High-dose Ascorbic Acid Research Articles

P3.02G.03 High-Dose Ascorbic Acid Sensitizes Immunotherapy in LKB1-Deficient Lung Cancer by Promoting Tumor Cell Pyroptosis

P3.02G.03 High-Dose Ascorbic Acid Sensitizes Immunotherapy in LKB1-Deficient Lung Cancer by Promoting Tumor Cell Pyroptosis

Revision of an Adult Burn Center's Resuscitation Guideline Leads to Lower Resuscitation Requirements.

In 2018, the institutional burn resuscitation guideline was updated to remove the use of high-dose ascorbic acid (HDAA) therapy, to lower 24-hour resuscitation fluid estimations from 4 to 2mL/kg/TBSA, and to optimize guidance around appropriate colloid resuscitation. This retrospective study compared the incidence of a composite safety outcome (acute kidney injury, or intra-abdominal hypertension requiring intervention) between the pre-guideline update to post-guideline update. Secondarily, 24-hour resuscitation volumes, hourly urine output, vasopressor use, and mechanical ventilation duration were compared as well. The composite safety outcome was similar between the 2 groups (40% vs 29%; p=0.27), but the post-group showed significantly lower 24-hour resuscitation volumes (3.74mL/kg/TBSA vs 2.94mL/kg/TBSA; p<0.01), as well as lower urine output (1.26mL/kg/hr vs 0.75mL/kg/hr; p<0.01). There was no difference between the groups with respect to vasopressor use, mechanical ventilation duration, or mortality. This study suggests that a simplified resuscitation protocol without HDAA, combined with a lower starting fluid rate led to significantly lower 24-hour resuscitation volumes without an increase in adverse safety events.

Prevention of systemic inflammatory response syndrome after emergency on-pump coronary artery bypass grafting with high-dose ascorbic acid: a prospective randomized controlled trial

INTRODUCTION: Emergency coronary artery bypass grafting (CABG) surgery carries a risk of postperfusion systemic inflammatory response syndrome (SIRS). The prophylactic use of high doses of ascorbic acid, which possesses an antioxidant and immunomodulatory effect, may be justified, but has not been sufficiently studied in this clinical scenario. OBJECTIVE: To determine the possibilities of preventing the systemic inflammatory response with ascorbic acid (AA) during emergency coronary artery bypass grafting under cardiopulmonary bypass (CPB). MATERIALS AND METHODS: We prospectively examined 60 patients (32 men and 28 women, aged 63 (59; 70) years who underwent CABG (3 ± 1 bypass), performed for emergency indications under CPB 95 (77; 122) min. Patients were randomly divided into two groups: patients in the main group (n = 30) were given 4 grams of AA intravenously 1 hour before the skin incision, patients in the control group (n = 30) received standard pre-operative prevention of SIRS. RESULTS: The use of AA (n = 30) was accompanied by a decrease in the incidence of SIRS (20 and 47 %; p = 0.048) and a reduction in postoperative hospitalization (9 [8; 10] and 11 [10; 16] days; p = 0.013). CONCLUSIONS: Prophylactic use of AA is safe and can reduce the frequency of individual manifestations of SIRS and the duration of postoperative hospitalization.

Indoxacarb poisoning causing methemoglobinemia treated with parenteral vitamin C: a case report

IntroductionThis case study reports on a suicide attempt involving indoxacarb and vitamin C. Indoxacarb is a neurotoxic insecticide used in agriculture and as a flea controller in pets. Cotton, vegetables, and fruits are treated with indoxacarb, an insecticide that can be applied both indoors and outdoors. It causes skin allergies, methemoglobinemia, and hemolytic anemia. It is also attributed to allergic reactions through ingestion, inhalation, physical contact, and translaminar action. This case report highlights use of vitamin C in methemoglobinemia caused by indoxacarb poisoning. Indoxacarb poisoning has the potential to be extremely serious and even lethal. In this instance, the patient initially had no symptoms after ingesting a substance containing indoxacarb in an attempt at suicide. However, further tests revealed methemoglobinemia and low oxygen levels.Case presentationA 28-year-old south-east Asian female patient ingested an insecticide containing 5.25% novaluron, 4.5% indoxacarb, and 25% thiamethoxam, and reported that she noticed muddy brown urine but presented with no active signs or symptoms of poisoning. Upon examination, the patient was fully conscious, alert, and hemodynamically stable, but had an oxygen saturation of 84%. Gastric lavage was performed, and blood investigations revealed a muddy-brown-colored blood sample and methemoglobin levels of 12%. The patient was treated with high-dose vitamin C and showed significant improvement, with a drop in methemoglobin levels to 1.2% and an increase in oxygen saturation to 97%.DiscussionIndoxacarb poisoning can cause severe methemoglobinemia. Vitamin C may be a useful treatment option for methemoglobinemia caused by indoxacarb, particularly in cases in which traditional treatment with methylene blue is contraindicated or not tolerated. Hence high doses of ascorbic acid, that is, vitamin C, were administered to the patient, which lowered their methemoglobin levels and improved oxygen levels without much safety concerns.ConclusionThis example emphasizes the significance of early indoxacarb poisoning detection and treatment as well as the possible advantages of utilizing ascorbic acid in the management of methemoglobinemia, and highlights the use of vitamin C in the treatment of methemoglobinemia caused by indoxacarb poisoning. Therefore, it is important for healthcare professionals to be aware of the potential for indoxacarb to cause methemoglobinemia and to consider vitamin C as a treatment option.

