The electroneutral Na+-HCO3- cotransporter NBCn1 (SLC4A7) modulates colonic enterocyte pHi, proliferation, and migration.

NBCn1 (SLC4A7) is one of the two major Na+-HCO3- cotransporters in the human colonic epithelium, expressed predominantly in the highly proliferating colonocytes at the cryptal base. Increased NBCn1 expression levels are reported in tumors, including colorectal cancer. The study explores its importance for maintenance of the intracellular pH (pHi), as well as the proliferative, adhesive, and migratory behavior of the self-differentiating Caco2BBe colonic tumor cell line. In the self-differentiating Caco2BBe cells, NBCn1 mRNA was highly expressed from the proliferative stage until full differentiation. The downregulation of NBCn1 expression by RNA interference affected proliferation and differentiation and decreased intracellular pH (pHi) of the cells in correlation with the degree of knockdown. In addition, a disturbed cell adhesion and reduced migratory speed were associated with NBCn1 knockdown. Murine colonic Nbcn1-/- enteroids also displayed reduced proliferative activity. In the migrating Caco2BBe cells, NBCn1 was found at the leading edge and in colocalization with the focal adhesion markers vinculin and paxillin, which suggests that NBCn1 is involved in the establishment of cell-matrix adhesion. Our data highlight the physiological significance of NBCn1 in modulating epithelial pH homeostasis and cell-matrix interactions in the proliferative region of the colonic epithelium and unravel the molecular mechanism behind pathological overexpression of this transporter in human colorectal cancers.NEW & NOTEWORTHY The transporter NBCn1 plays a central role in maintaining homeostasis within Caco2BBe colonic epithelial cells through its regulation of intracellular pH, matrix adhesion, migration, and proliferation. These observations yield valuable insights into the molecular mechanism of the aberrant upregulation of this transporter in human colorectal cancers.

Bicarbonate secretion and acid/base sensing by the intestine.

The transport of bicarbonate across the enterocyte cell membrane regulates the intracellular as well as the luminal pH and is an essential part of directional fluid movement in the gut. Since the first description of "active" transport of HCO3- ions against a concentration gradient in the 1970s, the fundamental role of HCO3- transport for multiple intestinal functions has been recognized. The ion transport proteins have been identified and molecularly characterized, and knockout mouse models have given insight into their individual role in a variety of functions. This review describes the progress made in the last decade regarding novel techniques and new findings in the molecular regulation of intestinal HCO3- transport in the different segments of the gut. We discuss human diseases with defects in intestinal HCO3- secretion and potential treatment strategies to increase luminal alkalinity. In the last part of the review, the cellular and organismal mechanisms for acid/base sensing in the intestinal tract are highlighted.

Genomic investigation and clinical correlates of the in vitro ß-lactam: NaHCO3 responsiveness phenotype among methicillin-resistant Staphylococcus aureus isolates from a randomized clinical trial.

NaHCO3 responsiveness is a novel phenotype where some methicillin-resistant Staphylococcus aureus (MRSA) isolates exhibit significantly lower minimal inhibitory concentrations (MIC) to oxacillin and/or cefazolin in the presence of NaHCO3. NaHCO3 responsiveness correlated with treatment response to ß-lactams in an endocarditis animal model. We investigated whether treatment of NaHCO3-responsive strains with ß-lactams was associated with faster clearance of bacteremia. The CAMERA2 trial (Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus) randomly assigned participants with MRSA bloodstream infections to standard therapy, or to standard therapy plus an anti-staphylococcal ß-lactam (combination therapy). For 117 CAMERA2 MRSA isolates, we determined by broth microdilution the MIC of cefazolin and oxacillin, with and without 44 mM of NaHCO3. Isolates exhibiting ≥4-fold decrease in the MIC to cefazolin or oxacillin in the presence of NaHCO3 were considered "NaHCO3-responsive" to that agent. We compared the rate of persistent bacteremia among participants who had infections caused by NaHCO3-responsive and non-responsive strains, and that were assigned to combination treatment with a ß-lactam. Thirty-one percent (36/117) and 25% (21/85) of MRSA isolates were NaHCO3-responsive to cefazolin and oxacillin, respectively. The NaHCO3-responsive phenotype was significantly associated with sequence type 93, SCCmec type IVa, and mecA alleles with substitutions in positions -7 and -38 in the regulatory region. Among participants treated with a ß-lactam, there was no association between the NaHCO3-responsive phenotype and persistent bacteremia (cefazolin, P = 0.82; oxacillin, P = 0.81). In patients from a randomized clinical trial with MRSA bloodstream infection, isolates with an in vitro ß-lactam-NaHCO3-responsive phenotype were associated with distinctive genetic signatures, but not with a shorter duration of bacteremia among those treated with a ß-lactam.

