Therapeutic effects of Coriandrum sativum extracts:A review

Medicinal plants,as a good therapeutic strategy,can be used to treat a wide spectrum of diseases.Coriandrum sativum(C.sativum)is a plant from Apiaceae family.Numerous reports indicate that C.sativum has positive effects on anxiety,seizure,learning and memory ability,as well as pain.This annual plant can also treat colitis,increase appetite,reduce blood pressure,and attenuate myocardial damage.Additionally,it improves liver and kidney function and diabetes mellitus and inhibits osteoclast activity.These beneficial effects of C.sativum mainly are attributed to its antioxidant and anti-inflammatory properties.The present paper reviews the impacts of C.sativum on different body systems.Information was extracted by searching the Web of Science,PubMed,Scopus,and Google Scholar from January 2010 until the end of February 2024.

TonEBP expression is essential in the IL-1β–induced migration and invasion of human A549 lung cancer cells

Lung cancer has the highest mortality rate among all cancers,in part because it readily metastasizes.The tumor microenvironment,comprising blood vessels,fibroblasts,immune cells,and macrophages[including tumor-associated macrophages(TAMs)],is closely related to cancer cell growth,migration,and invasion.TAMs secrete several cytokines,including interleukin(IL)-1β,which participate in cancer migration and invasion.p21-activated kinase 1(PAK1),an important signaling molecule,induces cell migration and invasion in several carcinomas.Tonicityresponsive enhancer-binding protein(TonEBP)is also known to participate in cancer cell growth,migration,and invasion.However,the mechanisms by which it increases lung cancer migration remain unclear.Therefore,in this study,we aimed to elucidate the mechanisms by which IL-1βand TonEBP affect lung cancer cell migration and invasion.We found that A549 cocultured-MΦ-secreted IL-1βinduced A549 cell migration and invasion via the PAK1 pathway.TonEBP deficiency reduced A549 cell migration and invasion and increased responsiveness to IL-1β–induced migration and invasion.PAK1 phosphorylation,which was promoted by IL-1β,was reduced when TonEBP was depleted.These results suggest that TonEBP plays an important role in IL-1βinduction and invasiveness of A549 cells via the PAK1 pathway.These findings could be valuable in identifying potential targets for lung cancer treatment.

The emerging role of mesenchymal stem cell-derived extracellular vesicles to ameliorate hippocampal NLRP3 inflammation induced by binge-like ethanol treatment in adolescence

Our previous studies have reported that activation of the NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain damage.Mesenchymal stem cell-derived extracellular vesicles(MSC-EVs)have been shown to restore the neuroinflammatory response,along with myelin and synaptic structural alterations in the prefrontal cortex,and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent mice.Considering the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles,the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue,which inhibited the activation of the NLRP3 inflammasome,was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking.We demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes(e.g.,pyrin domain-containing 1,caspase recruitment domain-containing 4,and absent in melanoma 2,as well as the alterations in inflammatory genes(interleukin-1β,interleukin-18,inducible nitric oxide synthase,nuclear factor-kappa B,monocyte chemoattractant protein-1,and C–X3–C motif chemokine ligand 1)and miRNAs(miR-21a-5p,miR-146a-5p,and miR-141-5p)induced by binge-like ethanol treatment in adolescent mice.Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways.Taken together,these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.

Role of the globus pallidus in motor and non-motor symptoms of Parkinson's disease

