Quinpirole ameliorates nigral dopaminergic neuron damage in Parkinson's disease mouse model through activating GHS-R1a/D2R heterodimers.

Growth hormone secretagogue receptor 1a (GHS-R1a) is an important G protein-coupled receptor (GPCR) that regulates a variety of functions by binding to ghrelin. It has been shown that the dimerization of GHS-R1a with other receptors also affects ingestion, energy metabolism, learning and memory. Dopamine type 2 receptor (D2R) is a GPCR mainly distributed in the ventral tegmental area (VTA), substantia nigra (SN), striatum and other brain regions. In this study we investigated the existence and function of GHS-R1a/D2R heterodimers in nigral dopaminergic neurons in Parkinson's disease (PD) models in vitro and in vivo. By conducting immunofluorescence staining, FRET and BRET analyses, we confirmed that GHS-R1a and D2R could form heterodimers in PC-12 cells and in the nigral dopaminergic neurons of wild-type mice. This process was inhibited by MPP+ or MPTP treatment. Application of QNP (10 µM) alone significantly increased the viability of MPP+-treated PC-12 cells, and administration of quinpirole (QNP, 1 mg/kg, i.p. once before and twice after MPTP injection) significantly alleviated motor deficits in MPTP-induced PD mice model; the beneficial effects of QNP were abolished by GHS-R1a knockdown. We revealed that the GHS-R1a/D2R heterodimers could increase the protein levels of tyrosine hydroxylase in the SN of MPTP-induced PD mice model through the cAMP response element binding protein (CREB) signaling pathway, ultimately promoting dopamine synthesis and release. These results demonstrate a protective role for GHS-R1a/D2R heterodimers in dopaminergic neurons, providing evidence for the involvement of GHS-R1a in PD pathogenesis independent of ghrelin.

To compare the influence of blind insertion and up-down optimized glottic exposure manoeuvre on oropharyngeal leak pressure using SaCoVLM™ video laryngeal mask among patients undergoing general anesthesia.

To compare the potential influences of blind insertion and up-down optimized glottic exposure manoeuvre on the oropharyngeal leak pressure (OPLP) in using SaCoVLM™ video laryngeal mask (VLM) among patients undergoing general anesthesia. A randomized self-control study controlled was conducted to investigate the effect of two insertion techniques on OPLP. A total of 60 patients (male or female, 18-78 years, BMI 18.0-30.0 kg m-2 and ASA I-II) receiving selective surgery under general anesthesia were randomly recruited. After induction of anesthesia, the SaCoVLM™ was inserted by blind insertion manoeuvre. The glottic exposure grading(V1) of the SaCoVLM™ visual laryngeal mask and the OPLP(P1) were recorded. And the glottic exposure grading(V2) and OPLP(P2) of SaCoVLM™ were recorded again when the glottic exposure grading was optimal. The glottis exposure grading and OPLP were compared before and after different insertion manoeuver. The glottic exposure grading (V2) obtained by using up-down optimized glottic exposure manoeuvre was better than that obtained by using blind insertion manoeuvre (V1)(P < 0.001). The OPLP was significantly lower in the blind insertion manoeuvre (P1) than in the up-down optimized glottic exposure manoeuvre (P2) (32.4 ± 5.0 cmH2O vs. 36.3 ± 5.2 cmH2O, P < 0.001). In using SaCoVLM™, higher OPLP and better glottic exposure grading were achieved through up-down optimized glottic exposure manoeuvre, protecting the airway while real-time monitoring of conditions around the glottis, which significantly improves airway safety. Our results suggests that up-down optimized glottic exposure manoeuver may be a useful technique for SaCoVLM™ insertion.Trial registration: ChiCTR, ChiCTR2000028802. Registered 4 January 2020, http://www.chictr.org.cn/ChiCTR2000028802.

Preliminary evaluation of SaCoVLM™ video laryngeal mask airway in airway management for general anesthesia.