Role of pH Regulatory Proteins and Dysregulation of pH in Prostate Cancer.

Prostate cancer is the fourth most commonly diagnosed cancer, and although it is often a slow-growing malignancy, it is the second leading cause of cancer-associated deaths in men and the first in Europe and North America. In many forms of cancer, when the disease is a solid tumor confined to one organ, it is often readily treated. However, when the cancer becomes an invasive metastatic carcinoma, it is more often fatal. It is therefore of great interest to identify mechanisms that contribute to the invasion of cells to identify possible targets for therapy. During prostate cancer progression, the epithelial cells undergo epithelial-mesenchymal transition that is characterized by morphological changes, a loss of cell-cell adhesion, and invasiveness. Dysregulation of pH has emerged as a hallmark of cancer with a reversed pH gradient and with a constitutively increased intracellular pH that is elevated above the extracellular pH. This phenomenon has been referred to as "a perfect storm" for cancer progression. Acid-extruding ion transporters include the Na+/H+ exchanger NHE1 (SLC9A1), the Na+HCO3- cotransporter NBCn1 (SLC4A7), anion exchangers, vacuolar-type adenosine triphosphatases, and the lactate-H+ cotransporters of the monocarboxylate family (MCT1 and MCT4 (SLC16A1 and 3)). Additionally, carbonic anhydrases contribute to acid transport. Of these, several have been shown to be upregulated in different human cancers including the NBCn1, MCTs, and NHE1. Here the role and contribution of acid-extruding transporters in prostate cancer growth and metastasis were examined. These proteins make significant contributions to prostate cancer progression.

The immunomodulatory effect of oral NaHCO3 is mediated by the splenic nerve: multivariate impact revealed by artificial neural networks.

Stimulation of the inflammatory reflex (IR) is a promising strategy for treating systemic inflammatory disorders. Recent studies suggest oral sodium bicarbonate (NaHCO3) as a potential activator of the IR, offering a safe and cost-effective treatment approach. However, the mechanisms underlying NaHCO3-induced anti-inflammatory effects remain unclear. We investigated whether oral NaHCO3's immunomodulatory effects are mediated by the splenic nerve. Female rats received NaHCO3 or water (H2O) for four days, and splenic immune markers were assessed using flow cytometry. NaHCO3 led to a significant increase (p < 0.05, and/or partial eta squared > 0.06) in anti-inflammatory markers, including CD11bc + CD206 + (M2-like) macrophages, CD3 + CD4 + FoxP3 + cells (Tregs), and Tregs/M1-like ratio. Conversely, proinflammatory markers, such as CD11bc + CD38 + TNFα + (M1-like) macrophages, M1-like/M2-like ratio, and SSChigh/SSClow ratio of FSChighCD11bc + cells, decreased in the spleen following NaHCO3 administration. These effects were abolished in spleen-denervated rats, suggesting the necessity of the splenic nerve in mediating NaHCO3-induced immunomodulation. Artificial neural networks accurately classified NaHCO3 and H2O treatment in sham rats but failed in spleen-denervated rats, highlighting the splenic nerve's critical role. Additionally, spleen denervation independently influenced Tregs, M2-like macrophages, Tregs/M1-like ratio, and CD11bc + CD38 + cells, indicating distinct effects from both surgery and treatment. Principal component analysis (PCA) further supported the separate effects. Our findings suggest that the splenic nerve transmits oral NaHCO3-induced immunomodulatory changes to the spleen, emphasizing NaHCO3's potential as an IR activator with therapeutic implications for a wide spectrum of systemic inflammatory conditions.