The globus pallidus plays a pivotal role in the basal ganglia circuit. Parkinson's disease is characterized by degeneration of dopamine-producing cells in the substantia nigra, which leads to dopamine deficiency in the brain that subsequently manifests as various motor and non-motor symptoms. This review aims to summarize the involvement of the globus pallidus in both motor and non-motor manifestations of Parkinson's disease. The firing activities of parvalbumin neurons in the medial globus pallidus, including both the firing rate and pattern, exhibit strong correlations with the bradykinesia and rigidity associated with Parkinson's disease. Increased beta oscillations, which are highly correlated with bradykinesia and rigidity, are regulated by the lateral globus pallidus. Furthermore,bradykinesia and rigidity are strongly linked to the loss of dopaminergic projections within the cortical-basal ganglia-thalamocortical loop. Resting tremors are attributed to the transmission of pathological signals from the basal ganglia through the motor cortex to the cerebellum-ventral intermediate nucleus circuit. The cortico–striato–pallidal loop is responsible for mediating pallidi-associated sleep disorders. Medication and deep brain stimulation are the primary therapeutic strategies addressing the globus pallidus in Parkinson's disease. Medication is the primary treatment for motor symptoms in the early stages of Parkinson's disease, while deep brain stimulation has been clinically proven to be effective in alleviating symptoms in patients with advanced Parkinson's disease,particularly for the movement disorders caused by levodopa. Deep brain stimulation targeting the globus pallidus internus can improve motor function in patients with tremordominant and non-tremor-dominant Parkinson's disease, while deep brain stimulation targeting the globus pallidus externus can alter the temporal pattern of neural activity throughout the basal ganglia–thalamus network. Therefore, the composition of the globus pallidus neurons, the neurotransmitters that act on them, their electrical activity,and the neural circuits they form can guide the search for new multi-target drugs to treat Parkinson's disease in clinical practice. Examining the potential intra-nuclear and neural circuit mechanisms of deep brain stimulation associated with the globus pallidus can facilitate the management of both motor and non-motor symptoms while minimizing the side effects caused by deep brain stimulation.

Therapeutic potential of Zataria multiflora:A narrative review of current evidence

Zataria multiflora Boiss is a perennial plant with a wide spectrum of biological and pharmacological activities including antidiabetic,antinociceptive,anti-asthmatic,anti-fever,anti-spastic,anti-oxidative,anti-inflammatory,and antimicrobial properties.This paper reviews the therapeutic effects of Zataria multiflora based on recent reports.The relevant reports were extracted by checking the electronic databases including PubMed,Scopus,Web of Science,and Google Scholar from the beginning of 2010 until the end of May 2023.The neuroprotective effects of Zataria multiflora can be attributed to inhibition of acetylcholinesterase,enhancement of brain-derived neurotrophic factor,and alleviation of brain oxidative damage.Zataria multiflora also exerts its protective effects on the respiratory system,liver,and kidney by reducing the level of inflammatory cytokines,scavenging the free radicals,and augmenting the antioxidant enzymes.Additionally,Zataria multiflora accelerates wound healing via upregulating transforming growth factor-β,insulin-like growth factor 1,fibroblast growth factor 2,and vascular endothelial growth factor,and inducing angiogenesis and collagen biosynthesis.Overall,the protective impacts of Zataria multiflora on different organs are mainly attributed to its antioxidant and antiinflammatory properties.

Effectiveness of high intensity interval training on cardiorespiratory fitness and endothelial function in type 2 diabetes:A systematic review

BACKGROUND Type 2 diabetes mellitus(T2DM)is a chronic metabolic syndrome characterized by insulin resistance and hyperglycemia that may lead to endothelial dysfunction,reduced functional capacity and exercise intolerance.Regular aerobic exercise has been promoted as the most beneficial non-pharmacological treatment of cardiovascular diseases.High intensity interval training(HIIT)seems to be superior than moderate-intensity continuous training(MICT)in cardiovascular diseases by improving brachial artery flow-mediated dilation(FMD)and cardiorespiratory fitness to a greater extent.However,the beneficial effects of HIIT in patients with T2DM still remain under investigation and number of studies is limited.AIM To evaluate the effectiveness of high intensity interval training on cardiorespiratory fitness and endothelial function in patients with T2DM.METHODS We performed a search on PubMed,PEDro and CINAHL databases,selecting papers published between December 2012 and December 2022 and identified published randomized controlled trials(RCTs)in the English language that included community or outpatient exercise training programs in patients with T2DM.RCTs were assessed for methodological rigor and risk of bias via the Physiotherapy Evidence Database(PEDro).The primary outcome was peak VO_(2 ) and the secondary outcome was endothelial function assessed either by FMD or other indices of microcirculation.RESULTS Twelve studies were included in our systematic review.The 12 RCTs resulted in 661 participants in total.HIIT was performed in 310 patients(46.8%),MICT to 271 and the rest 80 belonged to the control group.Peak VO_(2 ) increased in 10 out of 12 studies after HIIT.Ten studies compared HIIT with other exercise regimens(MICT or strength endurance)and 4 of them demonstrated additional beneficial effects of HIIT over MICT or other exercise regimens.Moreover,4 studies explored the effects of HIIT on endothelial function and FMD in T2DM patients.In 2 of them,HIIT further improved endothelial function compared to MICT and/or the control group while in the rest 2 studies no differences between HIIT and MICT were observed.CONCLUSION Regular aerobic exercise training has beneficial effects on cardiorespiratory fitness and endothelial function in T2DM patients.HIIT may be superior by improving these parameters to a greater extent than MICT.

