A biomimetic ZIF nanoagent for synergistic regulation of glutamine metabolism and intracellular acidosis of cancer

A homotypic cancer cell membrane camouflaged zeolitic imidazolate framework (ZIF)-based nanoagent with co-loading of two inhibitors has been developed, which could suppress the efflux of protons to induce intracellular acidic...

Ocean Acidification: Comparative Impacts on the Photophysiology of a Temperate Symbiotic Sea Anemone and a Tropical Coral

<p>Ocean acidification has the potential to drastically alter the coral reef ecosystem by reducing the calcification rate of corals and other reef-builders, and hence a considerable amount of research is now focused on this issue. It also is conceivable that acidification may affect other physiological processes of corals. In particular, acidification may alter photosynthetic physiology and hence the productivity of the coraldinoflagellate symbiosis that is pivotal to the reef's survival and growth. However, very little is known about the impacts of acidification on the photophysiology of corals or, indeed, other invertebrate-algal symbioses. This gap in our knowledge was addressed here by measuring the impacts of acidification (pH 7.6 versus pH 8.1) on the photophysiology and health of the tropical coral Stylophora pistillata and its isolated dinoflagellate symbionts ('zooxanthellae'), and the temperate sea anemone Anthopleura aureoradiata. The comparative nature of this study allowed for any differences between tropical and temperate symbioses, and zooxanthellae in a symbiotic or free-living state, to be assessed. Corals, anemones and cultured zooxanthellae were maintained in flowthrough seawater systems, and treated either with non-acidified (control) seawater at pH 8.1, or seawater acidified with CO2 or HCl to pH 7.6. A variety of parameters, including zooxanthellar density, chlorophyll content, photosynthetic health (Yi), and the ratio of gross photosynthetic production to respiration (P:R) were measured via cell counts, spectrophotometry, respirometry and PAM fluorometry, at a series of time-points up to a maximum of 42 days. Acidification generated by the addition of CO2 had no discernible effect on Yi of either the corals or anemones. However, in the coral, chlorophyll content per zooxanthella cell increased by 25%, which was countered by a near-significant decline (22%) in the rate of gross photosynthesis per unit chlorophyll; as zooxanthellar density remained unchanged, this led to a constant P:R ratio. When acidified via CO2, the isolated zooxanthellae exhibited no impacts in recorded Yi or chlorophyll levels. The response of the anemone to acidification via CO2 was different to that observed in the coral, as the density of zooxanthellae increased, rather than the chlorophyll content per cell, leading to an increased rate of gross photosynthesis. However P:R again remained constant as the increased photosynthesis was matched by an increased rate of respiration. In contrast to the impacts of CO2, HCl adversely impacted the chlorophyll content per cell in both the isolated zooxanthellae and sea anemone, and Yi, gross photosynthesis per cell, and overall gross photosynthesis in the sea anemone; however, despite the decline in gross photosynthesis, P:R remained constant due to the concurrent decline in respiration. Unfortunately, the corals in the HCl experiment died due to technical issues. There are two plausible reasons for this difference between CO2 and HCl. Firstly, HCl may have caused intracellular acidosis which damaged chloroplast structure and photosynthetic function. Secondly, the increased levels of aqueous CO2 stimulated photosynthetic function and hence mitigated for the effects of lowered pH. In addition, evidence is presented for a pH threshold for A. aureoradiata of between pH 6 and pH 6.75 (acidified with HCl), at which point photosynthesis 'shuts-down'. This suggests that, even without the potentially beneficial effects from increased CO2 levels, it is likely that oceanic pH would need to decrease to less than pH 6.75 for any acidosis effects to compromise the productivity of this particular symbiosis. Since acidification will have the benefits of increased CO2 and will reach nowhere near such low pH levels as those extremes tested here, it is proposed that ocean acidification via increased dissolution of CO2 into our oceans will have no impact on the photosynthetic production of symbiotic cnidarians. Indeed, it is entirely likely that increased CO2 will add some benefit to the usually carbon-limited symbiotic zooxanthellae. Ocean acidification is not likely to benefit corals however, with compromised calcification rates likely to undermine the viability of the coral. Symbiotic sea anemones, which do not bio-mineralise CaCO3, are better placed to take advantage of the increased CO2 as we move toward more acidic oceans.</p>

