Conditions Of Acidosis Research Articles

Effect of Bioplastic Material on Adhesion, Growth, and Proliferative Activity of Human Fibroblasts When Incubated in Solutions Mimic the Acidity of Wound an Acute and Chronic Inflammation.

: The aim of this study was to characterize the effect of bioplastic material based on collagen, hyaluronic acid, and elastin on the viability and proliferative activity of human fibroblasts in conditions simulating the acidity of acute and chronic wounds. : Bioplastic material was made according to the method described in RF patent no.2722744. Adhesive properties and proliferative activity of human fibroblasts were assessed visually using fluorescent microscopy. The number of apoptotic and necrotic cells was assessed by flow cytometry (BD FACSCanto II) using the commercial FITC Annexin V Apoptosis Detection Kit I (BD Pharmingen). The strength, Young's modulus, and elasticity of the gels were determined on a TA.XT-plus texture analyzer (Stable Micro Systems, Great Britain). : Using the methods of luminescent microscopy and flow cytometry, we found that the cell viability (namely, adhesive properties and proliferative activity) decreases after incubation on condition mimic of physiological acidosis. We found that bioplastic material contributes to the preservation of adhesive properties, viability, and proliferative activity of fibroblasts in physiological acidosis conditions. The results obtained indicate that bioplastic material based on soluble dermis components can be used as a biologically active component of wound dressings to increase the effectiveness of reparative regeneration, especially in cases of excessive acute inflammation.

Ruminal acidosis and its definition: A critical review

Ruminal acidosis occurs as a continuum of disorders, stemming from ruminal dysbiosis and disorders of metabolism, of varying severity. The condition has a marked temporal dynamic expression resulting in cases expressing quite different rumen concentrations of VFA, lactic acid, ammonia, and rumen pH over time. Clinical ruminal acidosis is an important condition of cattle and subclinical ruminal acidosis (SRA) is very prevalent in many dairy populations with estimates between 10 to 26% of cows in early lactation. Estimates of the duration of a case suggest the lactational incidence of the condition may be as high as 500 cases per 100 cows in the first 100 d of lactation. Historical confusion about the etiology and pathogenesis of ruminal acidosis led to definitions that are not fit for purpose as acidic ruminal conditions solely characterized by ruminal pH determination at a single point fail to reflect the complexity of the condition. Use of a model, based on integrated ruminal measures including VFA, ammonia, lactic acid, and pH, for evaluating ruminal acidosis is fit for purpose, as indicated by meeting postulates for assessing metabolic disease, but requires a method to simplify application in the field. While it is likely that this model, that we have termed the Bramley Acidosis Model (BAM), will be refined, the critical value in the model is that it demonstrates that ruminal acidosis is much more than ruminal pH. Disease, milk yield and milk composition are more associated with the BAM than rumen pH alone. Two single VFA, propionate and valerate are sensitive and specific for SRA, especially when compared with rumen pH. Even with the use of such a model, astute evaluations of the condition whether in experimental or field circumstances will be aided by ancillary measures that can be used in parallel or in series to enhance diagnosis and interpretation. Sensing methods including rumination detection, behavior, milk analysis, and passive analysis of rumen function have the potential to improve the detection of SRA; however, these may advance more rapidly if SRA is defined more broadly than by ruminal pH alone.

Disturbances of Ruminal Microbiota and Liver Inflammation, Mediated by LPS and Histamine, in Dairy Cows Fed a High-Concentrate Diet.

