Pharmacokinetics of Edaravone Oral Suspension in Patients With Amyotrophic Lateral Sclerosis.

PURPOSE: Edaravone is a neuroprotective agent approved as an intravenous treatment for amyotrophic lateral sclerosis (ALS). The intravenous administration of edaravone places a burden on patients and there is a clinical need for oral agents for the treatment of ALS. This report aimed to assess the pharmacokinetics and safety of an edaravone oral suspension in patients with ALS after oral and percutaneous endoscopic gastrostomy (PEG) tube administration. METHODS: Two single-dose, open-label phase 1 clinical studies were conducted. Edaravone oral suspension (105 mg of edaravone in 5 mL aqueous suspension) was administered orally and via PEG tube to 9 and 6 Japanese patients with ALS, respectively. Plasma and urinary pharmacokinetics of unchanged edaravone and its metabolites (sulfate and glucuronide conjugates) were determined. Safety was also evaluated. FINDINGS: After reaching maximum plasma concentration, the mean plasma concentration-time of unchanged edaravone showed a triphasic elimination. Mean plasma concentration-time profiles of the metabolites were higher than those of unchanged edaravone. The mean urinary excretion ratios were higher for the glucuronide conjugate than for either unchanged edaravone or the sulfate conjugate. In patients administered edaravone orally, a single adverse event occurred (blood urine present), which was mild and improved without medical intervention. No adverse drug reactions or serious adverse events were reported. In patients administered edaravone via PEG tube, 5 treatment-emergent adverse events were reported in 3 patients; none were related to the study drug. No adverse drug reactions were reported. IMPLICATIONS: In patients with ALS, a single dose of edaravone oral suspension was well absorbed and mainly eliminated in urine as the glucuronide conjugate. No safety concerns emerged. Pharmacokinetics were similar to those previously reported in healthy participants following oral administration. This indicates that effective drug concentrations were achieved and edaravone can be successfully administered both orally and via a PEG tube in patients with ALS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04176224 (oral administration) and NCT04254913 (PEG tube administration), www. CLINICALTRIALS: gov.

Neutralization of extracellular histones by sodium-Β-O-methyl cellobioside sulfate in septic shock.

BACKGROUND: Extracellular histones have been associated with severity and outcome in sepsis. The aim of the present study was to assess the effects of sodium-ß-O-Methyl cellobioside sulfate (mCBS), a histone-neutralizing polyanion, on the severity and outcome of sepsis in an experimental model. METHODS: This randomized placebo-controlled experimental study was performed in 24 mechanically ventilated female sheep. Sepsis was induced by fecal peritonitis. Animals were randomized to three groups: control, early treatment, and late treatment (n = 8 each). mCBS was given as a bolus (1 mg/kg) followed by a continuous infusion (1 mg/kg/h) just after sepsis induction in the early treatment group, and 4 h later in the late treatment group. Fluid administration and antimicrobial therapy were initiated 4 h T4 after feces injection, peritoneal lavage performed, and a norepinephrine infusion titrated to maintain mean arterial pressure (MAP) between 65-75 mmHg. The experiment was blinded and lasted maximum 24 h. RESULTS: During the first 4 h, MAP remained > 65 mmHg in the early treatment group but decreased significantly in the others (p < 0.01 for interaction, median value at T4: (79 [70-90] mmHg for early treatment, 57 [70-90] mmHg for late treatment, and 55 [49-60] mmHg for the control group). mCBS-treated animals required significantly less norepinephrine to maintain MAP than controls (p < 0.01 for interaction) and had lower creatinine (p < 0.01), lactate (p < 0.01), and interleukin-6 (p < 0.01) levels, associated with reduced changes in H3.1 nucleosome levels (p = 0.02). Early treatment was associated with lower norepinephrine requirements than later treatment. Two control animals died; all the mCBS-treated animals survived. CONCLUSIONS: Neutralization of extracellular histones with mCBS was associated with reduced norepinephrine requirements, improved tissue perfusion, less renal dysfunction, and lower circulating IL-6 in experimental septic shock and may represent a new therapeutic approach to be tested in clinical trials.

Tunable Sulfated Alginate-based Hydrogel Platform with enhanced anti-inflammatory and antioxidant capacity for promoting burn wound repair.