Effect of sodium bicarbonate Ringer's solution on lung injury in rats with traumatic hemorrhagic shock.

This study aimed to explore the impact of different pH values of resuscitation fluid on traumatic hemorrhagic shock (THS), focusing on their effects on glycocalyx and inflammation. A rat model of THS was induced by hemorrhage from a left femur fracture, while an oxygen-glucose deprivation/reoxygenation (OGD/R)-induced HULEC-5a cell model was considered as an in vitro THS model. The lung tissue pathology and glycocalyx structure were assessed through hematoxylin-eosin (H&E) staining and transmission electron microscope examination. The levels of glycocalyx-related factors and inflammation-related factors were determined by enzyme-linked immunosorbent assay (ELISA). The expression of glycocalyx-related proteins, cell junction-related proteins, and proteins involved in the PI3K/Akt/NF-κB signaling pathway was analyzed by western blot. The results showed that both sodium bicarbonate Ringer's solution (BRS) and lactate Ringer's solution (LRS) were effective in restoring mean arterial pressure and heart rate in THS rats. However, LRS has a stronger impact on promoting inflammation and damaging the glycocalyx compared with BRS. In OGD/R-induced HULEC-5a cells, a pH of 7.4 and 6.5 increased inflammation and disrupted the glycocalyx, while a pH of 8.1 had no significant effect on inflammation or glycocalyx. Furthermore, the PI3K/Akt/NF-κB signaling pathway was activated by fluid resuscitation and different pH values. However, the activating effect of BRS and pH 8.1 on the PI3K/Akt/NF-κB signaling pathway was milder compared with LRS and pH6.5. In conclusion, an alkaline recovery environment was more beneficial for the treatment of THS.

Endoscopic lithotripsy combined with drug lithotripsy vs. drug lithotripsy for the treatment of phytobezoars: analysis of 165 cases.

AIM: To analyze efficacy of endoscopic lithotripsy combined with drug lithotripsy as compared with drug lithotripsy for the treatment of phytobezoars. METHODS: We collected and evaluated case records of 165 patients with phytobezoars from 2014 to 2023. And we analyzed demographic and clinical characteristics, imaging features, endoscopic features, complications of phytobezoars, and compared efficacy between endoscopic lithotripsy combined with drug lithotripsy (Group A) and drug lithotripsy (sodium bicarbonate combined with proton pump inhibitor) (Group B). RESULTS: The median age of patients with phytobezoars was 67.84 ± 4.286 years old. Abdominal pain was the most common symptom and peptic ulcers (67.5%) were the most common complication. Bezoar-induced ulcers were more frequent in the gastric angle. The success rate of phytobezoars vanishing in Group A and Group B were similar (92.3% vs. 85.1% within 48 h, 98.7% vs. 97.7% within a week), while the average hospitalization period, average hospitalization cost, second endoscopy rate, and average endoscopic operation time were significantly lower in patients in Group B than in Group A. CONCLUSION: Drug lithotripsy is the preferred effective and safe treatment option for phytobezoars. We advise that an endoscopy should be completed after 48 h for drug lithotripsy.

13-Week Repeated Oral Toxicity and Toxicokinetic Studies of Rabeprazole Sodium and Sodium Bicarbonate Combination in Dogs.