Ocean Acidification: Comparative Impacts on the Photophysiology of a Temperate Symbiotic Sea Anemone and a Tropical Coral

<p>Ocean acidification has the potential to drastically alter the coral reef ecosystem by reducing the calcification rate of corals and other reef-builders, and hence a considerable amount of research is now focused on this issue. It also is conceivable that acidification may affect other physiological processes of corals. In particular, acidification may alter photosynthetic physiology and hence the productivity of the coraldinoflagellate symbiosis that is pivotal to the reef's survival and growth. However, very little is known about the impacts of acidification on the photophysiology of corals or, indeed, other invertebrate-algal symbioses. This gap in our knowledge was addressed here by measuring the impacts of acidification (pH 7.6 versus pH 8.1) on the photophysiology and health of the tropical coral Stylophora pistillata and its isolated dinoflagellate symbionts ('zooxanthellae'), and the temperate sea anemone Anthopleura aureoradiata. The comparative nature of this study allowed for any differences between tropical and temperate symbioses, and zooxanthellae in a symbiotic or free-living state, to be assessed. Corals, anemones and cultured zooxanthellae were maintained in flowthrough seawater systems, and treated either with non-acidified (control) seawater at pH 8.1, or seawater acidified with CO2 or HCl to pH 7.6. A variety of parameters, including zooxanthellar density, chlorophyll content, photosynthetic health (Yi), and the ratio of gross photosynthetic production to respiration (P:R) were measured via cell counts, spectrophotometry, respirometry and PAM fluorometry, at a series of time-points up to a maximum of 42 days. Acidification generated by the addition of CO2 had no discernible effect on Yi of either the corals or anemones. However, in the coral, chlorophyll content per zooxanthella cell increased by 25%, which was countered by a near-significant decline (22%) in the rate of gross photosynthesis per unit chlorophyll; as zooxanthellar density remained unchanged, this led to a constant P:R ratio. When acidified via CO2, the isolated zooxanthellae exhibited no impacts in recorded Yi or chlorophyll levels. The response of the anemone to acidification via CO2 was different to that observed in the coral, as the density of zooxanthellae increased, rather than the chlorophyll content per cell, leading to an increased rate of gross photosynthesis. However P:R again remained constant as the increased photosynthesis was matched by an increased rate of respiration. In contrast to the impacts of CO2, HCl adversely impacted the chlorophyll content per cell in both the isolated zooxanthellae and sea anemone, and Yi, gross photosynthesis per cell, and overall gross photosynthesis in the sea anemone; however, despite the decline in gross photosynthesis, P:R remained constant due to the concurrent decline in respiration. Unfortunately, the corals in the HCl experiment died due to technical issues. There are two plausible reasons for this difference between CO2 and HCl. Firstly, HCl may have caused intracellular acidosis which damaged chloroplast structure and photosynthetic function. Secondly, the increased levels of aqueous CO2 stimulated photosynthetic function and hence mitigated for the effects of lowered pH. In addition, evidence is presented for a pH threshold for A. aureoradiata of between pH 6 and pH 6.75 (acidified with HCl), at which point photosynthesis 'shuts-down'. This suggests that, even without the potentially beneficial effects from increased CO2 levels, it is likely that oceanic pH would need to decrease to less than pH 6.75 for any acidosis effects to compromise the productivity of this particular symbiosis. Since acidification will have the benefits of increased CO2 and will reach nowhere near such low pH levels as those extremes tested here, it is proposed that ocean acidification via increased dissolution of CO2 into our oceans will have no impact on the photosynthetic production of symbiotic cnidarians. Indeed, it is entirely likely that increased CO2 will add some benefit to the usually carbon-limited symbiotic zooxanthellae. Ocean acidification is not likely to benefit corals however, with compromised calcification rates likely to undermine the viability of the coral. Symbiotic sea anemones, which do not bio-mineralise CaCO3, are better placed to take advantage of the increased CO2 as we move toward more acidic oceans.</p>

Use of intravenous sodium bicarbonate in neonatal intensive care units in Italy: a nationwide survey