BACKGROUND: To preliminary evaluate the application of SaCoVLM™ video laryngeal mask airway in airway management of general anesthesia. METHODS: We recruited 100 adult patients (ages 18-78 years, male 19, female 81, weight 48-90 kg) with normal predicted airway (Mallampati I ~ II, unrestricted mouth opening, normal head and neck mobility) and ASA I-II who required general anaesthesia. The SaCoVLM™ was inserted after anesthesia induction and connected with the anesthesia machine for ventilation. Our primary outcome was glottic visualization grades. Secondary outcomes included seal pressure, success rate of insertion, intraoperative findings (gastric reflux and contraposition), gastric drainage and 24-h complications after operation. RESULTS: The laryngeal inlet was exposed in all the patients and shown on the video after SaCoVLM™ insertion. The status of glottic visualization was classified: grade 1 in 55 cases, grade 2 in 23 cases, grade 3 in 14 cases and grade 4 in 8 cases. The first-time success rate of SaCoVLM™ insertion was 95% (95% CI = 0.887 to 0.984), and the total success rate was 96% (95% CI = 0.901 to 0.989). The sealing pressure of SaCoVLM™ was 34.1 ± 6.2 cmH2O and the gastric drainage were smooth. Only a small number of patients developed mild complications after SaCoVLM™ was removed (such as blood stains on SaCoVLM™ and sore throat). CONCLUSIONS: The SaCoVLM™ can visualize partial or whole laryngeal inlets during the surgery, with a high success rate, a high sealing pressure and smooth gastroesophageal drainage. SaCoVLM™ could be a promise new effective supraglottic device to airway management during general anesthesia. TRIAL REGISTRATION: ChiCTR, ChiCTR2000028802 .Registered 4 January 2020.

Comparison of SaCoVLM™ video laryngeal mask-guided intubation and i-gel combined with flexible bronchoscopy-guided intubation in airway management during general anesthesia: a non-inferiority study.

BACKGROUND: When a difficult airway is unanticipatedly encountered and the initial laryngoscopic intubation fails, a supraglottic airway device (SAD) may be placed to aid ventilation and oxygenation, and act as a conduit for intubation. SaCoVLM™, as new SAD, can offer a direct vision to guide intubation. However, no study has evaluated the performance of SaCoVLM™ video laryngeal mask (VLM) intubation and i-gel combined with flexible bronchoscopy (FB)-guided intubation in airway management during general anesthesia. METHODS: A total of 120 adult patients were randomly allocated into the SaCoVLM™ group (Group S) and i-gel group (Group I). After induction of general anesthesia, guided tracheal intubation under direct vision of the SaCoVLM™ was conducted in Group S, while Group I received FB-guided tracheal intubation using the i-gel. The success rate of SAD placement, first-pass success rate of guided tracheal tube placement, and total success rate in both groups were recorded. The time for SAD placement, time for guided tracheal intubation, total intubation time (time for SAD placement and intubation), glottic exposure grading and postoperative intubation complications (i.e., dysphagia, hoarseness, pharyngalgia, etc.) of both groups were also compared. RESULTS: The first-time success rate of SAD placement was 98% in two groups. The first-pass success rate of guided endotracheal intubation was 92% in Group S and 93% in Group I (P = 0.74 > 0.05). The total intubation time was 30.8(± 9.7) s and 57.4(± 16.6) s (95% CI = -31.5 to -21.7) in Group S and Group I, respectively (P < 0.01). The total complication rate was 8% in Group S and 22% in Group I (P < 0.05). The laryngeal inlet could be observed in the S group through the visual system of SaCoVLM™. No dysphagia or hoarseness was reported. CONCLUSION: SaCoVLM™ can reveal the position of laryngeal inlet, thus providing direct vision for tracheal intubation. SaCoVLM™ -guided intubation is faster, and does not rely on FB, compared to i-gel combined with FB-guided intubation. Besides, SaCoVLM™ has a lower post-intubation complication rate. TRIAL REGISTRATION: Chinese Clinical Trials Registry (ChiCTR2100043443); Date of registration: 18/02/2021.

