Sex Differences in Antinociceptive Tolerance Development to Δ
            9
            ‐THC and CP55,940 in Wild‐type and Desensitization‐Resistant S426A/S430A Mice

This paper concerns with the quantitative determination of ommochrome precursors in the Malpighian tubes of Drosophila melanogaster during the individual development. After separation by paper chromatography the amounts of tryptophane, kynurenine and 3-hydroxykynurenine have been estimated by a spectrophotometer. The concentrations of these three substances obtained from wild-type Malpighian tubes have been compared with the quantities of the mutants brown (bw) and red Malpighian tubes (red). During development there are significant variabilities in contents of tryptophane, kynurenine and 3-hydroxykynurenine in the Malpighian tubes. In the larval tubes large quantities of ommochrome precursors are accumulated. With the beginning of metamorphosis there is a distinct decrease in these substances. After hatching the amount increases steadily until reaching a constant level. In the Malpighian tubes there are also sex differences: in females the concentration of kynurenine and 3-hydroxykynurenine is higher than in males. The results obtained from the mutants brown and red Malpighian tubes are on principle the same as those obtained from wild-type. A strong reduction of kynurenine contents is found in the mutant red Malpighian tubes. Perhaps in this mutant the kynurenine-hydroxilase-activity is lower than in wild-type. The amounts of ommochrome precursors, accumulated in the larval Malpighian tubes, do not correspond in all cases to the contents of xanthommatine formed in the eyes of the adults.

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Differential Roles of the Adrenal Gland in the Suppression of Morphine Antinociceptive Tolerance Development by α- and β-Adrenergic Blockers

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)39927-5 ◽

1991 ◽

Vol 55 (4) ◽

pp. 555-558

Author(s):

Masakatsu Takahashi ◽

Tomoko Okada ◽

Hiroshi Kaneto

Keyword(s):

Adrenal Gland ◽

Tolerance Development ◽

Adrenergic Blockers ◽

Antinociceptive Tolerance

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Sex Differences in Presynaptic Density and Neurogenesis in Middle-Aged ApoE4 and ApoE Knockout Mice

Journal of Neurodegenerative Diseases ◽

10.1155/2013/531326 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

A. Rijpma ◽

D. Jansen ◽

I. A. C. Arnoldussen ◽

X. T. Fang ◽

M. Wiesmann ◽

...

Keyword(s):

Sex Differences ◽

Molecular Layer ◽

Compensatory Mechanism ◽

Wild Type ◽

Middle Aged ◽

Apoe Knockout Mice ◽

Presynaptic Density ◽

Apoe Ko Mice ◽

Apoe Genotypes ◽

Apoe Ko

Atherosclerosis and apolipoprotein E ε4 (APOE4) genotype are risk factors for Alzheimer’s disease (AD) and cardiovascular disease (CVD). Sex differences exist in prevalence and manifestation of both diseases. We investigated sex differences respective to aging, focusing on cognitive parameters in apoE4 and apoE knockout (ko) mouse models of AD and CVD. Presynaptic density and neurogenesis were investigated immunohistochemically in male and female apoE4, apoE ko, and wild-type mice. Middle-aged female apoE4 mice showed decreased presynaptic density in the inner molecular layer of the dentate gyrus of the hippocampus. Middle-aged female apoE ko mice showed a trend towards increased neurogenesis in the hippocampus compared with wild-type mice. No differences in these parameters could be observed in middle-aged male mice. Specific harmful interactions between apoE4 and estrogen could be responsible for decreased presynaptic density in female apoE4 mice. The trend of increased neurogenesis found in female apoE ko mice supports previous studies suggesting that temporarily increased amount of synaptic contacts and/or neurogenesis is a compensatory mechanism for synaptic failure. To our knowledge, no other studies investigating presynaptic density in aging female apoE4 or apoE ko mice are available. Sex-specific differences between APOE genotypes could account for some sex differences in AD and CVD.

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Soluble guanylyl cyclase activation by HMR-1766 (ataciguat) in cells exposed to oxidative stress

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.51.2008 ◽

2008 ◽

Vol 295 (4) ◽

pp. H1763-H1771 ◽

Cited By ~ 28

Author(s):

Zongmin Zhou ◽

Anastasia Pyriochou ◽

Anastasia Kotanidou ◽

Georgios Dalkas ◽

Martin van Eickels ◽

...