The ecosystem of ruminal microbiota profoundly affects the health and milk production of dairy cows. High-concentrate diets are widely used in dairy farms and evoke a series of metabolic disorders. Several studies have reported the effects of high-concentrate diets on the ruminal microbiome, while the effect of changes in ruminal microbial flora, induced by high-concentrate diet feeding, on the liver of dairy cows has not been studied before. In this study, 12 mid-lactating Holstein Friesian cows (weight of 455 ± 28 kg; parities of 2.5 ± 0.5; starting milk yield of 31.59 ± 3.2 kg/d; DMI of 21.7 ± 1.1 kg/d; and a DIM at the start of the experiment of 135 ± 28 d) were fitted with ruminal fistulas, as well as with portal and hepatic vein catheters. All cows were randomly divided into 2 groups; then, they fed with low-concentrate diets (LC, concentrate: forage = 40:60) and high-concentrate diets (HC, concentrate: forage = 60:40) for 18 weeks. The forage sources were corn silage and alfalfa hay. After the cows of two groups were euthanized over two consecutive days, ruminal microbiota; the concentration of LPS in the rumen content; cecum content; the levels of blood and histamine in rumen fluid, blood, and the liver; the histopathological status of the rumen and cecum; and the inflammatory response of the liver were assessed in dairy cows under conditions of subacute ruminal acidosis (SARA). These conditions were caused by high-concentrate diet feeding. All data were analyzed using the independent t-test in SPSS. The results showed that high-concentrate diet feeding increased the concentration of LPS and histamine in the rumen and plasma of veins (p < 0.05). The abundance of Bacteroidetes at the phylum level, and of both Bacteroidetes and Saccharibacteria at the genus level, was decreased, while the abundance of Firmicutes at the phylum level and Oscillibacter at the genus level was increased by high-concentrate diet feeding. The decreased pH values of ruminal contents (LC = 6.02, HC = 5.90, p < 0.05) and the increased level of LPS in the rumen (LC = 4.921 × 105, HC = 7.855 × 105 EU/mL, p < 0.05) and cecum (LC = 11.960 × 105, HC = 13.115 × 105 EU/mL, p < 0.01) induced the histopathological destruction of the rumen and cecum, combined with the increased mRNA expression of IL-1β (p < 0.05). The histamine receptor H1R and the NF-κB signaling pathway were activated in the liver samples taken from the HC group. In conclusion, the elevated concentrations of LPS and histamine in the gut may be related to changes in the ruminal microbiota. LPS and histamine induced the inflammatory response in the ruminal epithelium, cecum epithelium, and liver. However, the cause-effect mechanism needs to be proved in future research. Our study offers a novel therapeutic strategy by manipulating ruminal microbiota and metabolism to decrease LPS and histamine release and to improve the health of dairy cows.

Influence of acute dietary nitrate supplementation on oxygen delivery/consumption and critical impulse during maximal effort forearm exercise in males: a randomized crossover trial.

Beetroot juice supplementation (BRJ) should increase nitric oxide bioavailability under conditions of muscle deoxygenation and acidosis that are a normal consequence of the maximal effort exercise test used to identify forearm critical impulse. We hypothesized BRJ would improve oxygen delivery:demand matching and forearm critical impulse performance. Healthy males (20.8±2.4 years) participated in a randomized crossover trial between October 2017 and May 2018 (Queen's University, Kingston, ON). Participants completed 10 min of rhythmic maximal effort forearm handgrip exercise 2.5 h post placebo (PL) vs. BRJ (9 completed PL/BRJ vs. 4 completed BRJ/PL) within a 2 week period. Data are presented as mean±SD. There was a main effect of drink (PL>BRJ) for oxygen extraction (P=0.033, ηp2=0.351) and oxygen consumption/force (P=0.017, ηp2=0.417). There was a drink × time interaction (PL>BRJ) for oxygen consumption/force (P=0.035, ηp2=0.216) between 75 and 360s (1.25-6min) from exercise onset. BRJ did not influence oxygen delivery (P=0.953, ηp2=0.000), oxygen consumption (P=0.064, ηp2=0.278), metabolites ((lactate) (P=0.196, ηp2=0.135), pH (P=0.759, ηp2=0.008)) or power-duration performance parameters (critical impulse (P=0.379, d=0.253), W' (P=0.733, d=0.097)). BRJ during all-out handgrip exercise does not influence oxygen delivery or exercise performance. Oxygen cost of contraction with BRJ is reduced as contraction impulse is declining during maximal effort exercise resulting in less oxygen extraction.