Amidst progressive advancements in tissue engineering, there has been a significant enhancement in the efficacy of anti-inflammatory hydrogel dressings, addressing a myriad of clinical challenges on wound healing. A frequent complication during the initial stages of deep second-degree burn wound healing is the onset of an inflammatory storm, typically occurring without effective intervention. This event disrupts normal biological healing sequences, leading to undesirable regression. In response, we have customized a tunable, multidimensional anti-inflammatory hydrogel platform based on sulfated alginates (Algs), loaded with Prussian blue (PB) nanozymes. This platform competently eliminates surplus reactive oxygen species (ROS) present in the wound bed. Algs, functioning as a mimic of sulfated glycosaminoglycans (including heparin, heparan sulfate, and chondroitin sulfate) in the extracellular matrices (ECM), demonstrate a high affinity towards inflammatory chemokines such as interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1). This affinity effectively impedes the infiltration of inflammatory cells into the wound. Concurrently, Algs markedly modulate the macrophage phenotype transition from M1 to M2. Ultimately, our potent anti-inflammatory hydrogels, which strategically target inflammatory chemokines, M1 macrophages, and ROS, successfully attenuate dysregulated hyperinflammation in wound sites. Precise immunomodulation administered to deep second-degree burn wounds in mice has demonstrated promotion of neovascular maturation, granulation tissue formation, collagen deposition, and wound closure. Our biomimetic hydrogels, therefore, represent a significant expansion in the repertoire of anti-inflammatory strategies available for clinical practice.

Advanced culture strategy shows varying bioactivities of sulfated polysaccharides of Poria cocos.

This study compares the bioactivity of six sulfated polysaccharides derived from glucose- and sucrose-feeding extracted from P. cocos. Anti-inflammatory potentials of these polysaccharides were evaluated by pretreating lipopolysaccharide (LPS)-induced inflammation in RAW264.7 cells. Of the tested polysaccharides, the sulfated polysaccharide derived from sucrose-feeding at the concentration of 40 g/l (referred to as "suc 40") exhibited the highest anti-inflammatory activity, of 83 %, and 33 % inhibition of IL-6 and TNF-α secretion, respetively. It achieved this by inhibiting the p-38 and c-Jun N-terminal kinase (JNK) MAPK signaling pathways. On the other hand, the sulfated polysaccharide derived from glucose-feeding at a concentration of 20 g/l (referred to as "glc 20") demonstrated the greatest anti-lung cancer activity. This was achieved by inducing apoptotic-related molecules, such as poly (ADP-ribose) polymerase (PARP) and CHOP. Furthermore, glc 20 had the highest contents of sulfate, fucose, and mannose compared to the other tested polysaccharides. This suggests that the composition of monosaccharide residues are critical factors influencing the anti-inflammatory and anti-cancer activities of these sulfated polysaccharides. Overall, this study highlights the potential of sulfated polysaccharides derived from P. cocos to function as bioactive compounds with anti-inflammatory and anti-cancer properties.

Fucoidan (A Sulfated Polysaccharide) and Cerebroprotein in Combination Alleviate the Neuroinflammation-mediated Neural Damage and Functional Deficits in the Focal Cerebral Ischemia Model of Rat.

Cerebral ischemic reperfusion injury could emanate a cascade of events ensuing in neural death and severe neurobehavioural deficits. The currently available interventions have failed to target the multimodal, interlinked mechanisms that operate cerebral ischemia-induced damage and functional loss. So an integrative intervention has become a mandate to overcome the deleterious mechanisms involved in cerebral ischemic pathophysiology. In this study, adult male Sprague dawley rats were exposed to 2 hours of right middle cerebral artery occlusion (rMCAo) followed by reperfusion, and the intervention group received Fucoidan alone at a dose of 50 mg/kg, i.p (intraperitoneal), Cerebrolysin alone at a dose of 2.5 mg/kg body weight and the combination of both. The sham rats were exposed to surgical procedures, except for the rMCAo. The assessments of the groups were made 24 h after the rMCAo. The stand-alone treatment with Fucoidan, Cerebrolysin has shown a better outcome in the neurobehavioral and, histopathological assessments and the combination has made a significant reduction in the neurological deficits and the infarct volume when compared to the standalone groups. The BBB integrity was well preserved in the combination group when compared with the lesion and standalone groups. Moreover, the combined intervention reduced the level of pro-inflammatory cytokines TNFα, NFkB, IL1α, IL1-ß, IL-6, CD68, COX-2, and mRNA expression of inflammatory genes IL1α, IL1-ß, IL-6, IBA-1, and COX-2 effectively. In conclusion, the present study suggests that rMCAo induced neuroinflammation and neurobehavioural alterations were attenuated by intervention with a combination of Fucoidan and cerebrolysin; Further, Fucoidan and Cerebrolysin combination improved the ischemic tolerance level by promoting the proteins and genes that regulate the inflammatory cytokines and in aiding better recovery after ischemic reperfusion injury.