Keyword(s):

Oxidative Stress ◽

Vascular Tone ◽

Soluble Guanylyl Cyclase ◽

Vascular Diseases ◽

Wild Type ◽

Cross Tolerance ◽

Wild Type Enzyme ◽

Tolerance Development ◽

Cgmp Formation ◽

In Cells

Many vascular diseases are characterized by increased levels of ROS that destroy the biological activity of nitric oxide and limit cGMP formation. In the present study, we investigated the cGMP-forming ability of HMR-1766 in cells exposed to oxidative stress. Pretreatment of smooth muscle cells with H2O2reduced cGMP production stimulated by sodium nitroprusside (SNP) or BAY 41-2272. However, pretreatment with H2O2significantly increased HMR-1766 responses. Similar results were obtained with SIN-1, menadione, and rotenone. In addition, HMR-1766 was more effective in stimulating heme-free sGC compared with the wild-type enzyme. Interestingly, in cells expressing heme-free sGC, H2O2inhibited instead of potentiated HMR-1766 responses, suggesting that the ROS-induced enhancement of cGMP formation was heme dependent. Moreover, using truncated forms of sGC, we observed that the NH2-terminus of the β1-subunit is required for the action of HMR-1766. Finally, to study tolerance development to HMR-1766, cells were pretreated with this sGC activator and reexposed to HMR-1766 or SNP. Results from these experiments demonstrated lack of tolerance development to HMR-1766 as well as lack of cross-tolerance with SNP. We conclude that HMR-1766 is an improved sGC activator as it has the ability to activate oxidized/heme-free sGC and is resistant to the development of tolerance; these observations make HMR-1766 a promising agent for treating diseases associated with increased vascular tone combined with enhanced ROS production.

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TNFR1 signaling resistance associated with female stem cell cytokine production is independent of TNFR2-mediated pathways

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90508.2008 ◽

2008 ◽

Vol 295 (4) ◽

pp. R1124-R1130 ◽

Cited By ~ 6

Author(s):

Troy A. Markel ◽

Paul R. Crisostomo ◽

Meijing Wang ◽

Yue Wang ◽

Tim Lahm ◽

...

Keyword(s):

Stem Cells ◽

Sex Differences ◽

Stem Cell ◽

Cytokine Production ◽

Cytokine Signaling ◽

Common Source ◽

Tnf Receptor ◽

Wild Type ◽

Marrow Mesenchymal Stem Cells ◽

Cell Cytokine Production

End-organ ischemia is a common source of patient morbidity and mortality. Stem cell therapy represents a novel treatment modality for ischemic diseases and may aid injured tissues through the release of beneficial paracrine mediators. Female bone marrow mesenchymal stem cells (MSCs) have demonstrated a relative resistance to detrimental TNF receptor 1 (TNFR1) signaling and are thought to be superior to male stem cells in limiting inflammation. However, it is not known whether sex differences exist in TNF receptor 2 (TNFR2)-ablated MSCs. Therefore, we hypothesized that 1) sex differences would be observed in wild-type (WT) and TNFR2-ablated MSC cytokine signaling, and 2) the production of IL-6, VEGF, and IGF-1 in males, but not females, would be mediated through TNFR2. MSCs were harvested from male and female WT and TNFR2 knockout (TNFR2KO) mice and were subsequently exposed to TNF (50 ng/ml) or LPS (100 ng/ml). After 24 h, supernatants were collected and measured for cytokines. TNF and LPS stimulated WT stem cells to produce cytokines, but sex differences were only seen in IL-6 and IGF-1 after TNF stimulation. Ablation of TNFR2 increased VEGF and IGF-1 production in males compared with wild-type, but no difference was observed in females. Female MSCs from TNFR2KOs produced significantly lower levels of VEGF and IGF-1 compared with male TNFR2KOs. The absence of TNFR2 signaling appears to play a greater role in male MSC cytokine production. As a result, male, but not female stem cell cytokine production may be mediated through TNFR2 signaling cascades.

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Sex Differences in Angiotensin II-Induced Hypertension and Kidney Injury: Role of AT1a Receptors in The Proximal Tubule of The Kidney

Clinical Science ◽

10.1042/cs20201574 ◽

2021 ◽

Author(s):

Ana Paula Oliverio Leite ◽

Xiao Chun Li ◽

Ruman Hassan ◽

Xiaowen Zheng ◽

Barbara T Alexander ◽

...