Effect of lactate supplementation to skeletal muscle cells on fiber type transition and cellular bioenergetics

It is well-known that lactate (LAC) is the primary cellular end-product of glycolysis. However, during intense exercise and transient hypoxic conditions, the intracellular LAC levels are significantly elevated. Recently, our in vitro biochemical and biophysical studies have revealed that LAC avidly binds to oxy-myoglobin (oxy-Mb) in acidic conditions and rapidly releases oxygen (O2). Based on these results, we hypothesize that LAC plays a significant role in tissue O2 management combating hypoxic conditions in high demanding exercising tissues, such as Mb rich skeletal muscles type I oxidative fibers. Here, we have investigated three types of mouse C2C12 cell line models, i.e. Wild-type (WT) cells, Mb knock-out (MbKO) cells, and Empty vector (EV) cells. 5-day old differentiated C2C12 cells were supplemented with varying concentrations (3 mM, 5 mM and 8 mM) of sodium lactate added to the DMEM growth medium. Thereafter, cells were incubated in temperature regulated CO2 incubator for varying time periods (3 h, 6 h, and 24 h) to evaluate the early and prolonged effect on tissue fiber type transition and cellular bioenergetics. Metabolic assays such as hexokinase activity, LAC dehydrogenase (LDH) activity, and glucose uptake were performed using the intracellular cell lysate whereas extracellular LAC levels were measured using LAC assay kit. Seahorse experiments were conducted to measure the cellular glycolytic and mitochondrial ATP production rates. Our findings revealed that, there was no significant difference in myotube width in C2C12 cells either with or without LAC supplementation across all the test conditions. Intriguingly, at lower LAC supplementation (1.8 mM) conditions, the extracellular LAC levels were found to be significantly increased in WT cells compared to MbKO cells. However, at mimicking hyperlactatemia (5 mM LAC) and lactic acidosis (8 mM LAC) conditions, distinct extracellular LAC levels were recorded with WT and MbKO cells. Our results clearly suggests that Mb containing cells effciently utilize LAC for cellular bioenergetics and other biochemical processes. Similarly, in response to increasing LAC supplementation levels, LDH activity was also found to higher in WT cells compared to MbKO cells. Furthermore, glucose uptake in MbKO cells was significantly decreased. Finally, significantly lower rates of glycolytic ATP production was observed when compared to mitochondrial ATP production in WT cells with similar overall ATP production rates in all treatment conditions and incubation periods. However, marginal decrease in both glycolytic and mitochondrial ATP production rates were observed in MbKO cells. Overall, this study clearly demonstrated that external supplementation of LAC to C2C12 cells had no significant effect on fiber type transition but reveals that Mb plays a significant role in LAC utilization. USDA-ARS project 6026-51000-012-06S, Sturgis Foundation Pilot Grant G1-54750-01 and ACRI-ABI Investigator Initiated Grant Award GR037175-4450S ABI. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cecropin A Alleviates LPS-Induced Oxidative Stress and Apoptosis of Bovine Endometrial Epithelial Cells.

Dairy cows receiving a prolonged high-concentrate diet express an elevated concentration of lipopolysaccharides (LPSs) in the peripheral blood circulation, accompanied by a series of systemic inflammatory responses; however, the specific impacts of inflammation are yet to be determined. Cecropin-like antimicrobial peptides have become a research hotspot regarding antimicrobial peptides because of their excellent anti-inflammatory activities, and cecropin A is a major member of the cecropin family. To elucidate the mechanism of cecropin A as anti-inflammatory under the condition of sub-acute ruminal acidosis (SARA) in dairy cows, we induced inflammation in bEECs with LPS (10 µg/mL) and then added cecropin A (25 µM). Afterwards, we detected three categories of indexes including oxidative stress indices, inflammation-related genes, and apoptosis-related genes in bovine endometrial epithelial cells (bEECs). The results indicated that cecropin A has the ability to reduce inflammatory factors TNF-α, IL-1β, and IL-8 and inhibit the MAPK pathway to alleviate inflammation. In addition, cecropin A is able to reduce reactive oxygen species (ROS) levels and alleviates LPS-induced oxidative stress and mitochondrial dysfunction by downregulating NADPH Oxidase (NOX), and upregulating catalase (CAT), glutathione peroxidase (GPX), and superoxide dismutase (SOD). Furthermore, cecropin A demonstrates the ability to inhibit apoptosis by suppressing the mitochondrial-dependent apoptotic pathway, specifically Fas/FasL-caspase-8/-3. The observed increase in the Bcl-2/Bax ratio, a known apoptosis regulator, further supports this finding. In conclusion, our study presents novel solutions for addressing inflammatory responses associated with SARA.