A 3-O-sulfated heparan sulfate dodecasaccharide (12-mer) suppresses thromboinflammation and attenuates early organ injury following trauma and hemorrhagic shock.

Introduction: Dysregulated inflammation and coagulation are underlying mechanisms driving organ injury after trauma and hemorrhagic shock. Heparan sulfates, cell surface glycosaminoglycans abundantly expressed on the endothelial surface, regulate a variety of cellular processes. Endothelial heparan sulfate containing a rare 3-O-sulfate modification on a glucosamine residue is anticoagulant and anti-inflammatory through high-affinity antithrombin binding and sequestering of circulating damage-associated molecular pattern molecules. Our goal was to evaluate therapeutic potential of a synthetic 3-O-sulfated heparan sulfate dodecasaccharide (12-mer, or dekaparin) to attenuate thromboinflammation and prevent organ injury. Methods: Male Sprague-Dawley rats were pre-treated subcutaneously with vehicle (saline) or dekaparin (2 mg/kg) and subjected to a trauma/hemorrhagic shock model through laparotomy, gut distention, and fixed-pressure hemorrhage. Vehicle and dekaparin-treated rats were resuscitated with Lactated Ringer's solution (LR) and compared to vehicle-treated fresh-frozen-plasma-(FFP)-resuscitated rats. Serial blood samples were collected at baseline, after induction of shock, and 3 hours after fluid resuscitation to measure hemodynamic and metabolic shock indicators, inflammatory mediators, and thrombin-antithrombin complex formation. Lungs and kidneys were processed for organ injury scoring and immunohistochemical analysis to quantify presence of neutrophils. Results: Induction of trauma and hemorrhagic shock resulted in significant increases in thrombin-antithrombin complex, inflammatory markers, and lung and kidney injury scores. Compared to vehicle, dekaparin treatment did not affect induction, severity, or recovery of shock as indicated by hemodynamics, metabolic indicators of shock (lactate and base excess), or metrics of bleeding, including overall blood loss, resuscitation volume, or hematocrit. While LR-vehicle-resuscitated rodents exhibited increased lung and kidney injury, administration of dekaparin significantly reduced organ injury scores and was similar to organ protection conferred by FFP resuscitation. This was associated with a significant reduction in neutrophil infiltration in lungs and kidneys and reduced lung fibrin deposition among dekaparin-treated rats compared to vehicle. No differences in organ injury, neutrophil infiltrates, or fibrin staining between dekaparin and FFP groups were observed. Finally, dekaparin treatment attenuated induction of thrombin-antithrombin complex and inflammatory mediators in plasma following trauma and hemorrhagic shock. Conclusion: Anti-thromboinflammatory properties of a synthetic 3-O-sulfated heparan sulfate 12-mer, dekaparin, could provide therapeutic benefit for mitigating organ injury following major trauma and hemorrhagic shock.

Vitamin D alleviates cognitive dysfunction and brain damage induced by copper sulfate intake in experimental rats: focus on its combination with donepezil.

This study aimed to demonstrate the potential benefits of donepezil (DPZ) and vitamin D (Vit D) in combination to counteract the neurodegenerative disorders induced by CuSO4 intake in experimental rats. Neurodegeneration (Alzheimer-like) was induced in twenty-four male Wistar albino rats by CuSO4 supplement to drinking water (10 mg/L) for 14 weeks. AD rats were divided into four groups: untreated AD group (Cu-AD) and three treated AD groups; orally treated for 4 weeks with either DPZ (10 mg/kg/day), Vit D (500 IU/kg/day), or DPZ + Vit D starting from the 10th week of CuSO4 intake. Another six rats were used as normal control (NC) group. The hippocampal tissue content of ß-amyloid precursor protein cleaving enzyme 1 (BACE1), phosphorylated Tau (p-tau), clusterin (CLU), tumor necrosis factor-α (TNF-α), caspase-9 (CAS-9), Bax, and Bcl-2 and the cortical content of acetylcholine (Ach), acetylcholinesterase (AChE), total antioxidant capacity (TAC), and malondialdehyde (MDA) were measured. Cognitive function tests (Y-maze) and histopathology studies (hematoxylin and eosin and Congo red stains) and immunohistochemistry for neurofilament. Vit D supplementation alleviated CuSO4-induced memory deficits including significant reduction hippocampal BACE1, p-tau, CLU, CAS-9, Bax, and TNF-α and cortical AChE and MDA. Vit D remarkably increased cortical Ach, TAC, and hippocampal Bcl-2. It also improved neurobehavioral and histological abnormalities. The effects attained by Vit D treatment were better than those attained by DPZ. Furthermore, Vit D boosted the therapeutic potential of DPZ in almost all AD associated behavioral and pathological changes. Vit D is suggested as a potential therapy to retard neurodegeneration.