Apolipoprotein A-IV Inhibits AgRP/NPY Neurons and Activates Pro-Opiomelanocortin Neurons in the Arcuate Nucleus.

BACKGROUND/AIMS: Apolipoprotein A-IV (apoA-IV) in the brain potently suppresses food intake. However, the mechanisms underlying its anorexigenic effects remain to be identified. METHODS: We first examined the effects of apoA-IV on cellular activities in hypothalamic neurons that co-express agouti-related peptide (AgRP) and neuropeptide Y (NPY) and in neurons that express pro-opiomelanocortin (POMC). We then compared anorexigenic effects of apoA-IV in wild-type mice and in mutant mice lacking melanocortin 4 receptors (MC4Rs; the receptors of AgRP and the POMC gene product). Finally, we examined expression of apoA-IV in mouse hypothalamus and quantified its protein levels at fed versus fasted states. RESULTS: We demonstrate that apoA-IV inhibited the firing rate of AgRP/NPY neurons. The decreased firing was associated with hyperpolarized membrane potential and decreased miniature excitatory postsynaptic current. We further used c-fos immunoreactivity to show that intracerebroventricular (i.c.v.) injections of apoA-IV abolished the fasting-induced activation of AgRP/NPY neurons in mice. Further, we found that apoA-IV depolarized POMC neurons and increased their firing rate. In addition, genetic deletion of MC4Rs blocked anorexigenic effects of i.c.v. apoA-IV. Finally, we detected endogenous apoA-IV in multiple neural populations in the mouse hypothalamus, including AgRP/NPY neurons, and food deprivation suppressed hypothalamic apoA-IV protein levels. CONCLUSION: Our findings support a model where central apoA-IV inhibits AgRP/NPY neurons and activates POMC neurons to activate MC4Rs, which in turn suppresses food intake.

Study on dynamic response and long-term settlement of silty soil around Shanghai metro tunnel.

At present, the method for calculating long-term tunnel settlement predictions under metro loading considers only one working condition of passenger loading, which is inconsistent with actual working conditions. To establish a tunnel settlement model that accounts for variations in passenger flow, this study uses data mining methods to categorize metro operation into three working conditions: "peak period, secondary period, and low period." The impact of these passenger flow conditions on the dynamic response of the soil around the tunnel is analyzed. Then, based on the principles of calculus, a calculus-based prediction model is established to consider the changing patterns of metro passenger flow. The model is applied to analyze the long-term settlement characteristics of Shanghai Metro Line 10. The results indicate that, under identical conditions, soil displacement and dynamic deviatoric stress around the tunnel increase with passenger capacity. The calculus prediction model aligns more closely with actual working conditions than the conventional model. The predicted tunnel settlement of Shanghai Metro Line 10 after 20 years of operation is approximately 37.07 mm, with most settlement occurring in the early stages, primarily due to cumulative plastic deformation of the soil.

Astrocyte-derived apolipoprotein D is required for neuronal survival in Parkinson's disease.

Apolipoprotein D (ApoD), a lipocalin transporter of small hydrophobic molecules, plays an essential role in several neurodegenerative diseases. It was reported that increased immunostaining for ApoD of glial cells surrounding dopaminergic (DAergic) neurons was observed in the brains of Parkinson's disease (PD) patients. Although preliminary findings supported the role of ApoD in neuroprotection, its derivation and effects on the degeneration of nigral DAergic neurons are largely unknown. In the present study, we observed that ApoD levels released from astrocytes were increased in PD models both in vivo and in vitro. When co-cultured with astrocytes, due to the increased release of astrocytic ApoD, the survival rate of primary cultured ventral midbrain (VM) neurons was significantly increased with 1-methyl-4-phenylpyridillium ion (MPP+) treatment. Increased levels of TAp73 and its phosphorylation at Tyr99 in astrocytes were required for the increased ApoD levels and its release. Conditional knockdown of TAp73 in the nigral astrocytes in vivo could aggravate the neurodegeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated PD mice. Our findings reported that astrocyte-derived ApoD was essential for DAergic neuronal survival in PD models, might provide new therapeutic targets for PD.