Successful Treatment, with Chemotherapy and Intravenous Administration of Ascorbic Acid, of a Patient with Peripheral T-Cell Lymphoma, Not Otherwise Specified

Here, we report the case of a 64-year-old man with peripheral T-cell lymphoma, not otherwise specified, who complained of diffuse lymphadenopathy and pancytopenia. This patient received the CHOP regimen followed by the CHP plus brentuximab vedotin regimen, and eventually experienced severe adverse effects, such as leukocytopenia and thrombocytopenia. He was then intravenously administered high doses of ascorbic acid to enhance the effects of chemotherapy drugs and reduce the intensity of the side effects. Positron emission tomography-computed tomography revealed a complete response of the lesions to combination therapy. This case report demonstrated the feasibility, efficacy, and acceptable toxicity of high-dose ascorbic acid in patients undergoing chemotherapy.

Effect of high-dose intravenous ascorbic acid on microcirculation and endothelial glycocalyx during sepsis and septic shock: a double-blind, randomized, placebo-controlled study

Previous studies indicate supplemental vitamin C improves microcirculation and reduces glycocalyx shedding in septic animals. Our randomized, double-blind, placebo-controlled trial aimed to investigate whether a high dose of intravenous ascorbic acid (AA) might improve microcirculation and affect glycocalyx in septic patients. In our study, 23 septic patients were supplemented with a high dose (50 mg/kg every 6 h) of intravenous AA or placebo for 96 h. Sublingual microcirculation was examined using a handheld Cytocam-incident dark field (IDF) video microscope. A sidestream dark field video microscope (SDF), connected to the GlycoCheck software (GlycoCheck ICU®; Maastricht University Medical Center, Maastricht, the Netherlands), was employed to observe glycocalyx. We found a significantly higher proportion of perfused small vessels (PPV) 6 h after the beginning of the trial in the experimental group compared with placebo. As an indicator of glycocalyx thickness, the perfused boundary region was lower in capillaries of the 5–9 μm diameter in the AA group than placebo after the first dose of AA. Our data suggest that high-dose parenteral AA tends to improve microcirculation and glycocalyx in the early period of septic shock. The study was retrospectively registered in the clinicaltrials.gov database on 26/02/2021 (registration number NCT04773717).

Metabolic profile changes of kidney aging and protective effects of Polygonatum sibiricum polysaccharides on D-galactose-induced aging mice