Zataria multiflora and its constituent,carvacrol,counteract sepsis-induced aortic and cardiac toxicity in rat:Involvement of nitric oxide and oxidative stress

Background:Zataria multiflora and carvacrol showed various pharmacological prop-erties including anti-inflammatory and anti-oxidant effects.However,up to now no studies have explored its potential benefits in ameliorating sepsis-induced aortic and cardiac injury.Thus,this study aimed to investigate the effects of Z.multiflora and carvacrol on nitric oxide(NO)and oxidative stress indicators in lipopolysaccharide(LPS)-induced aortic and cardiac injury.Methods:Adult male Wistar rats were assigned to:Control,lipopolysaccharide(LPS)(1 mg/kg,intraperitoneal(i.p.)),and Z.multiflora hydro-ethanolic extract(ZME,50–200 mg/kg,oral)-and carvacrol(25–100 mg/kg,oral)-treated groups.LPS was in-jected daily for 14 days.Treatment with ZME and carvacrol started 3 days before LPS administration and treatment continued during LPS administration.At the end of the study,the levels of malondialdehyde(MDA),NO,thiols,and antioxidant enzymes were evaluated.Results:Our findings showed a significant reduction in the levels of superoxide dis-mutase(SOD),catalase(CAT),and thiols in the LPS group,which were restored by ZME and carvacrol.Furthermore,ZME and carvacrol decreased MDA and NO in car-diac and aortic tissues of LPS-injected rats.Conclusions:The results suggest protective effects of ZME and carvacrol on LPS-induced cardiovascular injury via improved redox hemostasis and attenuated NO pro-duction.However,additional studies are needed to elucidate the effects of ZME and its constituents on inflammatory responses mediated by LPS.

Activation of Nrf2 alleviates Parkinson’s disease-like pathology:a new strategy targeting the C/EBPβ/α-Syn pathway

Parkinson’s disease(PD)is a prevalent neurological disorder around the globe,currently affecting over 6 million people globally[1].It is estimated that by 2040,this number may double to more than 12 million[2].Aging is strongly associated with PD,as it is a significant risk factor for its development[3].Clinically,PD presents with various motor and non-motor signs.Movement-related issues mainly consist of slowed motion,involuntary shaking at rest,stiff muscles,and balance difficulties.At the same time,non-movement-related issues include impaired sense of smell,sleep disturbances,bowel irregularities,feelings of sadness,and problems with the body’s automatic functions[4].The typical pathological features of PD patients include the gradual loss of dopaminergic neurons within the substantia nigra pars compacta,coupled with the buildup ofα-synuclein(α-Syn)in neurons,the aggregates of which form inclusions known as Lewy bodies[5].The A53T mutant of humanα-Syn has a propensity to aggregate,a characteristic closely associated with the neurotoxicity seen in familial PD[6].A synthesis of both in vitro and in vivo research indicates that the misfolding and aggregation ofα-Syn are key pathogenic mechanisms in the development of PD[7-9].

Analgesic Efficacy of Intrathecal Bupivacaine with or without Morphine in Lower Limb Orthopedic Surgery. A Comparative Study