The subchronic toxicity and toxicokinetics of a combination of rabeprazole sodium and sodium bicarbonate were investigated in dogs by daily oral administration for 13 consecutive weeks with a 4-week recovery period. The dose groups consisted of control (vehicles), (5 + 200), (10 + 400), and (20 + 800) mg/kg of rabeprazole sodium + sodium bicarbonate, 20 mg/kg of rabeprazole sodium only, and 800 mg/kg of sodium bicarbonate only. Esophageal ulceration accompanied by inflammation was observed in only one animal in the male (20 + 800) mg/kg rabeprazole sodium + sodium bicarbonate group. However, the severity of the ulceration was moderate, and the site of occurrence was focally extensive; thus, it was assumed to be a treatment-related effect of rabeprazole sodium + sodium bicarbonate. In the toxicokinetics component of this study, systemic exposure to rabeprazole sodium (AUClast and Cmax at Day 91) was greater in males than females, suggesting sex differences. AUClast and Cmax at Day 91 were increased compared to those on Day 1 in a dose-dependent manner. A delayed Tmax and no drug accumulation were observed after repeated dosage. In conclusion, we suggest under the conditions of this study that the no-observed-adverse-effect level (NOAEL) of the combination of rabeprazole sodium + sodium bicarbonate in male and female dogs is (10 + 400) and (20 + 800) mg/kg, respectively.

Sodium Bicarbonate Decreases Alcohol Consumption in Mice.

We previously reported that mice with low neuronal pH drink more alcohol, demonstrating the importance of pH for alcohol reward and motivation. In this study, we tested whether systemic pH affects alcohol consumption and if so, whether it occurs by changing the alcohol reward. C57BL/6J mice were given NaHCO3 to raise their blood pH, and the animals' alcohol consumption was measured in the drinking-in-the-dark and two-bottle free choice paradigms. Alcohol consumption was also assessed after suppressing the bitterness of NaHCO3 with sucrose. Alcohol reward was evaluated using a conditioned place preference. In addition, taste sensitivity was assessed by determining quinine and sucrose preference. The results revealed that a pH increase by NaHCO3 caused mice to decrease their alcohol consumption. The decrease in high alcohol contents (20%) was significant and observed at different ages, as well as in both males and females. Alcohol consumption was also decreased after suppressing NaHCO3 bitterness. Oral gavage of NaHCO3 did not alter quinine and sucrose preference. In the conditioned place preference, NaHCO3-treated mice spent less time in the alcohol-injected chamber. Conclusively, the results show that raising systemic pH with NaHCO3 decreases alcohol consumption, as it decreases the alcohol reward value.

K+-Driven Cl-/HCO3- Exchange Mediated by Slc4a8 and Slc4a10.

Slc4a genes encode various types of transporters, including Na+-HCO3- cotransporters, Cl-/HCO3- exchangers, or Na+-driven Cl-/HCO3- exchangers. Previous research has revealed that Slc4a9 (Ae4) functions as a Cl-/HCO3- exchanger, which can be driven by either Na+ or K+, prompting investigation into whether other Slc4a members facilitate cation-dependent anion transport. In the present study, we show that either Na+ or K+ drive Cl-/HCO3- exchanger activity in cells overexpressing Slc4a8 or Slc4a10. Further characterization of cation-driven Cl-/HCO3- exchange demonstrated that Slc4a8 and Slc4a10 also mediate Cl- and HCO3--dependent K+ transport. Full-atom molecular dynamics simulation on the recently solved structure of Slc4a8 supports the coordination of K+ at the Na+ binding site in S1. Sequence analysis shows that the critical residues coordinating monovalent cations are conserved among mouse Slc4a8 and Slc4a10 proteins. Together, our results suggest that Slc4a8 and Slc4a10 might transport K+ in the same direction as HCO3- ions in a similar fashion to that described for Na+ transport in the rat Slc4a8 structure.

Metabolic Acidosis in CKD: Pathogenesis, Adverse Effects, and Treatment Effects.