Background Metabolic Acidosis (MA) is a disturbance of the acid-base balance that can occur in preterm and critically ill term neonates due to different etiologies. Intravenous sodium bicarbonate (SB) has been traditionally used to correct such unbalance, despite the lack of evidence about its safety and efficacy. In literature, reported undesirable effects of treatment with SB in neonates include worsening of intracellular acidosis, impairment of myocardial function, cerebral blood flow fluctuations and intracranial hemorrhage. A national survey was conducted by the Neonatal Pharmacotherapy Study Group of the Italian Society of Neonatology with the aim to assess and describe attitudes and practices concerning the use of SB, particularly for the treatment of MA in Italian NICUs. Methods A questionnaire regarding treatment of MA and SB prescription habits was sent to the directors of 120 Italian NICUs from June 2017 to March 2018. Results The survey response rate was 97.5% (117/120 centers). Findings showed that in 55% of the surveyed NICUs (64/117 units) it is common practice to correct MA with intravenous SB. On the other hand, the remaining 45% of the units try to solve the metabolic disturbances adopting different approaches (improving perfusion, adjusting ventilation parameters or increasing blood volume). Moreover, to prevent the occurrence of MA, 37.6% of the NICUs (44/117) include buffer salts (lactate, acetate or both) in parenteral nutrition prescriptions. SB is also used as a treatment for other conditions, mainly pathologies with bicarbonate loss and tubular acidosis (respectively in 53.8 and 32.5% of the NICUs). Conclusion This survey showed how SB is a commonly used treatment for MA in more than half of Italian NICUs, with indications and prescription criteria that significantly vary across centers. Based on current knowledge, it is reasonable to suggest that the management of neonatal MA should be firstly directed to identify the underlying disorders. Thus, the use of SB should be reserved only for selected cases, also considering the severity of SB adverse effects and the lack of evidence about its efficacy. Guidance for the management of MA is required to harmonize practices and reduce the use of potentially inappropriate and unsafe treatments.

Eccentric Cycling Training Improves Erythrocyte Antioxidant and Oxygen Releasing Capacity Associated with Enhanced Anaerobic Glycolysis and Intracellular Acidosis

The antioxidant capacity of erythrocytes protects individuals against the harmful effects of oxidative stress. Despite improved hemodynamic efficiency, the effect of eccentric cycling training (ECT) on erythrocyte antioxidative capacity remains unclear. This study investigates how ECT affects erythrocyte antioxidative capacity and metabolism in sedentary males. Thirty-six sedentary healthy males were randomly assigned to either concentric cycling training (CCT, n = 12) or ECT (n = 12) at 60% of the maximal workload for 30 min/day, 5 days/week for 6 weeks or to a control group (n = 12) that did not receive an exercise intervention. A graded exercise test (GXT) was performed before and after the intervention. Erythrocyte metabolic characteristics and O2 release capacity were determined by UPLC-MS and high-resolution respirometry, respectively. An acute GXT depleted Glutathione (GSH), accumulated Glutathione disulfide (GSSG), and elevated the GSSG/GSH ratio, whereas both CCT and ECT attenuated the extent of the elevated GSSG/GSH ratio caused by a GXT. Moreover, the two exercise regimens upregulated glycolysis and increased glucose consumption and lactate production, leading to intracellular acidosis and facilitation of O2 release from erythrocytes. Both CCT and ECT enhance antioxidative capacity against severe exercise-evoked circulatory oxidative stress. Moreover, the two exercise regimens activate erythrocyte glycolysis, resulting in lowered intracellular pH and enhanced O2 released from erythrocytes.

Use of intravenous sodium bicarbonate in neonatal intensive care units in Italy: a nationwide survey.