Modelling muscle wasting in chronic kidney disease under conditions of acidosis and steroid exposure

Modelling muscle wasting in chronic kidney disease under conditions of acidosis and steroid exposure

Identification of RhBG Mutations that Impair NH3/NH4+ Transport in Patients with Chronic Kidney Disease

Background: Acid-base disturbances are common in many illnesses, and metabolic acidosis is a major complication in patients with chronic kidney disease (CKD). The kidneys respond to acidosis by increasing urinary excretion of total ammonia (NH 3 /NH 4 + ) and to a lesser extent titratable acids. In the collecting duct, total ammonia is secreted by the NH 3 /NH 4 + transporters, RhBG and RhCG. RhBG transports NH 3 and NH 4 + at the basolateral membrane of intercalated cells. In CKD patients, the increase in ammonium excretion in response to acidosis is markedly impaired. Recent studies suggest that the reduced ability of the kidney to excrete ammonium is likely a cause of detrimental renal outcome in CKD and faster progression towards end-stage renal disease. Hypothesis: This study aims to identify loss of function mutations of RhBG (nsSNPs) that impair NH 3 /NH 4 + transport which may contribute to the deleterious effect of acidosis in CKD. Methods: We used Chronic Renal Insufficiency Cohort (CRIC) study to select SNPs of RhBG that are present in CKD patients but not in controls, or have a significant odds ratio (OR). Transport studies were conducted on Xenopus oocytes expressing Rh proteins or mutants. Wild-type RhBG (RhBG-WT) or RhBG-mutants were expressed by microinjecting oocytes with respective mRNA. H 2 O-injected oocytes served as negative controls. Each oocyte was perfused with solutions containing 5 mM NH 3 /NH 4 + or 5 mM MA/MA + (methylamine/methylammonium, a surrogate of NH 3 /NH 4 + ) to test RhBG function. Using ion-selective microelectrodes, we measured changes in intracellular pH, whole cell currents or surface pH to assess transport of NH 3 or NH 4 + . Results: Two RhBG mutations, G148R and G148W, which are only present in the patient group from CRIC cohort, significantly inhibited transport of NH 3 and NH 4 + (and MA/MA + ) compared with RhBG-WT (p&lt;0.05) in Xenopus oocytes. Two other mutations, G86S and G86C, positively associated with CKD patients (OR=4.65, p&lt;0.05), showed different inhibition patterns: G86S maintained the ability to transport NH 4 + , NH 3 and MA + while G86C inhibited NH 3 and NH 4 + transport but MA + transport was less affected compared with RhBG-WT. Both G86S and G86C showed a 50% decrease in MA transport (p&lt;0.05) that was still significantly higher than negative control. Conclusions: We discovered two RhBG mutations, G148R and G148W, in CKD patients that completely inhibited the transport of NH 3 /NH 4 + . The other two mutations, G86S and G86C, partially inhibited transport, and G86C was more deleterious than G86S in its inhibitory effect on NH 4 + and NH 3 transport. Significance: This study is the first to identify, in a cohort of CKD patients, 4 mutations with functional effects on NH 3 /NH 4 + transport. This work provides the foundation to further investigate whether naturally occurring genetic variations that impair ammonia secretion are associated with fast CKD progression under acidosis conditions. Funding grants: NIH-U54 GM104940, Paul Teschan Research, NIH-R01, Carol Lavin Bernick, Tulane institutional This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Megasphaera elsdenii and Saccharomyces cerevisiae as direct fed microbials and their impact on ruminal microbiome during an acute acidosis challenge in continuous culture.