Keyword(s):

Sex Differences ◽

Angiotensin Ii ◽

Proximal Tubule ◽

Kidney Injury ◽

Proximal Tubules ◽

Ang Ii ◽

Wild Type ◽

Male And Female ◽

Induced Hypertension ◽

Different Strains

In the present study, we tested the hypothesis that there are significant sex differences in angiotensin II (Ang II)-induced hypertension and kidney injury using male and female wild-type and proximal tubule-specific AT1a receptor knockout mice (PT-Agtr1a-/-). Twelve groups (n=8-12 per group) of adult male and female wild-type and PT-Agtr1a-/- mice were infused with a pressor dose of Ang II via osmotic pump for 2 weeks (1.5 mg/kg/day, i.p.) and simultaneously treated with or without losartan (20 mg/kg/day, p.o.) to determine the respective roles of AT1a receptors in the proximal tubules versus systemic tissues. Basal systolic, diastolic, and mean arterial pressure were approximately 13 ± 3 mmHg lower (P<0.01), while basal 24 h urinary Na+, K+, and Cl- excretion were significantly higher in both male and female PT-Agtr1a-/- mice than wild-type controls (P<0.01) without significant sex differences between different strains. Both male and female wild-type and PT-Agtr1a-/- mice developed hypertension (P<0.01), and the magnitudes of the pressor responses to Ang II were similar between male and female wild-type and PT-Agtr1a-/- mice (n.s.). Likewise, Ang II-induced hypertension was significantly attenuated in both male and female PT-Agtr1a-/- mice (P<0.01). Furthermore, losartan attenuated the hypertensive responses to Ang II to similar extents in both male and female wild-type and PT-Agtr1a-/- mice. Finally, Ang II-induced kidney injury was attenuated in PT-Agtr1a-/- mice (P<0.01). In conclusion, the present study demonstrates that deletion of AT1a receptors in the proximal tubules of the kidney attenuates Ang II-induced hypertension and kidney injury without revealing significant sex differences.

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Abstract 143: Bridging the Gender Gap: Sex Differences in Von Willebrand Factor Aptamer Inhibition Across Species

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.143 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

David L Dornbos ◽

Debra G Wheeler ◽

Jeanne Green ◽

Nicholas Venetos ◽

Allyson Huttinger ◽

...

Keyword(s):

Sex Differences ◽

Continuous Infusion ◽

Gender Gap ◽

Ex Vivo ◽

Platelet Reactivity ◽

Platelet Inhibition ◽

Wild Type ◽

Platelet Activity ◽

The Right

Introduction: A gender gap exists in stroke, with increased morbidity and mortality in women. The underlying mechanisms remain unknown, although differences in platelet biology may play a role. Inhibition of the interaction between VWF and GP 1B-IX-V has demonstrated thrombolytic efficacy. Hypothesis: We hypothesized that sex differences in reperfusion after stroke were attributable to the VWF-GP IB-IX-V axis, and inhibition of this interaction would yield clear discrepancies. Methods: Adult wild-type (C57BL/6J) mice were anesthetized, the right carotid artery exposed and baseline carotid flow obtained by Doppler. Thrombosis was induced with a FeCl 3 patch. After 20-minute stabilization, mice were intravenously administered vehicle (n, male=12, female=8) or VWF aptamer. Aptamer (0.5 mg/kg) administration was assessed using a bolus (5 min; n, male=5, female=8) method. Given the minimal observed thrombolytic effect in females, a continuous infusion (45 min; n, female=5) was also attempted. Next, blood from male (n=8) and female (n=8) adult wild-type beagles was mixed with VWF aptamer (control, 6.25 nM, 12.5 nM, 25 nM, and 100 nM), and platelet reactivity was assessed (Platelet Function Analyser-100). Statistical analysis was performed using a two-way ANOVA with multiple comparisons. Results: Bolus VWF aptamer restored carotid blood flow in male mice (Figure 1), compared to females (p<0.001) and vehicle (p<0.01). With continuous infusion, reperfusion in female mice was significantly higher than vehicle (p<0.01). Male canines (264.3 ± 70.3 s) demonstrated significantly more platelet inhibition (p<0.01) than females (175.3 ± 83.2 s) at the 12.5 nM VWF aptamer concentration. Conclusions: Following VWF inhibition, in vivo thrombolytic efficacy in mice is gender dependent, while ex vivo platelet activity varies in canines. The mechanisms underlying these differences in platelet biology are unclear, but this indicates that the VWF-GP IB-IX-V axis plays a role.

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Sex Differences in Constitutive Autophagy

BioMed Research International ◽

10.1155/2014/652817 ◽

2014 ◽

Vol 2014 ◽

pp. 1-5 ◽

Cited By ~ 22

Author(s):

Sara Oliván ◽

Ana Cristina Calvo ◽

Raquel Manzano ◽

Pilar Zaragoza ◽

Rosario Osta

Keyword(s):

Skeletal Muscle ◽

Spinal Cord ◽

Sex Differences ◽

Sexual Dimorphism ◽

Animal Models ◽

Sex Bias ◽

Wild Type ◽

Male And Female ◽

Physiological Conditions ◽

Sequestosome 1

Sex bias has been described nowadays in biomedical research on animal models, although sexual dimorphism has been confirmed widely under pathological and physiological conditions. The main objective of our work was to study the sex differences in constitutive autophagy in spinal cord and skeletal muscle tissue from wild type mice. To examine the influence of sex on autophagy, mRNA and proteins were extracted from male and female mice tissues. The expressions of microtubule-associated protein 1 light chain 3 (LC3) and sequestosome 1 (p62), markers to monitor autophagy, were analyzed at 40, 60, 90, and 120 days of age. We found significant sex differences in the expression of LC3 and p62 in both tissues at these ages. The results indicated that sex and tissue specific differences exist in constitutive autophagy. These data underlined the need to include both sexes in the experimental groups to minimize any sex bias.