Metabolic acidosis is a frequent complication of chronic kidney disease and is associated with a number of adverse outcomes, including worsening kidney function, poor musculoskeletal health, cardiovascular events, and death. Mechanisms that prevent metabolic acidosis detrimentally promote further kidney damage, creating a cycle between acid accumulation and acid-mediated kidney injury. Disrupting this cycle through the provision of alkali, most commonly using sodium bicarbonate, is hypothesized to preserve kidney function while also mitigating adverse effects of excess acid on bone and muscle. However, results from clinical trials have been conflicting. There is also significant interest to determine whether sodium bicarbonate might improve patient outcomes for those who do not have overt metabolic acidosis. Such individuals are hypothesized to be experiencing acid-mediated organ damage despite having a normal serum bicarbonate concentration, a state often referred to as subclinical metabolic acidosis. Results from small- to medium-sized trials in individuals with subclinical metabolic acidosis have also been inconclusive. Well-powered clinical trials to determine the efficacy and safety of sodium bicarbonate are necessary to determine if this intervention improves patient outcomes.

Effect of partial substitution of complex phosphates with sodium bicarbonate on aggregation, conformation and gel properties of beef-pork-chicken complex myofibrillar proteins.

BACKGROUND: Complex phosphates (CP) can improve the physicochemical properties and gelation properties of myofibrillar fibrous protein (MP) in mixed meat products, but an excessive intake of phosphates over a long period of time is harmful to health. The present study investigated the effects of partial or complete substitution of CP with sodium bicarbonate (SB) on the physicochemical properties and gel properties of beef-pork-chicken mixed myofibrillar protein (BPC-MP), aiming to evaluate the feasibility of this method in reducing the amount of phosphate in mixed meat products. RESULTS: Under the optimal substitution conditions, the turbidity of BPC-MP was reduced by 37.8%, the net negative potential was increased by 28.9% and the modulus of elasticity (G') was increased. The tertiary structure indexes of protein (including fluorescence intensity, surface hydrophobicity and active thiol content) were significantly changed, whereas the α-helix and ß-turn angle contents in the secondary structure of protein were significantly increased. In addition, the water retention ability and strength of gel were also improved, which were increased by 20.7% and 42.6%, respectively. The results of scanning electron microscopy showed that the SB substitution group had a more compact and ordered microstructure. CONCLUSION: The results showed that partial substitution of CP with SB reduced the amount of phosphate added to BPC-MP and had a positive effect on the physicochemical and gel properties of BPC-MP. © 2024 Society of Chemical Industry.

Efficacy of an experimental toothpaste containing sodium bicarbonate, sodium hyaluronate and sodium fluoride on gingivitis.

BACKGROUND: Gingivitis is driven by plaque accumulation and, if left untreated, can progress to irreversible periodontitis. For many, the mechanical action of toothbrushing does not achieve adequate plaque control. The aim of this study was to investigate whether twice-daily use of a toothpaste containing 0.2% high molecular weight (HMW) sodium hyaluronate with 67% sodium bicarbonate and 0.221% sodium fluoride (experimental toothpaste) could improve gingival health compared with a regular fluoride toothpaste (negative control). The study also assessed whether the experimental toothpaste could provide additive gingival health benefit over a toothpaste containing only 67% sodium bicarbonate and 0.221% sodium fluoride (positive control). METHODS: This was a single-center, examiner-blinded, randomized, clinical study in healthy adults with mild-to-moderate gingivitis. At baseline, after abstaining from toothbrushing for 12 h, prospective participants underwent oral soft tissue (OST) and oral hard tissue examination followed by assessments for gingival inflammation (Modified Gingival Index [MGI]), gingival bleeding (Bleeding Index [BI]), and supra-gingival plaque (Turesky Plaque Index [TPI]). Eligible participants were stratified by gender and baseline number of bleeding sites (low: <45; high: ≥45 bleeding sites). Following randomization, participants underwent prophylactic dental treatment. Participants received a full OST examination, MGI, BI and TPI assessments after 3 days, 1, 2 and 6 weeks of product use. RESULTS: In total, 110 participants were screened for study entry and all were randomized to receive one of three toothpastes (experimental: sodium hyaluronate, sodium bicarbonate, sodium fluoride; positive control: sodium bicarbonate, sodium fluoride; negative control: regular fluoride toothpaste). For all measures, significant improvements were observed in participants receiving either sodium bicarbonate-containing toothpaste (experimental or positive control) compared with the regular fluoride toothpaste (negative control) at week 6. No significant difference was observed in any assessment or visit comparing the experimental toothpaste with the positive control. CONCLUSIONS: Both the experimental and the positive control toothpastes demonstrated clinically relevant improvements in gingival health compared with a regular fluoride toothpaste (negative control). However, no additional gingival health improvement was observed for the experimental toothpaste compared with the positive control, therefore, no additional gingival health benefit can be attributed to the inclusion of sodium hyaluronate in this formulation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04737538 (04/02/2021).