Modulating α-synuclein propagation and decomposition: Implications in Parkinson's disease therapy.

α-Synuclein (α-Syn) is closely related to the pathogenesis of Parkinson's disease (PD). Under pathological conditions, the conformation of α-syn changes and different forms of α-syn lead to neurotoxicity. According to Braak stages, α-syn can propagate in different brain regions, inducing neurodegeneration and corresponding clinical manifestations through abnormal aggregation of Lewy bodies (LBs) and lewy axons in different types of neurons in PD. So far, PD lacks early diagnosis biomarkers, and treatments are mainly targeted at some clinical symptoms. There is no effective therapy to delay the progression of PD. This review first summarized the role of α-syn in physiological and pathological states, and the relationship between α-syn and PD. Then, we focused on the origin, secretion, aggregation, propagation and degradation of α-syn as well as the important regulatory factors in these processes systematically. Finally, we reviewed some potential drug candidates for alleviating the abnormal aggregation of α-syn in order to provide valuable targets for the treatment of PD to cope with the occurrence and progression of this disease.

Deubiquitylase OTUD3 Mediates Endoplasmic Reticulum Stress through Regulating Fortilin Stability to Restrain Dopaminergic Neurons Apoptosis.

OTU domain-containing protein 3 (OTUD3) knockout mice exhibited loss of nigral dopaminergic neurons and Parkinsonian symptoms. However, the underlying mechanisms are largely unknown. In this study, we observed that the inositol-requiring enzyme 1α (IRE1α)-induced endoplasmic reticulum (ER) stress was involved in this process. We found that the ER thickness and the expression of protein disulphide isomerase (PDI) were increased, and the apoptosis level was elevated in the dopaminergic neurons of OTUD3 knockout mice. These phenomena were ameliorated by ER stress inhibitor tauroursodeoxycholic acid (TUDCA) treatment. The ratio of p-IRE1α/IRE1α, and the expression of X-box binding protein 1-spliced (XBP1s) were remarkably increased after OTUD3 knockdown, which was inhibited by IRE1α inhibitor STF-083010 treatment. Moreover, OTUD3 regulated the ubiquitination level of Fortilin through binding with the OTU domain. OTUD3 knockdown resulted in a decrease in the interaction ability of IRE1α with Fortilin and finally enhanced the activity of IRE1α. Taken together, we revealed that OTUD3 knockout-induced injury of dopaminergic neurons might be caused by activating IRE1α signaling in ER stress. These findings demonstrated that OTUD3 played a critical role in dopaminergic neuron neurodegeneration, which provided new evidence for the multiple and tissue-dependent functions of OTUD3.

Correlation of Ferroptosis and Other Types of Cell Death in Neurodegenerative Diseases.

Ferroptosis is defined as an iron-dependent, non-apoptotic cell death pathway, with specific morphological phenotypes and biochemical changes. There is a growing realization that ferroptosis has significant implications for several neurodegenerative diseases. Even though ferroptosis is different from other forms of programmed death such as apoptosis and autophagic death, they involve a number of common protein molecules. This review focuses on current research on ferroptosis and summarizes the cross-talk among ferroptosis, apoptosis, and autophagy that are implicated in neurodegenerative diseases. We hope that this information provides new ideas for understanding the mechanisms and searching for potential therapeutic approaches and prevention of neurodegenerative diseases.

Ghrelin Bridges DMV Neuropathology and GI Dysfunction in the Early Stages of Parkinson's Disease.