Our objective was to evaluate the effects of combinations of Saccharomyces cerevisiae and Megasphaera elsdenii as direct-fed microbials (DFM) on ruminal microbiome during an acute acidosis challenge in a continuous culture system. Treatments provided a DFM dose of 1 × 108 colony-forming unit (CFU)/mL, as follows: control (no DFM), YM1 (S. cerevisiae and M. elsdenii strain 1), YM2 (S. cerevisiae and M. elsdenii strain 2), and YMM (S. cerevisiae and half of the doses of M. elsdenii strains 1 and 2). We conducted four experimental periods of 11 d, which consisted of non-acidotic days (1 to 8) and acidotic challenge days (9 to 11) to establish acute ruminal acidosis conditions with a common basal diet containing 12% neutral detergent fiber and 58% starch. Treatments were applied from days 8 to 11, and samples of liquid and solid-associated bacteria were collected on days 9 to 11. Overall, 128 samples were analyzed by amplification of the V4 region of bacterial 16S rRNA, and data were analyzed with R and SAS for alpha and beta diversity, taxa relative abundance, and correlation of taxa abundance with propionate molar proportion. We observed a lower bacterial diversity (Shannon index, P = 0.02) when YM1 was added to the diet in comparison to the three other treatments. Moreover, compared to control, addition of YM1 to the diet increased relative abundance of phylum Proteobacteria (P = 0.05) and family Succinivibrioceae (P = 0.05) in the solid fraction and tended to increase abundance of family Succinivibrioceae (P = 0.10) and genus Succinivibrio (P = 0.09) in the liquid fraction. Correlation analysis indicated a positive association between propionate molar proportion and relative abundance of Proteobacteria (r = 0.36, P = 0.04) and Succinivibrioceae (r = 0.36, P = 0.05) in the solid fraction. The inclusion of YM1 in high-grain diets with a high starch content resulted in greater abundance of bacteria involved in succinate synthesis which may have provided the substrate for the greater propionate synthesis observed.

Diabetic ketoacidosis awareness and prevention for new onset Type 1 diabetes

Diabetic ketoacidosis (DKA) is an avoidable life-threatening condition and form of metabolic acidosis that develops with a relative or absolute deficiency of circulating insulin (Cashen & Peterson, 2019). The imbalance of insulin and counterregulatory hormone levels can lead to hyperglycemia, hyperosmolality, ketosis, and acidosis which results in cerebral edema and death if not addressed quickly. The incidence of DKA hospitalizations continues to increase, and the most common cause of DKA is new-onset Type 1 diabetes (T1D).

To what extent is end-tidal carbon dioxide a predictor of sepsis?

Background: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. It is a major cause of death worldwide; 245 000 cases are reported in the UK annually with a mortality rate of 20.3%. Rapid diagnosis and rapid treatment of sepsis can significantly reduce mortality but sepsis can be difficult to diagnose. End-tidal carbon dioxide (EtCO2) is the measurement of expired CO2 using capnometry and waveform capnography. For CO2 to be exhaled, it must be metabolised and transported before being exhaled by effective ventilation; EtCO2 can therefore provide an indication of metabolism, circulation and ventilation. EtCO2 has already been shown to be an indicator of other metabolic acidosis conditions so this review aims to identify the usefulness of EtCO2 in identifying sepsis. Methods: A systematic literature search was conducted between March and April 2021 using the CINAHL Plus and MEDLINE databases. The results were screened and evaluated. Results: Of the 44 papers identified in the original search, seven were included in this review. Conclusion: This review suggests an EtCO2 of ≤25 mmHg (3.3 kPa) in patients with a suspected infection is diagnostic of sepsis and therefore could be used to increase the speed and accuracy of diagnosis and potentially reduce sepsis mortality. It also identifies gaps in research around UK practice and in comparing EtCO2 against UK sepsis guidelines and diagnostic tools such as the UK Sepsis Trust guidelines.

Influence of Direct-fed Microbial Blend and Ferula Elaeochytris on in Vitro Rumen Fermentation Pattern and Degradability During Simulated Ruminal Acidosis.