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Sex and the G Protein–Coupled Estrogen Receptor Impact Vascular Stiffness

Hypertension ◽

10.1161/hypertensionaha.120.16915 ◽

2021 ◽

Author(s):

Benard O. Ogola ◽

Gabrielle L. Clark ◽

Caleb M. Abshire ◽

Nicholas R. Harris ◽

Kaylee L. Gentry ◽

...

Keyword(s):

Blood Pressure ◽

Estrogen Receptor ◽

Sex Differences ◽

G Protein ◽

Wall Thickness ◽

Left Ventricular ◽

Axial Stiffness ◽

Ang Ii ◽

Wild Type ◽

G Protein Coupled

Because arterial stiffness increases following menopause, estrogen may be a protective factor. Our previous work indicates that the GPER (G protein–coupled estrogen receptor) mediates estrogen’s vascular actions. In the current study, we assessed arterial stiffening using pulse wave velocity (PWV), a clinically relevant measurement that independently predicts cardiovascular mortality. We hypothesized that genetic deletion of GPER would attenuate sex differences in PWV and would be associated with changes in passive vascular mechanics. Control and Ang II (angiotensin II)–infused male and female wild-type and GPER knockout mice were assessed for blood pressure, intracarotid PWV, cardiac function, passive biaxial mechanics, constitutive modeling, and histology. Sex differences in PWV and left ventricular mass were detected in wild-type mice but absent in GPER knockout and Ang II–infused mice, regardless of genotype. Despite lower PWV, the material stiffness of female wild-type carotids was greater than males in control conditions and was maintained in response to Ang II due to increased wall thickness. PWV positively correlated with unloaded thickness as well as circumferential and axial stiffness only in females. In contrast, blood pressure positively associated with circumferential and axial stiffness in males. Taken together, we found that female wild-type mice were unique in their vascular adaptation to hypertension by increasing wall thickness to maintain stiffness. Given that carotid arteries are easily accessible clinically, systematic assessment of intracarotid PWV in women may provide insight into vascular damage that cannot be assumed from blood pressure measurements alone.

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Neuroimmune Consequences of eIF4E Phosphorylation on Chemotherapy-Induced Peripheral Neuropathy

Frontiers in Immunology ◽

10.3389/fimmu.2021.642420 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nilesh M. Agalave ◽

Prapti H. Mody ◽

Thomas A. Szabo-Pardi ◽

Han S. Jeong ◽

Michael D. Burton

Keyword(s):

Sex Differences ◽

Peripheral Neuropathy ◽

T Lymphocytes ◽

Immune Cells ◽

Wild Type ◽

Negative Effects ◽

Helper T Lymphocytes ◽

Complementary Role ◽

Dorsal Root Ganglia Neurons

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect that occurs in up to 63% of patients and has no known effective treatment. A majority of studies do not effectively assess sex differences in the onset and persistence of CIPN. Here we investigated the onset of CIPN, a point of therapeutic intervention where we may limit, or even prevent the development of CIPN. We hypothesized that cap-dependent translation mechanisms are important in early CIPN development and the bi-directional crosstalk between immune cells and nociceptors plays a complementary role to CIPN establishment and sex differences observed. In this study, we used wild type and eIF4E-mutant mice of both sexes to investigate the role of cap-dependent translation and the contribution of immune cells and nociceptors in the periphery and glia in the spinal cord during paclitaxel-induced peripheral neuropathy. We found that systemically administered paclitaxel induces pain-like behaviors in both sexes, increases helper T-lymphocytes, downregulates cytotoxic T-lymphocytes, and increases mitochondrial dysfunction in dorsal root ganglia neurons; all of which is eIF4E-dependent in both sexes. We identified a robust paclitaxel-induced, eIF4E-dependent increase in spinal astrocyte immunoreactivity in males, but not females. Taken together, our data reveals that cap-dependent translation may be a key pathway that presents relevant therapeutic targets during the early phase of CIPN. By targeting the eIF4E complex, we may reduce or reverse the negative effects associated with chemotherapeutic treatments.

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