Calcium signaling in vascular endothelial cells (ECs) and smooth muscle cells (VSMCs) is essential for the regulation of vascular tone. However, the changes to intracellular Ca²⁺ concentrations are often influenced by sex differences. Furthermore, a large body of evidence shows that sex hormone imbalance leads to dysregulation of Ca²⁺ signaling and this is a key factor in the pathogenesis of cardiovascular diseases. In this review, the effects of estrogens and androgens on vascular calcium-handling proteins are discussed, with emphasis on the associated genomic or nongenomic molecular mechanisms. The experimental models from which data were collected were also considered. The review highlights 1) in female ECs, transient receptor potential vanilloid 4 (TRPV4) and mitochondrial Ca²⁺ uniporter (MCU) enhance Ca²⁺-dependent nitric oxide (NO) generation. In males, only transient receptor potential canonical 3 (TRPC3) plays a fundamental role in this effect. 2) Female VSMCs have lower cytosolic Ca²⁺ levels than males due to differences in the activity and expression of stromal interaction molecule 1 (STIM1), calcium release-activated calcium modulator 1 (Orai1), calcium voltage-gated channel subunit-α_1C (Ca_V1.2), Na⁺-K⁺-2Cl⁻ symporter (NKCC1), and the Na⁺/K⁺-ATPase. 3) When compared with androgens, the influence of estrogens on Ca²⁺ homeostasis, vascular tone, and incidence of vascular disease is better documented. 4) Many studies use supraphysiological concentrations of sex hormones, which may limit the physiological relevance of outcomes. 5) Sex-dependent differences in Ca²⁺ signaling mean both sexes ought to be included in experimental design.

The plant Senecio nutans SCh. Bip. is used by Andean communities to treat altitude sickness. Recent evidence suggests it may produce vasodilation and negative cardiac inotropy, though the cellular mechanisms have not been elucidated. To determinate the mechanisms action of S. nutans on cardiovascular function in normotensive animals. The effect of the extract on rat blood pressure was measured with a transducer in the carotid artery and intraventricular pressure by a Langendorff system. The effects on sheep ventricular intracellular calcium handling and contractility were evaluated using photometry. Ultra-high-performance liquid-chromatography with diode array detection coupled with heated electrospray-ionization quadrupole-orbitrap mass spectrometric detection (UHPLC-DAD-ESI-Q-OT-MSn) was used for extract chemical characterization. In normotensive rats, S. nutans (10 mg/kg) reduced mean arterial pressure (MAP) by 40% (p < 0.05), causing a dose-dependent coronary artery dilation and decreased left ventricular pressure. In isolated cells, S. nutans extract (1 μg/ml) rapidly reduced the [Ca²⁺]_i transient amplitude and sarcomere shorting by 40 and 49% (p < 0.001), respectively. The amplitude of the caffeine evoked [Ca²⁺]_i transient was reduced by 24% (p < 0.001), indicating reduced sarcoplasmic reticulum (SR) Ca²⁺ content. Sodium-calcium exchanger (NCX) activity increased by 17% (p < 0.05), while sarcoendoplasmic reticulum Ca²⁺-ATPase (SERCA) activity was decreased by 21% (p < 0.05). LC-MS results showed the presence of vitamin C, malic acid, and several antioxidant phenolic acids reported for the first time. Dihydroeuparin and 4-hydroxy-3-(3-methylbut-2-enyl) acetophenone were abundant in the extract. In normotensive animals, S. nutans partially reduces MAP by decreasing heart rate and cardiac contractility. This negative inotropy is accounted for by decreased SERCA activity and increased NCX activity which reduces SR Ca²⁺ content. These results highlight the plant's potential as a source of novel cardio-active phytopharmaceuticals or nutraceuticals.