Background: Lower limb orthopaedic surgeries are commonly associated with moderate to severe postoperative pain. Adequate pain relief is essential for patients undergoing such procedures, as uncontrolled pain can lead to delayed recovery, prolonged hospitalization, and increased morbidity. Intrathecal administration of bupivacaine, a long-acting local anesthetic, has been shown to provide effective analgesia after lower limb orthopaedic surgery. However, the duration of analgesia with bupivacaine alone is limited, and the addition of an opioid, such as morphine, can prolong the duration of analgesia. Objective: The objective of this study was to document the comparative effect of adding morphine to intrathecal bupivacaine or only intrathecal bupivacaine for lower limb trauma orthopedic surgeries in terms of onset of action, duration of analgesia, pain severity, and side effects. Methods: This was a comparative longitudinal study design conducted at the Orthopaedic Unit of the Tamale Teaching Hospital. A simple random sampling technique was used to recruit 60 patients. A standard structured questionnaire was also used to collect data on the socio-demographics, and clinical features of patients, drug used,side effects and severity of pain at 24,48 and 72 hrs after surgery. Results: Co-administration of intrathecal bupivacaine with morphine produced good and long-lasting postoperative analgesia with a mean time of 1004.25 ± 310.43 minutes, whiles using only bupivacaine produced shorter postoperative analgesia with a mean time of 294.75 ± 195.53 minutes. The p-value p values of p = 0.635 and p = 0.689 respectively. Conclusion: The study revealed that co-administration of intrathecal bupivacaine with morphine emerged as a better option for postoperative pain management after lower limb orthopedic surgeries as compared to administering only bupivacaine regarding the duration of analgesia. Milder side effects like pruritus, nausea, and vomiting were seen in group B than in group A and were promptly well managed to the patient’s satisfaction.

Exosomes as mediators of neuron-glia communication in neuroinflammation

In recent years,a type of extracellular vesicles named exosomes has emerged that play an important role in intercellular communication under physiological and pathological conditions.These nanovesicles (30–150 nm) contain proteins,RNAs and lipids,and their internalization by bystander cells could alter their normal functions.This review focuses on recent knowledge about exosomes as messengers of neuron-glia communication and their participation in the physiological and pathological functions in the central nervous system.Special emphasis is placed on the role of exosomes under toxic or pathological stimuli within the brain,in which the glial exosomes containing inflammatory molecules are able to communicate with neurons and contribute to the pathogenesis of neuroinflammation and neurodegenerative disorders.Given the small size and characteristics of exosomes,they can cross the blood-brain barrier and be used as biomarkers and diagnosis for brain disorders and neuropathologies.Finally,although the application potential of exosome is still limited,current studies indicate that exosomes represent a promising strategy to gain pathogenic information to identify therapeutically targets and biomarkers for neurological disorders and neuroinflammation.

Effects of progesterone on gastric emptying and intestinal transit in male rats

瞄准：在胃肠的活动性上学习在后叶催产素(OT ) 和 P 之间的孕酮(P) 效果和相互作用的剂量依赖者。方法：以便监视胃的倒空和肠的运输， SD 雄的老鼠与正常经由一根导管被把管子插进盐(3 ml/kg ) 包含 Na (2 )(51 ) CrO (4 )(0.5 microCi/ml ) 和 10% 炭。OT 被溶解进盐的正常， P 被溶解进 75% 酒精。结果：低 P 做(1 mg/kg， i.p ) 提高了胃的倒空(75+/-3% ， P【0.05 ) 并且 P 的高剂量(5 mg/kg， i.p ) 禁止它(42+/-11.2% ， P【0.01 ) 。P (1 mg/kg ) 增加了肠的运输(4.2+/-0.3， P【0.05 ) 当更高的剂量(10-20 mg/kg ) 没有效果时。OT (0.8 mg/kg， i.p ) 禁止了胃的倒空(23.5+/-9.8% ， P【0.01 ) 。P (20 mg/kg ) 的禁止的效果(32+/-9.7% ， P【0.05 ) 并且当二化学药品同时被管理时，胃的倒空上的 OT (0.8 mg/kg ) 提高了对方(17+/-9.4% ， P【0.01 ) 。结论：当 P 的高剂量减少了时， P 的低剂量增加了官方补给的活动性它。在怀孕的以后的时期期间，提高了 OT 的血浆水平可以也参予胃肠的抑制。

Engagement of circular RNA HECW2 in non-autophagic role of ATG5 implicated in endothelial-mesenchymal transition