ObjectiveTo investigate the metabolic trajectory of kidney aging and the effects of Polygonatum sibiricum polysaccharides (PSP) against kidney aging in D-galactose (D-gal)-induced aging mice, based on ultra-performance liquid chromatography/Q-Exactive Orbitrap mass spectrometry (UPLC-Q-Exactive MS/MS). MethodsA total of 36 C57 BL/6J mice were randomly allocated to six groups: control (CON), model (MOD), PSP low-dose (PSP-L), PSP medium-dose (PSP-M), PSP high-dose (PSP-H), and positive drug ascorbic acid (VC) groups. To create models of aging mice, D-gal was intraperitoneally administered to all other groups of mice except the CON group. After modeling, the appropriate Chinese medicine [PSP-L: 150 mg/(kg·d), PSP-M: 300 mg/(kg·d), PSP-H: 600 mg/(kg·d)] or positive drug [ascorbic acid, 300 mg/(kg·d)] was administered for intervention. Key markers of renal function in urine and serum of mice in each group, such as creatinine (Crea), urea nitrogen (BUN), and uric acid (UA) levels, as well as key indicators of oxidative stress in serum and kidney, including superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) were determined to validate the successful establishment of kidney aging models and to estimate the effects of PSP. Hematoxylin and eosin (HE), periodic acid Schiff (PAS), and β-galactosidase staining were used to assess the renal pathological changes. The metabolic profiles of serum, kidney, and urine samples from CON, MOD, and PSP-H groups were analyzed by UPLC-Q-Exactive MS/MS, and pattern recognition methods were used to outline the metabolic trajectory of kidney aging and to identify the characteristic metabolites. ResultsAge-related alterations in renal histopathology and impaired renal function in mice were also associated with oxidative stress indicators. Following the injection of PSP [PSP-H: 600 mg/(kg·d)], the pathological indices associated with aging were adjusted to normal levels, renal function and oxidative stress were improved in aging mice, and renal pathological damage was markedly improved. Meanwhile, the potential biomarkers were identified by UPLC-Q-Exactive MS/MS analysis and were further analyzed to form related metabolic pathways, with P < 0.05 as a threshold. The results showed that purine, sphingolipid, glycerophospholipid, tryptophan, and riboflavin metabolisms were the main metabolic pathways associated with aging. After administration of PSP, these pathological indices returned to normal levels, and biomarkers related to the aging process, such as adenosine monophosphate (AMP), tryptophan, and 5-hydroxytryptophan, also demonstrated, to some degree, reverse regulation (promoting synthesis). ConclusionMetabolomics methods based on UPLC-Q-Exactive MS/MS and multivariate statistical analysis can be adopted to establish metabolic profiles in aging mice. PSP has been shown to protect against kidney aging by interfering with the purine, sphingolipid, glycerophospholipid, tryptophan, and riboflavin metabolisms in the kidney.

Retinoic acid and proteotoxic stress induce AML cell death overcoming stromal cell protection

BackgroundAcute myeloid leukemia (AML) patients bearing the ITD mutation in the tyrosine kinase receptor FLT3 (FLT3-ITD) present a poor prognosis and a high risk of relapse. FLT3-ITD is retained in the endoplasmic reticulum (ER) and generates intrinsic proteotoxic stress. We devised a strategy based on proteotoxic stress, generated by the combination of low doses of the differentiating agent retinoic acid (R), the proteasome inhibitor bortezomib (B), and the oxidative stress inducer arsenic trioxide (A).MethodsWe treated FLT3-ITD+ AML cells with low doses of the aforementioned drugs, used alone or in combinations and we investigated the induction of ER and oxidative stress. We then performed the same experiments in an in vitro co-culture system of FLT3-ITD+ AML cells and bone marrow stromal cells (BMSCs) to assess the protective role of the niche on AML blasts. Eventually, we tested the combination of drugs in an orthotopic murine model of human AML.ResultsThe combination RBA exerts strong cytotoxic activity on FLT3-ITD+ AML cell lines and primary blasts isolated from patients, due to ER homeostasis imbalance and generation of oxidative stress. AML cells become completely resistant to the combination RBA when treated in co-culture with BMSCs. Nonetheless, we could overcome such protective effects by using high doses of ascorbic acid (Vitamin C) as an adjuvant. Importantly, the combination RBA plus ascorbic acid significantly prolongs the life span of a murine model of human FLT3-ITD+ AML without toxic effects. Furthermore, we show for the first time that the cross-talk between AML and BMSCs upon treatment involves disruption of the actin cytoskeleton and the actin cap, increased thickness of the nuclei, and relocalization of the transcriptional co-regulator YAP in the cytosol of the BMSCs.ConclusionsOur findings strengthen our previous work indicating induction of proteotoxic stress as a possible strategy in FLT3-ITD+ AML therapy and open to the possibility of identifying new therapeutic targets in the crosstalk between AML and BMSCs, involving mechanotransduction and YAP signaling.

High-dose ascorbic acid potentiates immune modulation through STAT1 phosphorylation inhibition and negative regulation of PD-L1 in experimental sepsis.