The use of probiotics and phytobiotics has attracted interest because of their protective effect against acidosis. Ferula elaeochytris (FE) is considered a good source of bioactive compounds, mainly monoterpene α-pinene. This study aimed to investigate the effect of a direct-fed microbial blend (Pro) and FE on rumen fermentation parameters in vitro under normal and acidosis conditions. An in vitro experiment using the Hohenheimer Futterwerttest (HFT) gas production system was conducted. An acidosis challenge was made to compare the effectiveness of the probiotics blend and FE extract on ruminal pH regulation. To generate different ruminal fermentation parameters, the design of the trial considered the 2 additives (Pro and FE) × 6 incubation times (2, 4, 8, 12, 24 and 48 h) × 2 conditions (acidosis and normal) × 2 incubation runs for each feedstuff (barley, alfalfa and straw). An acidosis challenge was successfully induced. The Pro and FE additives had no impact on the observed rumen fermentation parameters such as volatile fatty acid concentration or ammonia (P = 0.001). The acidosis condition decreased total in vitro degradability (IVD) by 3.5% and 21.9% for barley and straw, respectively (P < 0.001). The additives had different significant effects on the IVD of nutrients during both normal and acidosis conditions. In alfalfa samples, FE supplementation significantly decreased the IVD of all observed nutrients under the ruminal acidosis condition, although it had no effect during the normal condition. An acidosis challenge was successfully induced and the effect of additives was varied on fermentation parameters and rumen degradability of different feeds either under normal or acidosis conditions.

The acidic tumor microenvironment enhances PD-L1 expression via activation of STAT3 in MDA-MB-231 breast cancer cells

Tumor acidosis, a common phenomenon in solid cancers such as breast cancer, is caused by the abnormal metabolism of cancer cells. The low pH affects cells surrounding the cancer, and tumor acidosis has been shown to inhibit the activity of immune cells. Despite many previous studies, the immune surveillance mechanisms are not fully understood. We found that the expression of PD-L1 was significantly increased under conditions of extracellular acidosis in MDA-MB-231 cells. We also confirmed that the increased expression of PD-L1 mediated by extracellular acidosis was decreased when the pH was raised to the normal range. Gene set enrichment analysis (GSEA) of public breast cancer patient databases showed that PD-L1 expression was also highly correlated with IL-6/JAK/STAT3 signaling. Surprisingly, the expression of both phospho-tyrosine STAT3 and PD-L1 was significantly increased under conditions of extracellular acidosis, and inhibition of STAT3 did not increase the expression of PD-L1 even under acidic conditions in MDA-MB-231 cells. Based on these results, we suggest that the expression of PD-L1 is increased by tumor acidosis via activation of STAT3 in MDA-MB-231 cells.

Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic Migraine.

Familial hemiplegic migraine (FHM) is a severe neurogenetic disorder for which three causal genes, CACNA1A, SCN1A, and ATP1A2, have been implicated. However, more than 80% of referred diagnostic cases of hemiplegic migraine (HM) are negative for exonic mutations in these known FHM genes, suggesting the involvement of other genes. Using whole-exome sequencing data from 187 mutation-negative HM cases, we identified rare variants in the CACNA1I gene encoding the T-type calcium channel Cav3.3. Burden testing of CACNA1I variants showed a statistically significant increase in allelic burden in the HM case group compared to gnomAD (OR = 2.30, P = 0.00005) and the UK Biobank (OR = 2.32, P = 0.0004) databases. Dysfunction in T-type calcium channels, including Cav3.3, has been implicated in a range of neurological conditions, suggesting a potential role in HM. Using patch-clamp electrophysiology, we compared the biophysical properties of five Cav3.3 variants (p.R111G, p.M128L, p.D302G, p.R307H, and p.Q1158H) to wild-type (WT) channels expressed in HEK293T cells. We observed numerous functional alterations across the channels with Cav3.3-Q1158H showing the greatest differences compared to WT channels, including reduced current density, right-shifted voltage dependence of activation and inactivation, and slower current kinetics. Interestingly, we also found significant differences in the conductance properties exhibited by the Cav3.3-R307H and -Q1158H variants compared to WT channels under conditions of acidosis and alkalosis. In light of these data, we suggest that rare variants in CACNA1I may contribute to HM etiology.

Myoglobin Interaction with Lactate Rapidly Releases Oxygen: Studies on Binding Thermodynamics, Spectroscopy, and Oxygen Kinetics.