Endothelial-mesenchymal transition(EndoMT) is associated with damage to blood-brain barrier(BBB) integrity.Circular RNAs(circRNAs) are highly expressed in the brain and are involved in brain diseases;however,whether circR NAs regulate the EndoM T in the brain remains unknown.Our study demonstrated that circH ECW2 regulated the EndoM T by directly binding to MIR30 D,a significantly downregulated miR NA from miR NA profiling,which subsequently caused an increased expression of ATG5.These findings shed new light on the understanding of the noncanonical role of ATG5 in the EndoMT induced by methamphetamine or lipopolysaccharide.The in vivo relevance was confirmed as microinjection of circHecw2 siRNA lentivirus into the mouse hippocampus suppressed the EndoMT induced by LPS.These findings provide novel insights regarding the contribution of circHECW2 to the nonautophagic role of ATG5 in the EndoMT process in the context of drug abuse and the broad range of neuroinflammatory disorders.

A dysfunction of CD4^+ T lymphocytes in peripheral immune system of Parkinson's disease model mice

Objective Parkinson's disease(PD),a neurodegenerative disorder,has been reported to be associated with brain neuroinflammation in its pathogenesis.Herein,changes in peripheral immune system were determined to better understand PD pathogenesis and provide possible target for treatment of PD through improvement of immune disorder.Methods l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine(MPTP) was intraperitoneally injected into mice to prepare PD model.Expression levels of pro-inflammatory and anti-inflammatory cytokines and transcription factors of CD4^+ T lymphocyte subsets in spleen and mesenteric lymph nodes and concentrations of the cytokines in serum were examined on day 7 after MPTP injection.Percentages of CD4^+ T lymphocyte subsets were measured by flow cytometry.Results MPTP induced PD-like changes such as motor and behavioral deficits and nigrostriatal impairment.Expression levels of the pro-inflammatory cytokines including interferon(IFN)-γ,interleukin(IL)-2,IL-17 and IL-22,in spleen and mesenteric lymph nodes were upregulated and their concentrations in serum were elevated in PD progression.But,the concentrations of the anti-inflammatory cytokines including IL-4,IL-10 and transforming growth factor(TGF)-β were not altered in the two lymphoid tissues or serum of PD mice.In addition,expression of T-box in T cells(T-bet),the specific transcription factor of helper T(Th) 1 cells,was downregulated,but expression of transcription factor forkhead box p3(Foxp3),the transcription factor of regulatory T(Treg) cells,was upregulated.In support of the results,the numbers of IFN-γ^+-producing CD4^+cells(Th1 cells) were reduced but CD4^+CD25^+ cells(Treg cells) were elevated in both the lymphoid tissues of PD mice.Conclusion PD has a dysfunction of peripheral immune system.It manifests enhancement of proinflammatory response and CD4^+T cell differentiation bias towards Treg cells away from Thl cells.

Effects of exercise on neurogenesis in the dentate gyrus and ability of learning and memory after hippocampus lesion in adult rats

Objective To explore the effects of exercise on dentate gyrus (DG) neurogenesis and the ability of learning and memory in hippocampus-lesioned adult rats. Methods Hippocampus lesion was produced by intrahippocampal microinjection of kainic acid (KA). Bromodeoxyuridine (BrdU) was used to label dividing cells. Y maze test was used to evaluate the ability of learning and memory. Exercise was conducted in the form of forced running in a motor-driven running wheel. The speed of wheel revolution was regulated at 3 kinds of intensity: lightly running, moderately running, or heavily running. Results Hippocampus lesion could increase the number of BrdU-labeled DG cells, moderately running after lesion could further enhance the number of BrdU-labeled cells and decrease the error number (EN) in Y maze test, while neither lightly running, nor heavily running had such effects. There was a negative correlation between the number of DG BrdU-labeled cells and the EN in the Y maze test after running. Conclusion Moderate exercise could enhance the DG neurogenesis and ameliorate the ability of learning and memory in hippocampus-lesioned rats.