Sepsis is a complex, multifactorial syndrome characterized by a dysregulated host response to infection, leading to severe organ dysfunction and high mortality rates among critically ill patients. Hypovitaminosis C and vitamin C deficiency are frequently observed in septic patients, prompting interest in the potential therapeutic role of ascorbic acid. Although intravenous administration of ascorbic acid has been investigated in multiple clinical trials for sepsis treatment, the specific immunomodulatory mechanisms underlying its effects remain elusive. This study aimed to investigate the protective effects of high-dose ascorbic acid on experimental sepsis. Results show that intravenous administration of high-dose ascorbic acid (250mg/kg) attenuated sepsis-induced organ dysfunctions in a cecal ligation and puncture (CLP)-induced septic mouse model. Ascorbic acid improved splenic cell apoptosis and increased the number of CD3+ T cells in septic mice induced by CLP. Furthermore, ascorbic acid downregulated PD-L1 expression in livers, reduced PD-1 expression in spleens, and inhibited the phosphorylation of STAT1 at Y701 in multiple organs of CLP-induced septic mice. The in vitro experiments also revealed that 800μM ascorbic acid suppressed STAT1 phosphorylation and inhibited lipopolysaccharide (LPS) and IFN-γ-induced PD-L1 expression in macrophages. These findings suggest that ascorbic acid prevents sepsis-associated organ dysfunction through the p-STAT1/PD-L1 signaling pathway. Our study provides new insights into the potential therapeutic use of ascorbic acid in sepsis.

Vitamin C Enhances Anticancer Immunity

The molecular mechanisms underlying vitamin C’s anticancer activity remain unclear. Recently, multiple high-quality studies demonstrated several potentially novel functions of vitamin C in regulating anticancer immunity, including modulating T cell infiltration of tumor microenvironment as well as increasing cancer cell immunogenicity. (First online: June 4, 2023) REFERENCES Creagan ET, Moertel CG, O'Fallon JR, Schutt AJ, O'Connell MJ, Rubin J, et al. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer: a controlled trial. N Engl J Med 1979; 301(13):687–90. doi: https://dx.doi.org/10.1056/NEJM197909273011303 Moertel CG, Fleming TR, Creagan ET, Rubin J, O'Connell MJ, Ames MM. High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy: a randomized double-blind comparison. N Engl J Med 1985; 312(3):137–41. doi: https://dx.doi.org/10.1056/NEJM198501173120301 Lin J, Cook NR, Albert C, Zaharris E, Gaziano JM, Van Denburgh M, et al. Vitamins C and E and beta carotene supplementation and cancer risk: a randomized controlled trial. J Natl Cancer Inst 2009; 101(1):14–23. doi: https://dx.doi.org/10.1093/jnci/djn438 Chen Q, Espey MG, Sun AY, Pooput C, Kirk KL, Krishna MC, et al. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci USA 2008; 105(32):11105–9. doi: https://dx.doi.org/10.1073/pnas.0804226105 Yun J, Mullarky E, Lu C, Bosch KN, Kavalier A, Rivera K, et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 2015; 350(6266):1391–6. doi: https://dx.doi.org/10.1126/science.aaa5004 Magri A, Germano G, Lorenzato A, Lamba S, Chila R, Montone M, et al. High-dose vitamin C enhances cancer immunotherapy. Sci Transl Med 2020; 12(532). doi: 10.1126/scitranslmed.aay8707. Xu YP, Lv L, Liu Y, Smith MD, Li WC, Tan XM, et al. Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy. J Clin Invest 2019; 129(10):4316–31. doi: https://dx.doi.org/10.1172/JCI129317 Wu X, Zhang Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet 2017; 18(9):517–34. doi: https://dx.doi.org/10.1038/nrg.2017.33 Luchtel RA, Bhagat T, Pradhan K, Jacobs WR, Jr., Levine M, Verma A, et al. High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model. Proc Natl Acad Sci USA 2020; 117(3):1666–77. doi: https://dx.doi.org/10.1073/pnas.1908158117 Morante-Palacios O, Godoy-Tena G, Calafell-Segura J, Ciudad L, Martinez-Caceres EM, Sardina JL, et al. Vitamin C enhances NF-kappaB-driven epigenomic reprogramming and boosts the immunogenic properties of dendritic cells. Nucleic Acids Res 2022; 50(19):10981–94. doi: https://dx.doi.org/10.1093/nar/gkac941