Myoglobin (Mb)-mediated oxygen (O2) delivery and dissolved O2 in the cytosol are two major sources that support oxidative phosphorylation. During intense exercise, lactate (LAC) production is elevated in skeletal muscles as a consequence of insufficient intracellular O2 supply. The latter results in diminished mitochondrial oxidative metabolism and an increased reliance on nonoxidative pathways to generate ATP. Whether or not metabolites from these pathways impact Mb-O2 associations remains to be established. In the present study, we employed isothermal titration calorimetry, O2 kinetic studies, and UV-Vis spectroscopy to evaluate the LAC affinity toward Mb (oxy- and deoxy-Mb) and the effect of LAC on O2 release from oxy-Mb in varying pH conditions (pH 6.0–7.0). Our results show that LAC avidly binds to both oxy- and deoxy-Mb (only at acidic pH for the latter). Similarly, in the presence of LAC, increased release of O2 from oxy-Mb was detected. This suggests that with LAC binding to Mb, the structural conformation of the protein (near the heme center) might be altered, which concomitantly triggers the release of O2. Taken together, these novel findings support a mechanism where LAC acts as a regulator of O2 management in Mb-rich tissues and/or influences the putative signaling roles for oxy- and deoxy-Mb, especially under conditions of LAC accumulation and lactic acidosis.

Ambient pH regulates lactate catabolism pathway of the ruminal Megasphaera elsdenii BE2-2083 and Selenomonas ruminantium HD4.

To explore the impact of ambient pH on lactate catabolism by Megasphaera elsdenii BE2-2083 and Selenomonas ruminantium HD4 in both pure culture and in binary mixed culture. The growth rate, substrate consumption, product formation, enzymatic activity and gene expression of M. elsdenii and S. ruminantium at various pHs were examined. Furthermore, the metabolism of lactate catabolism pathways for M. elsdenii and S. ruminantium in the co-culture system was investigated by chasing the conversion of sodium L-[3-13 C]-lactate in nuclear magnetic resonance. In the pure culture systems, ambient pH had significant effects on the growth of M. elsdenii, whereas S. ruminantium was less sensitive to pH changes. In addition, lactate metabolic genes and activities of key enzymes were affected by ambient pH in M. elsdenii and S. ruminantium. In the co-culture system, low ambient pH reduced the contribution lactate catabolism by M. elsdenii. M. elsdenii BE2-2083 and S. ruminantium HD4 lactate degradation affected by ambient pH. This study demonstrates the regulatory mechanisms of lactate decomposing bacteria in lactate catabolism under the condition of subacute ruminal acidosis.

Case of lactacidosis in acute kidney damage and metformin therapy

Тhe article provides a clinical observation of the development of a rare pathological condition of lactic acidosis in a patient with acute kidney injury while taking metformin and confirms the need for timely determination of blood lactate.&#x0D; Тhe clinical case confirms that the development of lactic acidosis in a patient with diabetes mellitus may have a mixed etiology and be associated not only with the use of metformin, but also with the presence of tissue hypoxia, exposure to an infectious process, and impaired renal function.&#x0D; The development of lactic acidosis is associated with an increase in secretion and / or a decrease in the rate of excretion of lactate, which is expressed in a state of metabolic acidosis and severe cardiovascular insufficiency. The development of lactic acidosis is most often associated with the presence of renal and / or hepatic insufficiency, diabetes mellitus, lung pathology, macromicrocirculation disorders, and hemoglobin function defects, the treatment with biguanide drugs (metformin). Diagnosis of lactic acidosis is based on the data from a biochemical blood test and electrolyte parameters the concentration of blood plasma lactate, the study of acid-base state of the blood and anion gap.

How Does Mucorales Benefit from the Dysregulated Iron Homeostasis During SARS-CoV-2 Infection?

Mucorales is the cause of mucormycosis, an emerging opportunistic infection in the era of coronavirus disease 2019 (COVID-19) pandemic. Condition of hyperglycemia, diabetes mellitus, and acidosis; dysregulated iron homeostasis in the form of hyperferritinemic syndrome, and high concentration of iron in circulation; and endothelial injury related to abundance glucose regulated protein 78 (GRP78), which are present in severe COVID-19, could favor Mucorales infection. In this short communication, we summarized how the dysregulated iron homeostasis in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection benefits Mucorales.