2,5-Di-(tert-butyl)-1,4-benzohydroquinone (TBQ) is a reversible inhibitor of SERCA, potentially making it a useful tool to study the effects of SERCA inhibition in cardiac cells. However, it is unknown if TBQ also has effects on other components of ventricular Ca handling. The aim of these experiments was to characterise the effects of TBQ on Ca handling in rat ventricular myocytes and assess its suitability as a specific inhibitor of SERCA. This was achieved by voltage clamp via perforated patch and [Ca(2+)]i measurement using Fluo-3 AM. TBQ produced a fully reversible, concentration dependent decrease in the rate of systolic Ca decay. 10μM TBQ decreased the amplitude of the systolic Ca transient by 48±5% and the rate of decay by 54±6%. SR Ca content was also reduced by 62±4%. However, 10μM TBQ also decreased the peak L-type Ca current by 23±7%. At higher concentrations (100μM), TBQ also activated an outward current with a current-voltage relationship consistent with a potassium current. This outward current was abolished by Glibenclamide (100μM). These data show that TBQ can be used to reversibly inhibit SERCA. However, at concentrations that decrease SERCA activity, TBQ also decreases the L-type Ca current and (at higher concentrations) activates an outward current which appears to be an ATP dependent potassium current. We conclude that TBQ cannot be used as a specific inhibitor of SERCA in rat ventricular myocytes.

Background: Leukemias are a common cancer in adults and children. While existing treatments are effective, they are associated with severe side-effects compounded by the emergence of drug resistance. This necessitates the need to develop new drugs and phytopharmaceuticals offer a largely untapped source. Oleoresins produced by plants in the genus Boswellia have been used for centuries in traditional medicine and recent work suggests they may exhibit anti-cancer activity. However, the underlying mechanisms remain unclear and most existing research focusses on Boswellia serrata; just one of many species in the Boswellia genus. To address these limitations, we elucidated the anti-cancer potential and associated mechanisms of action of Boswellia carterii.Methods: A methanolic solvent extraction method was optimised. The effect of methanolic extracts of B. carterii on leukaemia (K562, MOLT-4 and CCRF-CEM) and normal (PBMC) cell line viability was assessed using MTT assay and flow cytometry. Cell morphology, apoptosis (Annexin-V/propidium iodide), mitochondrial membrane potential (Rhodamine-123) and the cell cycle (propidium iodide) were evaluated using flow cytometry. Regulatory protein expression was quantified using Western Blot.Results: Methanolic extracts of B. carterii oleoresin reduced the viability of K562, MOLT-4 and CCRF-CEM cell lines with selectivity indexes of between 1.75 and 2.68. Extracts increased the proportion of cells in late apoptosis by 285.4% ± 51.6%. Mitochondrial membrane potential was decreased by 41% ± 2% and the expression of cleaved caspase-3, -7, and -9 was increased by 5.7, 3.3, and 1.5-fold respectively. Extracts increased the proportion of cells in _subG₁ and G₁ phase by 867.8% ± 122.9% and 14.0 ± 5.5 and decreased those in S phase and G₂/M by 63.4% ± 2.0% and 57.6% ± 5.3%. Expression of CDK2, CDK6, cyclin D1, and cyclin D3 were decreased by 2.8, 4.9, 3.9, and 2.5-fold.Conclusion: We are the first to report that methanolic extracts of B. carterii are selectively cytotoxic against three leukemia cell lines. Cytotoxic mechanisms likely include activation of the intrinsic apoptotic pathway and cell cycle arrest through downregulation of CDK2, CDK6, cyclin D1, and cyclin D3. Our findings suggest that B. carterii may be an important source of novel chemotherapeutic drugs and justifies further investigation.

When considering the diversity of students in higher education, an important but frequently overlooked characteristic is socioeconomic background. It is well known that those from socially disadvantaged backgrounds are less likely to progress to higher education, and accounts for an associated lack of diversity in the STEM workplace. The reasons for this are many and complex, though a lack of awareness of STEM-based education thence career pathways among secondary school learners remains a key contributor. To address this, we designed an adaptable and scalable high school outreach programme that sought to raise STEM (with a focus on bioscience) awareness through events that could be readily adapted to meet high school needs and resource constraints. Learner perceptions were recorded using a pre- and post-event questionnaire. Following the event, awareness of bioscience-based careers and the required prerequisite skills and qualifications were increased by 58 and 53 % respectively. The degree to which learners were considering a bioscience-based career was increased by 43 %. Though interest in attending university to study STEM was unaltered, awareness of the qualifications required to progress to university was increased by 58 %. These findings suggest that outreach events are an effective way to raise general awareness of STEM-based higher education learning thence careers and highlight the importance of tailoring outreach events to meet school and learner needs.