708 Clinical Impact of a Revised Burn Resuscitation Guideline at an Adult Burn Center

Abstract Introduction The American Burn Association recommends volume resuscitation at 2-4ml/kg/TBSA; however, in practice, fluid resuscitation often exceeds these goals. Additional strategies used for burn resuscitation include the use of colloid rescue and high dose ascorbic acid (HDAA). In 2018, our institution moved from a fluid resuscitation strategy which included calculating fluid requirements using 4ml/kg/TBSA and HDAA infusion for burns &amp;gt; 30% TBSA to a strategy that calculated fluids using a 2ml/kg/TBSA with the removal of HDAA. Additionally, the guidance for colloid rescue was updated to provide specific time points for evaluation of the need for initiation of this intervention. The primary objective of this study was to compare outcomes of the new institutional resuscitation strategy to the previous one. Methods This was a retrospective cohort study evaluating outcomes for acute burn resuscitation between the previous institutional resuscitation guideline with the updated guideline. This study included adult patients admitted for burn injury with &amp;gt;20% TBSA between August 1, 2016, to September 30, 2021. The primary outcome was a composite safety endpoint which included incidence of acute kidney injury and intra-abdominal hypertension requiring intervention. Acute kidney injury was defined as a serum creatinine increase 1.5 times baseline. Statistical analyses utilized the Mann-Whitney U test for non-normally distributed continuous data and the chi-squared and Fischer’s exact test for categorical data. A p-value of &amp;lt; 0.05 was considered statistically significant. Results The final analysis included 43 in the pre-group and 52 in the post-group update. Baseline characteristics between the groups were similar. The primary composite safety outcome was non-statistically significantly lower in the post-guideline update group (39.5% vs. 28.8%, p= 0.273). Total fluid volume administered (3.74 ml/kg/TBSA vs. 2.97 mL/kg/TBSA, p=0.007) and hourly urine output within the first 24 hours (1.26 mL/kg/hour vs. 0.75 mL/kg/hour, p=0.007) were significantly lower in the post-group. No differences were observed in vasopressor use (32.6% vs 36.5%, p=0.63), vasopressor duration (70.3 hours vs. 50.4 hours p=0.24), or duration of mechanical ventilation (5.1 days vs 10.4 days, p=0.113). Conclusions The burn resuscitation guideline update resulted in significantly lower 24 hour- fluid volumes, without negative hemodynamic consequences. Applicability of Research to Practice The comparison of two resuscitation protocols provides evidence for other institutions to help optimize their resuscitation practice

57 Effect of High-Dose Ascorbic Acid in Major Burn Patients: A Systematic Review and Meta-Analysis

Abstract Introduction High-dose ascorbic acid (HDAA) plays an important role in oxygen radical elimination which is a major cause of pathophysiological derangement in burn patients. However, there was limited explicit data on the clinical effect of HDAA in major burn patients. The purpose of this study was to identify the benefit and risks of HDAA in major burn patients. Methods MEDLINE, EMBASE, and Cochrane database searches were conducted. An additional search of relevant primary literature and review articles was performed. All the studies related to HDAA and burn were included in the analysis. HDAA group was defined by receiving ascorbic acid 66 mg/kg/day in the first 24 hours. The primary outcome was the 24-hour fluid requirement. The secondary outcomes were in-hospital mortality, 24-hour urine output, ventilator day, hospital length of stay, and in-hospital complications. Pooled incidences and 95% confidence interval (CI) were calculated and summarized using a random effect model on Stata/MP 16.1. Results Of 875 studies, 7 articles (293 patients) were included in this meta-analysis. HDAA significantly reduced 24-hour fluid requirement compared with usual care (no HDAA) (SMD -0.75 ml/kg per TBSA, 95% CI [-1.38 to -0.12]). HDAA group showed a decrease in 24-hour urine output (SMD, 0.65; 95% CI, 0.41 to 0.89). However, it did not demonstrate significant increase in acute kidney injury (RR 1.37, 95% CI [0.60 to 3.13]) and the need for renal replacement therapy (RR 1.31, 95% CI [0.50 to 3.44]). In terms of in-hospital complications, there was no significant difference in abdominal compartment syndrome (RR 0.22, 95% CI [0.08 to 0.89]) and pneumonia or acute respiratory distress syndrome (RR 1.03, 95% CI [0.70 to 1.51]). Though there was a trend to decrease mortality in the HDAA group, there was no statistical difference in mortality (RR 1.27, 95% CI [0.85 to 1.91]). HDAA group had a comparable hospital length of stay (SMD 0.1, 95% CI [-0.44 to 0.63]) and ventilator day (SMD 0.03, 95% CI [-0.64 to 0.70]). Conclusions High-dose ascorbic acid had a clinical benefit in the significant reduction of 24-hour fluid requirement without increasing the risk for acute kidney injury or the need for renal replacement therapy. Though it did not demonstrate a significant improvement in mortality or length of stay, there were no significant reported complications from high-dose ascorbic acid. A multicenter randomized controlled trial is warranted. Applicability of Research to Practice The potential benefit of HDAA in major burn

High-dose intravenous versus low-dose oral vitamin C in burn care: potential protective effects in the severely burned: a retrospective cohort study.