Effects of resveratrol on hydrogen peroxide-induced oxidative stress in embryonic neural stem cells

Resveratrol, a natural phenolic compound, has been shown to prevent cardiovascular diseases and cancer and exhibit neuroprotective effects. In this study, we examined the neuroprotective and antJoxJdant effects of resveratrol against hydrogen peroxide in embryonic neural stem cells. Hydrogen peroxide treatment alone increased catalase and glutathione peroxidase activities but did not change superoxide dismutase levels compared with hydrogen peroxide ＋ resveratrol treatment. Nitric oxide synthase activity and concomitant nitric oxide levels increased in response to hydrogen peroxide treatment. Conversely, resveratrol treatment decreased nitric oxide synthase activity and nitric oxide levels. Resveratrol also attenuated hydrogen peroxide-induced nuclear or mitochondrial DNA damage. We propose that resveratrol may be a promising agent for protecting embryonic neural stem cells because of its potential to decrease oxidative stress by inducing higher activity of antioxidant enzymes, decreasing nitric oxide production and nitric oxide synthase activity, and alleviating both nuclear and mitochondrial DNA damage.

Interleukin 17A deficiency alleviates neuroinflammation and cognitive impairment in an experimental model of diabetic encephalopathy

Interleukin 17A(IL-17A)was previously shown to be a key pro-inflammatory factor in diabetes mellitus and associated complications.However,the role of IL-17A in diabetic encephalopathy remains poorly understood.In this study,we established a mouse model of diabetic encephalopathy that was deficient in IL-17A by crossing Il17a-/-mice with spontaneously diabetic Ins2^(Akita)(Akita)mice.Blood glucose levels and body weights were monitored from 2-32 weeks of age.When mice were 32 weeks of age,behavioral tests were performed,including a novel object recognition test for assessing short-term memory and learning and a Morris water maze test for evaluating hippocampus-dependent spatial learning and memory.IL-17A levels in the serum,cerebrospinal fluid,and hippocampus were detected with enzyme-linked immunosorbent assays and real-time quantitative polymerase chain reaction.Moreover,proteins related to cognitive dysfunction(amyloid precursor protein,β-amyloid cleavage enzyme 1,p-tau,and tau),apoptosis(caspase-3 and-9),inflammation(inducible nitric oxide synthase and cyclooxygenase 2),and occludin were detected by western blot assays.Pro-inflammatory cytokines including tumor necrosis factor-α,interleukin-1β,and interferon-γin serum and hippocampal tissues were measured by enzyme-linked immunosorbent assays.Microglial activation and hippocampal neuronal apoptosis were detected by immunofluorescent staining.Compared with that in wild-type mice,mice with diabetic encephalopathy had higher IL-17A levels in the serum,cerebrospinal fluid,and hippocampus;downregulation of occludin expression;lower cognitive ability;greater loss of hippocampal neurons;increased microglial activation;and higher expression of inflammatory factors in the serum and hippocampus.IL-17A knockout attenuated the abovementioned changes in mice with diabetic encephalopathy.These findings suggest that IL-17A participates in the pathological process of diabetic encephalopathy.Furthermore,IL-17A deficiency reduces diabetic encephalopathy-mediated neuroinflammation and cognitive defects.These results highlight a role for IL-17A as a mediator of diabetic encephalopathy and potential target for the treatment of cognitive impairment induced by diabetic encephalopathy.

Effect of topical 0.05% cyclosporine A on corneal endothelium in patients with dry eye disease

· AIM: To determine the effect of topical 0.05% cyclosporine A (CsA) on corneal endothelium in patients with dry eye disease. · METHODS: Observational, prospective, case series study. Fifty-five eyes of 29 consecutive patients (9 males and 20 females; median age: 66.8 years, interquartile range: 61 -73.2 years) with moderate -severe dry eye disease were evaluated. All patients were treated with topical 0.05% CsA ophthalmic emulsion twice a day in addition to lubricant eyedrops 5 times a day. The follow- up period was 12 months. Before treatment and at 3 and 12 months post -treatment central corneal specular microscopy was performed. The endothelial cell density (ECD), coefficient of variation of cell size (CoV), and percentage of hexagonal cells (Hex %) were analyzed. ·RESULTS: The median ECDs pre-treatment and at 3 and 12 months post-treatment were 2 352.5/mm 2 (inter- quartile range, 2 178 -2548.5), 2 364/mm 2 (interquartile range, 2 174.25 -2 657.5), and 2 366 cells/mm 2 (inter - quartile range, 2 174.75-2 539.75), respectively (P=0.927, one way ANOVA). The median CoVs pre-treatment and at 3 and 12 months post -treatment were 34.5 (interquartile range, 30 -37), 35 (interquartile range, 30 -38), and 34 (interquartile range, 30.75-38.25), respectively (P=0.7193, one way ANOVA). The median Hex % values pre - treatment and at 3 and 12 months post -treatment were 53 (interquartile range, 47 -58), 54 (interquartile range, 45.75 -59), and 50.5 (interquartile range, 45.75 -58), respectively (P=0.824, one way ANOVA). · CONCLUSION: Treatment of patients with dry eye disease for 12 months with topical 0.05% CsA does not seem to cause substantial changes on corneal endothelium.