Ghrelin contributes to the communication between the brain and gastrointestinal (GI) tract. Both decreased ghrelin levels and functional GI disorders are early events in Parkinson's disease (PD) patients and animal models. However, the reason is not clear. Here it is found that choline acetyltransferase (ChAT)-positive neurons in the dorsal motor nucleus of the vagus nerve (DMV), are lost in PD transgenic mice. In response to the selective damaging of DMV neurons with mu p75-SAP, a rapid reduction both in plasma total and active ghrelin levels is observed. While by contrast, chemogenetic activation of DMV cholinergic neurons can increase the plasma ghrelin levels. Impairment of cholinergic neurons is accompanied by GI disorders, including decreased stool wet weight, stool dry weight, small intestine advancing rate, and gastric emptying rate, while exogenous ghrelin treatment can partially ameliorate GI dysfunction of A53T α-synuclein transgenic mice. Using pseudorabies virus retrograde trace method, the existence of a direct pathway from the stomach fundus to the DMV is shown. Taken together, the findings suggest that the reduction in plasma ghrelin levels in the early stages of PD may be the result of the lesion of cholinergic neurons in the DMV, thus linking neurodegeneration and GI dysfunction in PD.

ATP-sensitive potassium channels: A double-edged sword in neurodegenerative diseases.

ATP-sensitive potassium channels (KATP channels), a group of vital channels that link the electrical activity of the cell membrane with cell metabolism, were discovered on the ventricular myocytes of guinea pigs by Noma using the patch-clamp technique in 1983. Subsequently, KATP channels have been found to be expressed in pancreatic ß cells, cardiomyocytes, skeletal muscle cells, and nerve cells in the substantia nigra (SN), hippocampus, cortex, and basal ganglia. KATP channel openers (KCOs) diazoxide, nicorandil, minoxidil, and the KATP channel inhibitor glibenclamide have been shown to have anti-hypertensive, anti-myocardial ischemia, and insulin-releasing regulatory effects. Increasing evidence has suggested that KATP channels also play roles in Alzheimer's disease (AD), Parkinson's disease (PD), vascular dementia (VD), Huntington's disease (HD) and other neurodegenerative diseases. KCOs and KATP channel inhibitors protect neurons from injury by regulating neuronal excitability and neurotransmitter release, inhibiting abnormal protein aggregation and Ca2+ overload, reducing reactive oxygen species (ROS) production and microglia activation. However, KATP channels have dual effects in some cases. In this review, we focus on the roles of KATP channels and their related openers and inhibitors in neurodegenerative diseases. This will enable us to precisely take advantage of the KATP channels and provide new ideas for the treatment of neurodegenerative diseases.

Role of upregulation of the KATP channel subunit SUR1 in dopaminergic neuron degeneration in Parkinson's disease.

Accumulating evidence suggests that ATP-sensitive potassium (KATP ) channels play an important role in the selective degeneration of dopaminergic neurons in the substantia nigra (SN). Furthermore, the expression of the KATP channel subunit sulfonylurea receptor 1 (SUR1) is upregulated in the remaining nigral dopaminergic neurons in Parkinson's disease (PD). However, the mechanism underlying this selective upregulation of the SUR1 subunit and its subsequent roles in PD progression are largely unknown. In 3-, 6-, and 9-month-old A53T α-synuclein transgenic (α-SynA53T+/+ ) mice, only the SUR1 subunit and not SUR2B or Kir6.2 was upregulated, accompanied by neuronal damage. Moreover, the occurrence of burst firing in dopaminergic neurons was increased with the upregulation of the SUR1 subunit, whereas no changes in the firing rate were observed except in 9-month-old α-SynA53T+/+ mice. After interference with SUR1 expression by injection of lentivirus into the SN, the progression of dopaminergic neuron degeneration was delayed. Further studies showed that elevated expression of the transcription factors FOXA1 and FOXA2 could cause the upregulation of the SUR1 subunit in α-SynA53T+/+ mice. Our findings revealed the regulatory mechanism of the SUR1 subunit and the role of KATP channels in the progression of dopaminergic neuron degeneration, providing a new target for PD drug therapy.