Background: Metabolic Acidosis (MA) is a disturbance of the acid-base balance that can occur in preterm and critically ill term neonates due to different etiologies. Intravenous sodium bicarbonate (SB) has been traditionally used to correct such unbalance, despite the lack of evidence about its safety and efficacy. In literature, reported undesirable effects of treatment with SB in neonates include worsening of intracellular acidosis, impairment of myocardial function, cerebral blood flow fluctuations and intracranial hemorrhage. A national survey was conducted by the Neonatal Pharmacotherapy Study Group of the Italian Society of Neonatology with the aim to assess and describe attitudes and practices concerning the use of SB, particularly for the treatment of MA in Italian NICUs. Methods: A questionnaire regarding treatment of MA and SB prescription habits was sent to the directors of 120 Italian NICUs from June 2017 to March 2018. Results: The survey response rate was 97.5% (117/120 centers). Findings showed that in 55% of the surveyed NICUs (64/117 units) it is common practice to correct MA with intravenous SB. On the other hand, the remaining 45% of the units try to solve the metabolic disturbances adopting different approaches (improving perfusion, adjusting ventilation parameters or increasing blood volume). Moreover, to prevent the occurrence of MA, 37.6% of the NICUs (44/117) include buffer salts (lactate, acetate or both) in parenteral nutrition prescriptions. SB is also used as a treatment for other conditions, mainly pathologies with bicarbonate loss and tubular acidosis (respectively in 53.8% and 32.5% of the NICUs). Conclusion: This survey showed how SB is a commonly used treatment for MA in more than half of Italian NICUs, with indications and prescription criteria that significantly vary across centers. Based on current knowledge, it is reasonable to suggest that the management of neonatal MA should be firstly directed to identify the underlying disorders. Thus, the use of SB should be reserved only for selected cases, also considering the severity of SB adverse effects and the lack of evidence about its efficacy. Guidance for the management of MA is required to harmonize practices and reduce the use of potentially inappropriate and unsafe treatments.

The Pivotal Role Of Coconut Oil Or Liquid Paraffin As Antidote Effective In Reducing Acute Aluminum Phosphide Poisoning In Cardiogenic Shock

Introduction/Objective Aluminum phosphide (Alp) is a self-poisoning agent for raising the mortality rates in developing countries. Alp is known as “Rice-tablet” which is a cheap solid fumigant pesticide that is used for grain preservation which becomes a common mode of suicidal attempts in the rural community in Egypt. This study aims to identify the mechanism of salient features and management strategies were carried out on acute Alp-poisoned patients at Poison-Emergency-Unit, ElBehira-Hospitals. That was performed between Jan2018-Jun2019. Methods Patients were subjected to a full history evaluation of age, sex, Blood gases, and ECG, were demonstrated. Patients were grouped according to their outcome into survivors and non-survivors groups. Results The results demonstrated that (93%) of Alp-poisoning cases by oral-ingestion as suicidal attempts which were (54%) survived while (46%) non-survived. The blood-gases were showed that over 50% of the cases had metabolic acidosis with a highly-significant difference between survivors and non-survivors. PH and HCO3 values were significantly lower in non-survivors than those in the survivor group. Furthermore, SaO2 value was significantly higher in survivors than that of non-survivors. So the managing Alp-poisoning should be started for first 6hr since exposure. Treatment includes early gastric lavage with potassium-permanganate-(1:10,000), sodium-bicarbonate or coconut-oil/liquid-paraffin. The mechanism of Alp-poisoning explained that, phosphine gas inhibits 70% of mitochondrial cytochrome-c-oxidase in myocardial-tissue by the effect of free-radicals; electrolyte disturbance, and intracellular acidosis all cause a reduction in cardiac function, and multi-organ damage. These effects may cause arrhythmia and myocarditis which may be the cause of death. Conclusion It was concluded that myocardial depression with shock and metabolic acidosis may lead to respiratory failure due to acute Alp-poisoning. This case study reported that coconut oil play a pivotal role in managing acute Alp- poisoning even 6h post ingestion for reducing the oxidative outcomes of phosphine and recommended as antidote for acute Alp-intoxication.

Use of Intravenous Sodium Bicarbonate in Neonatal Intensive Care Units in Italy: A Nationwide Survey