Lyophilized rumen fluid as a ruminal fermentation modifier in high grain-fed acidotic goats.

Rumen cud transfaunation re-establishes rumen micro environment and improves fermentation in recipient animals affected with digestive disorders. Preserving rumen cud or fluid will increase its availability for the treatment of rumen fermentation disorders, without having to maintain donor animals. Rumen fluid collected from healthy goats, fed standard ration having roughage 70% and concentrate 30%, was lyophilized (prefreezing -80 °C, 48 h; lyophilization -45 °C, 32 h) using 5% glycerol as cryoprotectant. The 16 S metagenome analysis of the lyophilized rumen fluid (LRF) revealed an abundance of Prevotella (33.2%). Selenomonas ruminantium (1.87%) and Megasphaera elsdenii (0.23%) were also present. Twenty-four goats having history of high grain feeding and exhibiting clinical symptoms of rumen fermentation disorders were randomly distributed into either one of the two treatment groups viz., T1 = oral administration of LRF 31 g/animal/day and T2 = oral administration of sodium bicarbonate (SB) 15 g/animal/day. Post intervention LRF and SB, improved animal body condition, feed intake, fecal consistency, elevated the ruminal pH at 48 h, reduced propionate and lactate at 48 h, reduced total volatile fatty acids (TVFA) and ammonia nitrogen at 24 h. Significant reduction in serum blood urea nitrogen (BUN) and urea levels were observed even from 24 h post intervention irrespective of the treatments. LRF significantly improved acetate and decreased propionate production compared to SB. LRF at 7.5% (v/v) can thus be used to counteract ruminal fermentation disorders in goats sequel to high grain ration.

The effect of diminished metabolic acidosis on thermoregulatory response during exercise.

It was reported that metabolic acidosis inhibits the activity of warm-sensitive hypothalamic neurons. The present study was designed to test the hypothesis that metabolic alkalosis may improve heat loss during intensive exercise in men. Fifteen male subjects aged 22-24 years were submitted to incremental exercise on two randomized occasions one week apart. During the bicarbonate trial exercise was preceded by ingestion of NaHCO3 at a dose 250 mg/kg whilst during the placebo trial lactose was administered. Exercise load was increased every 3 min by 30 W until volitional exhaustion. Ambient temperature was kept at 23-24°C and humidity 50-60%. Tympanic and skin temperatures were recorded and the rate of sweating was assayed by humidity measurement of nitrogen flowing through a capsule attached to the mid posterior chest. Total sweat loss was determined by the changes in body mass. Venous blood samples were taken before exercise and at the end of each workload for determination of acid-base parameters. The subjects attained similar maximal workload in the two tests (260 ± 6 W) with heart rate 185 ± 6 beats/min. Blood concentration of hydrogen ions was lower (p < 0.001) in the bicarbonate than in the placebo trial throughout the whole exercise period. There were no significant differences between these tests in tympanic and mean skin temperatures, sweating rate and total sweat loss. The present data showed that in men attenuation of metabolic acidosis by bicarbonate ingestion did not influence thermoregulation during incremental exercise performed until volitional exhaustion, possibly due to too short duration of exertional uncompensated metabolic acidosis.

Does sodium bicarbonate based extra-cellular buffering support reduce high intensity exercise-induced fatigue and enhance short-term recovery assessed by selected blood biochemical indices?