Comparison of the supraglottic airway device BlockBusterTM and laryngeal mask airway Supreme in anaesthetised, paralyzed adult patients: a multicenter randomized controlled trial.

BACKGROUND: This multicenter prospective, randomized controlled clinical trial compared the clinical performance of supraglottic airway device (SAD) BlockBusterTM and laryngeal mask airway (LMA) Supreme for airway maintenance in anesthetized, paralyzed adult patients. METHODS: A total of 651 adult patients scheduled for elective surgery in 13 hospitals were randomly allocated into BlockBuster group (n = 351) or Supreme group (n = 300). The primary outcome was oropharyngeal leak pressure (OLP). Duration and ease of insertion, fiberscopic view of positioning, airway manipulations, and complications were also assessed. RESULTS: The OLP was significantly higher in BlockBuster group compared with Supreme group (29.9 ± 4.2 cmH2O vs 27.4 ± 4.3 cmH2O, p < 0.001). Success rate of insertion at the first attempt (90.2% vs 85.1%, p = 0.027), rate of optimal fiberscopic view (p = 0.002) and satisfactory positioning of SAD (p < 0.001) were significantly increased in BlockBuster group. CONCLUSIONS: Both SAD BlockBusterTM and LMA Supreme are safe, effective, and easy-to-use devices for airway maintenance in anesthetized, paralyzed adult patients, but the SAD BlockBusterTM is superior to LMA Supreme in terms of OLP, success rate at the first attempt, and fiber-optic view of positioning. TRIAL REGISTRATION: The trial is registered at www.chictr.org.cn (ChiCTR-ONC-16009105).

Effect of purple sweet potato anthocyanins on beta-amyloid-mediated PC-12 cells death by inhibition of oxidative stress.

Amyloid-beta peptide (Abeta) is known to induce the redox imbalance, mitochondrial dysfunction and caspase activation, resulting in neuronal cell death. Treatment with antioxidants provided a new therapeutic strategy for Alzheimer's disease (AD) patients. Here we investigate the effects of purple sweet potato anthocyanins (PSPA), the known strong free radical scavengers, on Abeta toxicity in PC12 cells. The results showed that pretreatment of PC12 cells with PSPA reduced Abeta-induced toxicity, intracellular reactive oxygen species (ROS) generation and lipid peroxidation dose-dependently. In parallel, cell apoptosis triggered by Abeta characterized with the DNA fragmentation and caspase-3 activity were also inhibited by PSPA. The concentration of intracellular Ca(2+) and membrane potential loss associated with cell apoptosis were attenuated by PSPA. These results suggested that PSPA could protect the PC-12 cell from Abeta-induced injury through the inhibition of oxidative damage, intracellular calcium influx, mitochondria dysfunction and ultimately inhibition of cell apoptosis. The present study indicates that PSPA may be a promising approach for the treatment of AD and other oxidative-stress-related neurodegenerative diseases.

The toxicity study on marine low-temperature lysozyme.

Marine low-temperature lysozyme is purified from a marine bacterium. The lysozyme can keep high activity at low-temperature and has broad-spectrum antibiotic reaction. This study was undertaken to investigate the major characteristics, acute and subchronic toxicity of marine low-temperature lysozyme. The relative molecular weight of this lysozyme was determined as approximate 16 kD; its optimum pH value and temperature towards Micrococcus lysodleikticus were pH 6.5 and 35 degrees C, respectively. The lysozyme activity was slightly enhanced by Zn(2+) and Cu(2+) and slightly inhibited by Mn(2+) and Ag(+). The lysozyme showed good compatibility to many common chemical agents such as EDTA (0.1%), KH(2)PO(4) (1.0%), etc. In experiments on acute toxicity, the drug was injected through the tail vein of mice, and intoxication symptoms and date of death were recorded. The 50% lethal dose (LD(50)) of Marine low-temperature lysozyme and 95%, 99% confidence interval (CI) was calculated. The subchronic study was designed to determine whether effects progressed with repeated Marine low-temperature lysozyme exposure. Wistar rats were tested by daily intragastric administration of Marine low-temperature lysozyme at the doses of 1.0; 0.5; 0.25 g/kg bw for 90 days. The LD(50) value of lysozyme was 4530 mg/kg bw; 90 days of Marine low-temperature lysozyme treatment at three doses, and there is no significant difference on blood biochemistry and organ index in drug treatment groups compared to saline treatment group. There is no affirmative pathologic change of all the observed organs in this study. The present results suggest that Marine low-temperature lysozyme can be safely used at the dose of experiment applied.