The hospital burn database was used to obtain data on all patients with second-degree or deeper burns of 20% total-body-surface-area or greater. Fourteen patients were selected at random to receive a scheduled dose of 1250mg intravenous ascorbic acid every 6h for 72h. This was considered the high-dose group. During same period, 40 patients received scheduled 500mg oral ascorbic acid every 6h for 72h and this was considered the low-dose group. We gathered sociodemographic and clinical variables associated with ascorbic acid dosing. In our study, statistically significant variables were fluid requirements (p<0.001), hospital stay (p=0.011), length of time intubated on ventilator (p<0.001), colloids used (p=0.002), and total procedures required (p=0.014). Despite higher modified Baux predicted mortality in the high-dose group (10 patients vs. 24 patients, p=0.026) there was no noted significant association in days until the first infection and mortality rate (p=0.451 and 0.326, respectively). The calculated modified Baux predicted a higher mortality rate with the higher dosing group, yet this study did not find a mortality difference between the groups. We speculate that high-dose intravenous ascorbic acid may have protective effects in burn resuscitation. This finding may support some previous studies that found that high-dose ascorbic acid may improve clinical outcomes.

High Dietary Cation and Anion Difference and High-Dose Ascorbic Acid Modify Acid–Base and Antioxidant Balance in Dairy Goats Fed under Tropical Conditions

High ambient temperature (HTa) causes acid-base imbalance and systemic oxidative stress, and this may indirectly affect the mammary gland. Furthermore, HTa induces intracellular oxidative stress, which has been proposed to affect cell metabolism directly. We previously showed in dairy goats that the negative effect of HTa was compromised by enhancing heat dissipation during a high dietary cation and anion difference (DCAD) regimen. Moreover, high-dose vitamin C or ascorbic acid (AA) supplements have been used to manage oxidative stress in ruminants. The present study hypothesized that high DCAD and AA supplements that could alleviate the HTa effect would influence the milk synthesis pathway and mammary gland function. The results showed that goats fed with high DCAD had higher blood pH than control goats in the 4th week. The high dose of AA supplement decreases urine pH in the 8th week. The percent reduction of urine pH from the AA supplement was significant in the DCAD group. The high-dose AA supplement decreased plasma glutathione peroxidase activity and malonaldehyde. This effect was enhanced by a high DCAD supplement. In addition, supplementation with AA increased milk protein and citrate and decreased milk FFA. These alterations indicate the intracellular biochemical pathway of energy metabolism and milk synthesis. It can be concluded that a high DCAD regimen and AA supplement in dairy goats fed under HTa could influence the milk synthesis pathway. The evidence suggests that HTa decreases mammary gland function by modification of acid-base homeostasis and oxidative stress.

Comparison of Hydrocortisone with Combined Hydrocortisone, Ascorbic Acid, and Thiamine as an Adjuvant Therapy on Septic Shock Patients on Mortality: A Systematic Review and Meta-analysis

BACKGROUND: Septic shock is still considered a global health problem because it is the main cause of morbidity and mortality in critical patients. Various clinical studies have proven that intravenous administration of high dose ascorbic acid and corticosteroid helps slow the inflammation cascade. These studies help lower the global sepsis and septic shock burden with cost-effective methods and minimum side effects. We systematically reviewed the comparison between hydrocortisone and hydrocortisone-ascorbic acid-thiamine (HAT) combined therapy as an adjuvant in the mortality rate of septic shock patients. METHODS: Four databases (PubMed, EMBASE, Scopus, and Cochrane) are comprehensively searched using specific keywords up to October 18, 2021. All published studies on the use of HAT on septic shock patients were collected and reviewed. RESULTS: Three randomized controlled trials and two controlled trials enrolling 635 patients were included in the study. HAT therapy was found to be not significant in reducing the intensive care unit (ICU) mortality rate (respiratory rate [RR] 0.89 95% confidence interval [CI] [0.60–1.32], p = 0.56), hospital mortality rate (RR 1.2 95% CI [0.90–1.59], p = 0.21), and 28 days mortality (RR 0.95, 95% CI [0.56–1.58], p = 0.83). CONCLUSION: HAT is ineffective in reducing ICU, hospital, and 28-days mortality in septic shock patients when compared with hydrocortisone therapy, although HAT adjuvant therapy significantly reduces ICU length of stay, ventilator usage duration, and vasopressor usage duration.

Prooxidant effects of high dose ascorbic acid administration on biochemical, haematological and histological changes in Cavia porcellus (Guinea pigs): a Guinea pig experimental model.