Exercise-induced metabolic processes induce muscle acidification which contributes to a reduction in the ability to perform repeated efforts. Alkalizing agents such as sodium bicarbonate (NaHCO3) prevent large blood pH changes, however, there is no evidence on whether regulation of acid-base balance may also support whole body homeostasis monitored through heamatological and biochemical blood markers in a dose-dependent manner. Thirty Cross-Fit-trained participants were studied in a randomized, multi cross-over, placebo (PLA)-controlled double-blind manner in which they performed a control session (CTRL, without supplementation), three NaHCO3 visits (three different doses) and PLA (sodium chloride in an equimolar amount of sodium as NaHCO3). Each visit consisted of two 30-s Wingate tests separated by CrossFit-specific benchmarks (Wall Balls and Burpees - both performed for 3 min). Blood samples were collected at rest, immediately post-exercise and after 45 min recovery. Significant differences between visits appeared for blood pH, percentage of lymphocytes and granulocytes, red blood cells count and haemoglobin concentration at post-exercise and 45-min recovery, and for white blood cells count, percentage of monocytes, concentration of magnesium and creatinine at 45-min recovery. Most of the observed differences for heamatological and biochemical markers were significant compared to CTRL, but not different after PLA. NaHCO3 supplementation compared to PLA did not significantly affect exercise or recovery shifts in studied blood indicators. However, the changes in these markers after NaHCO3 and PLA in relation to CTRL indicate a possible role of sodium.

Tumor microenvironment acidity modulates ROR1 to promote epithelial-mesenchymal transition and hepatocarcinoma metastasis.

The tendency of hepatocarcinoma to metastasize results in a high rate of mortality, making it a hot research topic in cancer studies. Although an acidic tumor microenvironment has been proven to promote cancer metastasis, the underlying regulatory mechanisms remain poorly defined. Here, we found that acidic conditions significantly enhanced cell migration and invasion ability in hepatocellular carcinoma, and the expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) was distinctly upregulated in acid-treated cells. In addition, siRNA-mediated knockdown of ROR1 could effectively inhibit acid-induced cell migration, invasion and epithelial-mesenchymal transition (EMT). Importantly, neutralization of acidic environments with NaHCO3 could downregulate acid-stimulated ROR1 expression, thereby retarding cell metastatic potential. Notably, the formation of metastatic nodules was significantly increased after intrapulmonary injection of acid-stimulated cancer cells, and this was inhibited by pretreating with NaHCO3. In summary, we reveal that an acidic tumor microenvironment modulates ROR1 expression to promote tumor metastasis, providing not only a better understanding of molecular mechanisms related to metastasis, but also a promising target for tumor management.

Clinical efficacy of sodium bicarbonate in treating pediatric metabolic acidosis with varying level of acid-base balance parameters: a real-world study.

BACKGROUND: Sodium bicarbonate (SB) infusion is commonly used to correct metabolic acidosis, but its clinical efficacy remains controversial. This study aims to investigate whether acid-base balance parameters should be a consideration for administering SB treatment. METHODS: Children with metabolic acidosis (pH < 7.35 and bicarbonate < 22 mmol/L) who were treated with or without 50 mg/ml SB injection were grouped and extracted from a retrospective cohort database of the Pediatric Intensive Care Unit. The interaction between acid-base balance parameters and SB treatment on mortality was analyzed through mortality curves and cross-effect models. Logistic regression was conducted to estimate the risk of death following SB treatment in the overall children as well as in subgroups, and potential confounding factors were adjusted for. After employing propensity score matching to account for confounding factors, further analysis was performed to evaluate the effectiveness of SB treatment within each chloride subgroup. RESULTS: A total of 5865 children with metabolic acidosis were enrolled, of which 2462 (42.0%) received SB treatment. In the overall population, it was found that SB treatment did not reduce hospital mortality or 28-day mortality. Interactions between acid-base balance parameters (chloride and anion gap) and SB treatment on mortality were observed. Subgroup analysis clarified that when chloride levels were below 107 mmol/L, children treated with SB had higher in-hospital mortality (29.8% vs 14.9%) and 28-day mortality (26.5% vs 13.4%), with adjusted ORs of 2.065 (95% CI, 1.435-2.97) and 1.947 (95% CI, 1.332-2.846), respectively. In contrast, when chloride levels were greater than or equal to 113 mmol/L, children treated with SB had a shorter stay in the PICU (median: 1.1 days vs 5.1 days, adjusted p = 0.004) and lower in-hospital mortality (4.3% vs 10.3%) and 28-day mortality (4.0% vs 8.4%), with adjusted ORs of 0.515 (95% CI, 0.337-0.788) and 0.614 (95% CI, 0.391-0.965), respectively. After controlling for confounding factors through matching, the impact of SB treatment on the risk of death in each chloride subgroup was consistent with the aforementioned results. However, treatment with SB did not significantly increase the risk of death in newborns or children with moderate to severe metabolic acidosis when chloride levels were below 107 mmol/L (p > 0.05). CONCLUSIONS: The use of sodium bicarbonate for treating metabolic acidosis has been found to increase mortality in children with low chloride levels but decrease mortality in those with high chloride levels in this study. Further prospective multi-center clinical studies and basic research are needed to validate these findings.