TAp63 contributes to sexual dimorphism in POMC neuron functions and energy homeostasis.

Sexual dimorphism exists in energy balance, but the underlying mechanisms remain unclear. Here we show that the female mice have more pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of hypothalamus than males, and female POMC neurons display higher neural activities, compared to male counterparts. Strikingly, deletion of the transcription factor, TAp63, in POMC neurons confers "male-like" diet-induced obesity (DIO) in female mice associated with decreased POMC neural activities; but the same deletion does not affect male mice. Our results indicate that TAp63 in female POMC neurons contributes to the enhanced POMC neuron functions and resistance to obesity in females. Thus, TAp63 in POMC neurons is one key molecular driver for the sexual dimorphism in energy homeostasis.

A polypeptide from Chlamys farreri abolishes UV-induced apoptosis in murine thymocytes in vitro.

Previously we reported that a polypeptide from Chlamys farreri (PCF) was a potent photoprotective agent against ultraviolet (UV) irradiation in vitro. To understand the mechanism by which PCF protects cells from irradiation, we studied anti-apoptotic effects of PCF against UV irradiation on the murine thymocytes in vitro. MTT and flow cytometric analysis assays showed that 2h pretreatment with PCF completely abolished UV induced cell death. TEM examination showed that PCF fully protected the ultrastructure of thymocytes exposed to UV irradiation. Lipid peroxidation and intracellular reactive oxygen species assays indicated that PCF efficiently blocked production of reactive oxygen intermediates induced by UV irradiation. Further, PCF protected UV-irradiated thymocytes from losing mitochondrial transmembrane potential and DNA fragmentation. Based on these observations we propose that PCF is a potent anti-apoptotic factor, which protects cells from irradiation at multiple steps.

Meta-chlorophenylpiperazine enhances leptin sensitivity in diet-induced obese mice.

BACKGROUND AND PURPOSE: Most forms of human obesity are characterized by impaired leptin sensitivity and, therefore, the effectiveness of anti-obesity leptin therapy in these leptin-resistant obese patients is marginal. Hence, the development of strategies to increase leptin sensitivity is of high priority in the field of obesity research. EXPERIMENTAL APPROACH: We first examined the effects of co-administration of leptin and meta-chlorophenylpiperazine (mCPP), an agonist of 5-HT2C and 5-HT1B receptors, on energy balance in leptin-resistant diet-induced obese (DIO) mice. We further assessed leptin-induced phosphorylation of the STAT-3 (pSTAT3) in various brain regions of DIO mice pretreated with mCPP or in mice genetically lacking 5-HT2C receptors. RESULTS: Co-administration of mCPP with leptin had an additive effect on reducing body weight in DIO mice. Furthermore, mCPP pretreatment in DIO mice enhanced leptin-induced pSTAT3 in the arcuate nucleus, the ventromedial hypothalamic nucleus, and the ventral premammillary nucleus. Finally, deletion of 5-HT2C receptors significantly blunted leptin-induced pSTAT3 in these same hypothalamic regions. CONCLUSIONS AND IMPLICATIONS: Our study provides evidence that drugs, which activate 5-HT2C receptors, could function as leptin sensitizers and be used in combination with leptin to provide additional weight loss in DIO.