of either CPF or DZN was administered to rats during gestational days 15-18 or postnatal days (PND) 1-4. We then assessed NADPH-diaphorase and neuronal NOS (nNOS) immunohistochemistry in forebrain sections on different postnatal days. Prenatal exposure to CPF and DZN induced a transient reduction of NADPH-d(+)/nNOS-immunoreactive (IR) neurons in most cortical regions on PND 4 but exceptionally increased them in the entorhinal/piriform cortex. On PND 15, NADPH-d(+)/nNOS-IR neurons showed morphological abnormalities within entorhinal/piriform cortex of the rats that gestationally exposed to CPF. Postnatal exposure to CPF and DZN did not induce widespread effects on the number of NADPH-d(+)/nNOS-IR neurons on PNDs 7 and 15 but significantly reduced them in most cortical regions and hippocampal subfields on PND 60. The OPs affected NADPH-d(+)/nNOS-IR neurons in a sex independent manner and apparently spared them in the striatum. While the NADPH-d reactivity of microvessels was normally diminished by age, OP treated rats evidently preserved the NADPH-d reactivity of microvessels in the cerebral cortex and hippocampus. The effects of OPs on NADPH-d(+)/nNOS-IR neurons may contribute to the long-lasting behavioral outcomes and expand the neurotransmitter system that need to be considered in OP neurotoxicity evaluations.

Prolonged hyperoxia preconditioning attenuates behavioral symptoms of 6-hydroxydopamine-induced Parkinsonism.

OBJECTIVES: Several lines of evidences show that hyperoxia preconditioning provides neuronal protection against central nervous system ischemic damages. Common pathways including mitochondrial dysfunction, apoptosis, and caspase activation are involved in acute neurodegeneration (e.g. after cerebral ischemia) and chronic neurodegeneration (e.g. neuronal death in Parkinson's disease). The aim of the present research was to study the effect of hyperoxia preconditioning on 6-hydroxydopamine (6-OHDA)-induced Parkinsonism. METHODS: Male Wistar rats were first subjected to either air with high oxygen concentration (>90%) or atmospheric air for prolonged (24 hours) or intermittent (six consecutive days, 4 hours each day) periods and then 6-OHDA was injected into their left striatums by stereotaxic surgery. Development and severity of the 6-OHDA-induced Parkinsonism was assessed using apomorphine-induced rotational test, elevated body swing test, and rotarod test within 2-5 weeks after the surgery. RESULTS: Significant data obtained in rats treated with prolonged hyperoxia, but not the intermittent hyperoxia. In these rats, the number of apomorphine-induced rotations was ∼60% lower than that in control and sham groups. Rats belonging to the prolonged hyperoxia group also showed considerably better motor performance and learning pattern in rotarod test. These results were confirmed by the data obtained in the elevated body swing test. DISCUSSION: Our findings show that the prolonged hyperoxia preconditioning attenuates the behavioral symptoms of 6-OHDA-induced Parkinsonism. Considering the well-known correlation between dopaminergic neuronal death in the substantia nigra and the behavioral symptoms of 6-OHDA-induced Parkinsonism, it could be speculated that the prolonged hyperoxia preconditioning induces the mechanisms that provide dopaminergic neuroprotection against Parkinsonism-induced toxins.

Ethosuximide reduces allodynia and hyperalgesia and potentiates morphine effects in the chronic constriction injury model of neuropathic pain.

Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system and treatment of neuropathic pain remains a challenge. The purpose of the present study was to examine the effect of ethosuximide, an anti-epileptic and relatively selective T-type calcium blocker and morphine, a prototypical opioid in the behavioral responses following the chronic constriction injury (CCI) model of neuropathic pain. Experiments were performed on eight groups (n=8) of male Sprague-Dawley rats (230-280 g). The animals were injected with saline, ethosuximide (100, 200, 300 mg/kg), morphine (4 mg/kg), and a combination of morphine (4 mg/kg) plus ethosuximide (100mg/kg, i.p.). The cold-and mechano-allodynia and thermal hyperalgesia were measured prior to surgery (the day 0) and 3, 5, 7, 14 and 21 days post surgery. Ethosuximide and morphine significantly decreased cold and mechano allodynia and thermal hyperalgesia. However, the co-administration of both drugs seems to be more effective than the ethosuximide or morphine alone on cold and mechano allodynia and thermal hyperalgesia .Our results suggest that ethosuximide block tactile and thermal hypersensitivity after the CCI model, also, ethosuximide potentiates the analgesic effects of morphine in neuropathic pain conditions and behavioral responses.