A high methionine,low folate and vitamin B_6/B_(12) containing diet can be associated with memory loss by epigenetic silencing of netrin-1

Memory-epigenetics which is the loss of memory due to epigenetic modifications can be due to the silencing of genes involved in cognitive functions and this is the basis of the current study.We hypothesize that a diet containing high methionine and low vitamins can lead to memory impairment by increasing global DNA methylation and therefore,silencing the netrin-1 gene,which encodes the glycoprotein involved in neurogenesis,axonal guidance and maintenance of the synaptic plasticity.Wild type(C57 BL/6 J) mice were fed with a diet containing excess methionine(1.2%),low-folate(0.08 mg/kg),vitamin B_6(0.01 mg/kg),and B_(12)(10.4 mg/kg) for 6 weeks.Mice were examined weekly for the long-term memory function,using a passive avoidance test,which determined loss of fear-motivated long-term memory starting from the fourth week of diet.Similarly,an increase in brain %5-methyl cytosine was observed starting from the 4 th week of diet in mice.Mice fed with a high methionine,low folate and vitamins containing diet showed a decrease in netrin-1 protein expression and an increase in netrin-1 gene promotor methylation,as determined by methylation-sensitive restriction enzyme-polymerase chain reaction analysis.The increase in methylation of netrin-1 gene was validated by high-resolution melting and sequencing analysis.Furthermore,the association of netrin-1 with memory was established by administering netrin that considerably restored long-term fear motivated memory.Taken together,these results suggest that a diet rich in methionine and lacking in folate and vitamin B_6/B_(12) can induce defects in learning and memory.Furthermore,the data indicates that decrease in netrin-1 expression due to hyper-methylation of its gene can be associated with memory loss.The animal procedures were approved by the Institutional Animal Care and Use Committee,University of Louisville,USA(No.A3586-01) on February 2,2018.

Quercetin protects liver injury induced by bile duct ligation via attenuation of Rac1 and NADPH oxidase1 expression in rats

BACKGROUND： Bile duct ligation （BDL） and subsequent cholestasis are correlated with oxidative stress, hepatocellular injury and fibrosis. Quercetin is a flavonoid with antifibrotic, and hepatoprotective properties. However, the molecular mechanism underlying quercetin-mediated hepatoprotection is not fully understood. The current study was to evaluate mecha- nisms of hepatoprotective effect of quercetin in BDL rat model. METHODS： We divided male Wistar rats into 4 groups （n=8 for each）： sham, sham＋quercetin （30 mg/kg per day）, BDL, and BDL＋quercetin （30 mg/kg per day）. Four weeks later, the rats were sacrificed, the blood was collected for liver enzyme mea- surements and liver for the measurement of Racl, Racl-GTP and NOX1 mRNA and protein levels by quantitative PCR and Western blotting, respectively. RESULTS： Quercetin significantly alleviated liver injury in BDL rats as evidenced by histology and reduced liver enzymes. Furthermore, the mRNA and protein expression of Racl, Racl-GTP and NOX1 were significantly increased in BDL rats compared with those in the sham group （P〈0.05）; quercetin treatment reversed these variables back toward normal （P〈0.05）. Another interesting finding was that the antioxidant markers e.g. superoxide dismutase and catalase were elevated in quercetin-treated BDL rats compared to BDL rats （P〈0.05）. CONCLUSION： Quercetin demonstrated hepatoprotective activity against BDL-induced liver injury through increasing antioxidant capacity of the liver tissue, while preventing the production of Racl, Racl-GTP and NOX1 proteins.