Ascorbic acid (AA) is a water-soluble vitamin that is well known for its antioxidant and immune-boosting properties. Owing to the wide-range application of AA in the treatment of numerous ailments and its sweet taste, it is usually abused i.e. overused. However, the effect of the abuse has rarely received attention. Therefore, this study was designed to assess the effect of oral administration of high-dose ascorbic acid on biochemical and haematological parameters as well as the effects on the kidney, liver and lungs. adult guinea pigs were divided into four (4) groups where group 1 served as the untreated control group and groups 2-4 were dosed with 29 mg, 662 mg and 1258 mg of ascorbic acid per day, respectively for 28 days. the result revealed that administration of high dose ascorbic acid significantly (P<0.05) increased serum creatinine from 50.0 ± 7.09 (NC) to AA29- 73.8 ± 4.5, AA-662-89.7 ± 3.3 and AA1258- 79.9 ± 5.7mmol/L and urea levels in the treatment group AA-1258 -18.3 ± 0.5 µmol/L compared to the normal group (NC-2.15 ± 0.6 µmol/L). Disturbance in electrolyte balance was observed with a significant (P<0.05) increase in Na+ from NC- 131.3 ± 3.5 mmol/L to 135.7 ± 3.6 mmol/L in the AA-1258 treatment group, Cl- ( NC- 67.1 ± 1.6 mmol/L increased to AA29- 92.1 ± 0.83, AA662- 95.3 ± 1.3 and AA-1258- 95.6 ± 0.4 mmol/L), and Ca2+ (NC- 2.66 ± 0.03 to AA1258- 3.36 ± 0.03 mmol/L) and a significant (P<0.05) decrease in serum K+ in the AA29-5.0 ± 0.2, AA662-5.2 ± 0.3 and AA1258-5.6 ± 0.3 mmol/L treatment groups compared to the normal group 6.6 ± 0.3 mmol/L. There was also a significant (P<0.05) increase in the differential blood count in the animals with a significant (P<0.05) increase in red blood count ( NC-5.11 ± 0.13 ×106/µL to AA1258- 5.75 ± 0.11×106/µL ), haematocrit count (NC 39.90 ± 0.52% to AA-29-42.08 ± 0.24 and AA1258-46.13 ± 0.86%), white blood count (NC 10.15 ± 1.01 ×103/µL to AA1258- 15.18 ± 1.65×103/µL ), total lymphocytes (NC 3.5 ± 0.51×103/µL to AA29-5.28 ±0.43×103/µL), monocytes (NC 0.45 ± 0.07×103/µL to AA1258 0.80 ± 0.07×103/µL), eosinophils (NC 0.23 ± 0.03×103/µL to AA12580.40 ± 0.03×103/µL), basophils (NC0.68 ± 0.10×103/µL to AA12581.20 ± 0.10×103/µL) and neutrophil count (NC 4.73 ± 0.68×103/µL to AA1258 8.36 ± 0.71×103/µL). The histopathological indices indicate cellular necrosis in the AA662 and AA1258 treatment groups of the kidney and liver respectively compared to the normal control which has normal cells. high dose of ascorbic acid can therefore be suggested to cause damage to the cells by causing cellular necrosis as observed in the histopathology results and has effect on the blood cells as observed in the increase compared to the normal control, and the consequences are possibly triggered through inflammatory responses.

Understanding the rod-to-tube transformation of self-assembled ascorbyl dipalmitate lipid nanoparticles stabilized with PEGylated lipids.

We previously established a nanoparticle-based drug delivery system (DDS) for high-dose ascorbic acid therapy by self-assembly of a lipid-modified ascorbic acid derivative, L-ascorbyl 2,6-dipalmitate (ASC-DP). The particles' morphology should be modified for effective DDSs. Here, we modulated the morphology of self-assembled ASC-DP nanoparticles using two different PEGylated lipids, distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG) and cholesterol-polyethylene glycol (Chol-PEG), with various PEG molecular weights. At the preparation molar ratio of 10 : 1 (ASC-DP/PEGylated lipid), rod-like nanoparticles emerged in the ASC-DP/DSPE-PEG system, whereas the ASC-DP/Chol-PEG system yielded tube-like nanoparticles. The internal structures of both rod-like ASC-DP/DSPE-PEG and tube-like ASC-DP/Chol-PEG nanoparticles were similar to that of repeated ASC-DP bilayers. The particles' surfaces featured PEGylated lipids, which stabilized the structure and dispersion of the nanoparticles. For both systems, the particle size increased slightly with increasing the PEGylated lipid's PEG molecular weight. Increasing the PEG molecular weight decreased the inner tunnel size of tube-like ASC-DP/Chol-PEG nanoparticles. A mechanism has been proposed for the rod-to-tube transformation. Surface-layer free-energy changes owing to the mixing of multiple lipids and PEG chain repulsion are thought to underlie the inner tunnels' formation. The rod-to-tube morphology of self-assembled ASC-DP nanoparticles can be modulated by controlling the PEGylated lipids' structure, including the lipid species and the PEG chain length.