Prolonged isoflurane anesthesia-induced acidosis decreases penile intracavernous pressure in rats.

Intracavernous pressure measurement following cavernous nerve electrostimulation has been extensively adopted for the evaluation of erectile function in animals. However, the effect of measurement time and acidosis during anesthesia is still lacking. To explore the effect of measurement time and acidosis during anesthesia. Fifty-six male Sprague-Dawley rats were used and anesthetized by a spontaneous inhalation of isoflurane. In the first step, rats were randomly divided into four groups: a control group and three time-delayed measurement groups (intracavernous pressure measurement beginning at 15, 30, and 45min after cavernous nerve exposure). In the second step, rats were randomly divided into three groups: a control group and two time-delayed measurement groups. Two intravenous fluid support strategies were used in time-delayed measurement groups: a normal saline solution and an isotonic Na2 CO3 solution. Isoflurane-anesthetized rats developed systemic acidosis that worsens with time during intracavernous pressure measurement, which results in a significant decrease in the maximum intracavernous pressure value, intracavernous pressure/mean arterial pressure ratio, and total intracavernous pressure measured. The Na2 CO3 infusion could effectively correct acidosis. The decrease in intracavernous pressure was related to the reduced nitric oxide synthase activity, decreased cyclic guanosine monophosphate concentration, and reactive oxygen species activation in rat penis under acidosis conditions. Prolonged isoflurane anesthesia-induced acidosis markedly depresses the erectile response to cavernous nerve electrostimulation in rats. In this situation, it is recommended to supplement with a Na2 CO3 infusion to maintain a normal acid-base balance.

Improvement of hypoventilation in Phox2b mutant mice modelling the congenital central hypoventilation syndrome by etonogestrel, a potent progestin. Perspectives for a possible potentiation by serotoninergic drugs

Congenital central hypoventilation syndrome (CCHS) is a life-threatening disorder characterized by hypoventilation during sleep and absence of the ventilatory response to CO2/H+. The disease-causing mutations are generally polyalanine repeat expansion mutations of PHOX2B. Knock-in mice bearing the 7-alanine expanded allele of PHOX2B (the most frequent mutation in patients) exhibit massive loss of retrotrapezoid nucleus neurons, lack CO2/H + chemosensitivity, and die within hours after birth. No pharmacological treatment is available. Clinical observations revealed a recovery of CO2/H+ chemosensitivity in two adult female patients with CCHS, both under desogestrel, a potent progestin used for contraceptive purpose. We previously showed that in mice, etonogestrel (ETO), the active metabolite of desogestrel, increased baseline respiratory frequency (fR) by a medullary action involving the serotoninergic (5-HT) systems. Accordingly, we hypothesized that ETO may stimulate fR on Phox2b mutant mice modelling CCHS and that 5-HT drugs would improve this respiratory effect of ETO. Experiments were made on ex vivo medullary-spinal cord preparations from conditional RTN Phox2b mutant (Egr2cre/+;Phox2b27Alaki) and OF1 WT newborn mice (P0-P2). fR was assessed by recording the 4th spinal ventral root. Effect of ETO on fR under normopH and metabolic acidosis (MA) conditions was evaluated in presence or not of 5-HT reuptake inhibitor. Without ETO, the increase in fR induced by MA observed in WT mice was absent in Egr2cre/+;Phox2b27Alaki mutant mice. ETO restored a respiratory response to MA in Egr2cre/+;Phox2b27Alaki mutant mice. In OF1 WT mice, when ETO was associated with 5-HT reuptake inhibitor, the increase in fR induced by MA was enhanced. Surprisingly, this potentiation was not retrieved in Egr2cre/+;Phox2b27Alaki mutant mice at concentrations used in OF1 WT. ETO was able to alleviate hypoventilation in Phox2b mutant mice modelling CCHS by a medullary action. Modulation of 5-HT systems may improve the respiratory effect of ETO in WT mice, but further studies are necessary to determine whether this increase of ETO effect by 5-HT extends to mutant mice.