Conversion efficiency of flight power is low, but increases with flight speed in the migratory bat Pipistrellus nathusii.

The efficiency with which flying animals convert metabolic power to mechanical power dictates an individual's flight behaviour and energy requirements. Despite the significance of this parameter, we lack empirical data on conversion efficiency for most species as in vivo measurements are notoriously difficult to obtain. Furthermore, conversion efficiency is often assumed to be constant across flight speeds, even though the components driving flight power are speed-dependent. We show, through direct measurements of metabolic and aerodynamic power, that conversion efficiency in the migratory bat (Pipistrellus nathusii) increases from 7.0 to 10.4% with flight speed. Our findings suggest that peak conversion efficiency in this species occurs near maximum range speed, where the cost of transport is minimized. A meta-analysis of 16 bird and 8 bat species revealed a positive scaling relationship between estimated conversion efficiency and body mass, with no discernible differences between bats and birds. This has profound consequences for modelling flight behaviour as estimates assuming 23% efficiency underestimate metabolic costs for P. nathusii by almost 50% on average (36-62%). Our findings suggest that conversion efficiency may vary around an ecologically relevant optimum speed and provide a crucial baseline for investigating whether this drives variation in conversion efficiency between species.

Sodium bicarbonate reduces ventilation without altering core temperature threshold or sensitivity of hyperthermia-induced hyperventilation in exercising humans.

Hyperthermia stimulates ventilation (hyperthermia-induced hyperventilation). In exercising humans, once the core temperature reaches ∼37°C, minute ventilation (V̇e) increases linearly with rising core temperature, and the slope of the relation between V̇e and core temperature reflects the sensitivity of the response. We previously reported that sodium bicarbonate ingestion reduces V̇e during prolonged exercise in the heat without affecting the sensitivity of hyperthermia-induced hyperventilation. Here, we hypothesized that reductions in V̇e associated with sodium bicarbonate ingestion reflect elevation of the core temperature threshold for hyperthermia-induced hyperventilation. Thirteen healthy young males ingested sodium bicarbonate (0.3 g/kg body wt) (NaHCO3 trial) or sodium chloride (0.208 g/kg body wt) (NaCl trial), after which they performed a cycle exercise at 50% of peak oxygen uptake in the heat (35°C and 50% relative humidity) following a pre-cooling. The pre-cooling enabled detection of an esophageal temperature (Tes: an index of core temperature) threshold for hyperthermia-induced hyperventilation. The Tes thresholds for increases in V̇e were similar between the two trials (P = 0.514). The slopes relating V̇E to Tes also did not differ between trials (P = 0.131). However, V̇e was lower in the NaHCO3 than in the NaCl trial in the range of Tes = 36.8-38.4°C (P = 0.007, main effect of trial). These results suggest that sodium bicarbonate ingestion does not alter the core temperature threshold or sensitivity of hyperthermia-induced hyperventilation during prolonged exercise in the heat; instead, it downshifts the exercise hyperpnea.