Phenytoin Toxicity with High Dose, Concomitant Ascorbic Acid Dosing.

High dose ascorbic acid may increase risk of phenytoin toxicity. This case report demonstrates high phenytoin levels resulting in adverse drug reactions subsequent to dosing concomitantly with high dose vitamin C, or ascorbic acid (AA), as a precaution against acquiring corona virus (COVID) infection. This patient suffered from a major seizure when he ran out of his phenytoin prescription. Subsequent initiation of phenytoin and later addition of high dose AA resulted in truncal ataxia and falls with bilateral wrist and finger extension weakness. Phenytoin and AA were discontinued, and the patient returned to baseline on a new medication regimen of lacosamide and gabapentin without any other major seizures one year later.

Mitochondrial respiration inhibitor enhances the anti-tumor effect of high-dose ascorbic acid in castration-resistant prostate cancer.

Previous evidences have demonstrated that anti-tumor effect of high-dose ascorbic acid is associated with the generation of reactive oxygen species (ROS) via autoxidation. Hypoxia induces therapy resistance in castration-resistant prostate cancer. As a mitochondrial respiration inhibitor, metformin has the potential to improve tumor oxygenation. In this study, we evaluate the anti-tumor effect of ascorbic acid combined with metformin in prostate cancer. We demonstrated that ascorbic acid inhibits prostate cancer cells proliferation by generating ROS, and metformin enhances the anti-tumor effects of ascorbic acid. Mechanistically, metformin reduces oxygen consumption rate and NADP+/NADPH value in prostate cancer cells, thereby increases the ROS content induced by ascorbic acid. In addition, our data demonstrated that ascorbic acid inhibits p-AKT signaling in a ROS-dependent pathway, leading to inhibition of p-mTOR expression. And metformin inhibits the p-mTOR expression by activating the AMPK signaling pathway, exerting a synergistic effect on tumor suppression with ascorbic acid. Furthermore, metformin improves tumor oxygenation, and the combined treatment effect of ascorbic acid and metformin were demonstrated in a xenograft model of prostate cancer. Taken together, our data demonstrate that metformin enhances the anti-tumor proliferation effect of ascorbic acid by increasing ROS content in castration-resistant prostate cancer. This provides a new strategy for the clinical application of high-dose ascorbic acid as an anti-tumor drug. KEY MESSAGES: Ascorbic acid inhibits tumor growth by inducing ROS generation. As a mitochondrial respiration inhibitor, metformin inhibits cellular oxygen consumption rate to improve oxygenation of prostate cancer. Metformin enhances anti-tumor effect of ascorbic acid by increasing ROS content. Ascorbic acid inhibits the mTOR expression via PI3K-AKT pathway, and metformin inhibits the mTOR expression by inhibiting AMPK signaling in prostate cancer cells.

In vitro effects of ascorbic acid on viability and metabolism of patients' osteosarcoma stem cells.

Stagnation in novelties of osteosarcoma (OS) treatment indicates the need for new therapeutic methods. OS cancer stem cells (OS-CSC) are taught to have the ability to self-renew and develop mechanisms of anticancer drug resistance, and this is why it is difficult to eradicate them. Their metabolism has been recognized as a potential target of therapeutic action. Ascorbic acid (AA) is considered to act pro-oxidative against OS-CSC in vitro by oxidative effect and by inhibition of glycolysis. This study examined an in vitro impact of AA on OS-CSC metabolism isolated from patients' biopsies, with the aim of better understanding of OS-CSC metabolism and the action of AA on OS-CSC. OS-CSC were isolated using a sphere culture system and identified as stem cells using Hoechst 33342 exclusion assay. Determination of the dominant type of metabolism of OS-CSC, parental OS cells, human mesenchymal stem cells (hMSC) and U2OS OS lineage before and after AA treatment was done by Seahorse XF (Agilent). Cytotoxicity of high-dose AA was confirmed by the MTT test and was proven for all the examined cell types as well as HEK293. Seahorse technology showed that OS-CSC can potentially use both glycolysis and oxidative phosphorylation (OXPHOS), and can turn to glycolysis and slow metabolic potential in unfavorable conditions such as incubation in AA.