Background Metabolic Acidosis (MA) is a disturbance of the acid-base balance that can occur in preterm and critically ill term neonates due to different etiologies. Intravenous sodium bicarbonate (SB) has been traditionally used to correct such unbalance, despite the lack of evidence about its safety and efficacy. In literature, reported undesirable effects of treatment with SB in neonates include worsening of intracellular acidosis, impairment of myocardial function, cerebral blood flow fluctuations and intracranial hemorrhage. A national survey was conducted by the Neonatal Pharmacotherapy Study Group of the Italian Society of Neonatology with the aim to assess and describe attitudes and practices concerning the use of SB, particularly for the treatment of MA in Italian NICUs. Methods A questionnaire regarding treatment of MA and SB prescription habits was sent to the directors of 120 Italian NICUs from June 2017 to March 2018. Results The survey response rate was 97.5% (117/120 centers). Findings showed that in 55% of the surveyed NICUs (64/117 units) it is common practice to correct MA with intravenous SB. On the other hand, the remaining 45% of the units try to solve the metabolic disturbances adopting different approaches (improving perfusion, adjusting ventilation parameters or increasing blood volume). Moreover, to prevent the occurrence of MA, 37.6% of the NICUs (44/117) include buffer salts (lactate, acetate or both) in parenteral nutrition prescriptions. SB is also used as a treatment for other conditions, mainly pathologies with bicarbonate loss and tubular acidosis (respectively in 53.8% and 32.5% of the NICUs). Conclusion This survey showed how SB is a commonly used treatment for MA in more than half of Italian NICUs, with indications and prescription criteria that significantly vary across centers. Based on current knowledge, it is reasonable to suggest that the management of neonatal MA should be firstly directed to identify the underlying disorders. Thus, the use of SB should be reserved only for selected cases, also considering the severity of SB adverse effects and the lack of evidence about its efficacy. Guidance for the management of MA is required to harmonize practices and reduce the use of potentially inappropriate and unsafe treatments.

Lactate and Acidity in the Cancer Microenvironment

Fermentative glycolysis, an ancient evolved metabolic pathway, is exploited by rapidly growing tissues and tumors but also occurs in response to the nutritional and energetic demands of differentiated tissues. The lactic acid it produces is transported across cell membranes through reversible H+/lactate− symporters (MCT1 and MCT4) and is recycled in organs as a major metabolic precursor of gluconeogenesis and an energy source. Concentrations of lactate in the tumor environment, investigated utilizing an induced metabolic bioluminescence imaging (imBI) technique, appear to be dominant biomarkers of tumor response to irradiation and resistance to treatment. Suppression of lactic acid formation by genetic disruption of lactate dehydrogenases A and B in aggressive tumors reactivated OXPHOS (oxidative phosphorylation) to maintain xenograft tumor growth at a halved rate. In contrast, disruption of the lactic acid transporters MCT1/4 suppressed glycolysis, mTORC1, and tumor growth as a result of intracellular acidosis. Furthermore, the global reduction of tumor acidity contributes to activation of the antitumor immune responses, offering hope for future clinical applications.

Etiology and Management of Acute Metabolic Acidosis: An Update

Background: The etiology of acute metabolic acidosis (aMA) is heterogeneous, and the consequences are potentially life-threatening. The aim of this article was to summarize the causes and management of aMA from a clinician’s perspective. Summary: We performed a systematic search on PubMed, applying the following search terms: “acute metabolic acidosis,” “lactic acidosis,” “metformin” AND “acidosis,” “unbalanced solutions” AND “acidosis,” “bicarbonate” AND “acidosis” AND “outcome,” “acute metabolic acidosis” AND “management,” and “acute metabolic acidosis” AND “renal replacement therapy (RRT)/dialysis.” The literature search did not consider diabetic ketoacidosis at all. Lactic acidosis evolves from various conditions, either with or without systemic hypoxia. The incidence of metformin-associated aMA is actually quite low. Unbalanced electrolyte preparations can induce hyperchloremic aMA. The latter potentially worsens kidney-related outcome parameters. Nevertheless, prospective and controlled data are missing at the moment. Recently, bicarbonate has been shown to improve clinically relevant endpoints in the critically ill, even if higher pH values (>7.3) are targeted. New therapeutics for aMA control are under development, since bicarbonate treatment can induce serious side effects. Key Messages: aMA is a frequent and potentially life-threatening complication of various conditions. Lactic acidosis might occur even in the absence of systemic hypoxia. The incidence of metformin-associated aMA is comparably low. Unbalanced electrolyte solutions induce hyperchloremic aMA, which most likely worsens the renal prognosis of critically ill patients. Bicarbonate, although potentially deleterious due to increased carbon dioxide production with subsequent intracellular acidosis, improves kidney-related endpoints in the critically ill.