Hypoglycemic and hypolipidemic effect of pentaamino acid fullerene C60 derivative in rats with metabolic disorder.

Pentaamino acid fullerene C60 derivative is a promising nanomaterial, which exhibited antihyperglycemic activity in high-fat diet and streptozotocin-induced diabetic rats. This study investigates the effect of pentaaminoacid C60 derivative (PFD) in rats with metabolic disorders. Rats were assigned to 3 groups (of 10 rats each) as follows: Group 1 (normal control), group 2 included the protamine-sulfate-treated rats (the untreated group of animals with the model metabolic disorder); group 3 (Protamine sulfate + PFD) included the protamine-sulfate-treated model rats that received an intraperitoneal injection of PFD. Metabolic disorder in rats was initiated by protamine sulfate (PS) administration. The PS + PFD group was injected intraperitoneally with PFD solution (3 mg/kg). Protamine sulfate induces biochemical changes (hyperglycemia, hypercholesterolemia, and hypertriglyceridemia) in the blood and morphological lesions in rat liver and pancreas. The potassium salt of fullerenylpenta-N-dihydroxytyrosine in protamine sulfate-induced rats normalized blood glucose level and the serum lipid profile and improved hepatic function markers. Treatment with PFD restored pancreas islets and liver structure of protamine sulfate-induced rats compared to the untreated group. PFD is a promising compound for further study as a drug against metabolic disorders.

Characterization and therapeutic effect of Sargassum coreanum fucoidan that inhibits lipopolysaccharide-induced inflammation in RAW 264.7 macrophages by blocking NF-κB signaling.

Inflammation is a complex host-protective response against harmful stimuli involving macrophage activation that results in secretion of inflammatory mediators, like nitric oxide (NO), pro-inflammatory cytokines, and prostaglandin E2 (PGE2). In this study, we evaluated fucoidan isolated using Viscozyme-assisted enzymatic extraction of Sargassum coreanum extract against lipopolysaccharide (LPS)-stimulated inflammation in RAW 264.7 macrophages and zebrafish model. Among the fucoidan fractions isolated using ion exchange chromatography, SCVF5 showed the highest sulfate and fucose contents based on chemical composition and monosaccharide analysis. Fourier-transform infrared (FT-IR) spectroscopy confirmed the presence of sulfate esters by the stretching vibrations of the SO peak at 1240 cm-1. SCVF5 showed anti-inflammatory effects by inhibiting NO and PGE2 generation in LPS-stimulated RAW 264.7 macrophages by downregulating inducible NO synthase and cyclooxygenase-2 expression. Treatment with SCVF5 suppressed pro-inflammatory cytokine production, such as TNF-α, (IL)-1ß, and IL-6 by modulating the nuclear factor-kappa B signaling cascade in LPS-induced RAW 264.7 cells. Furthermore, in vivo results showed that SCVF5 can potentially downregulate LPS-induced toxicity, cell death, and NO production in LPS-induced zebrafish model. Collectively, these results suggest that S. coreanum fucoidan has remarkable anti-inflammatory activity in vitro and in vivo and may have potential applications in the functional food, cosmetic, and pharmaceutical industries.

Longitudinal evaluation of dehydroepiandrosterone (DHEA), its sulfated form and estradiol with cancer-related cognitive impairment in early-stage breast cancer patients receiving chemotherapy.

The purpose of this study is to elucidate how patient-reported cognitive symptoms manifest from variations in hormone levels or precursors such as dehydroepiandrosterone (DHEA) and its sulfated form [collectively termed as DHEA(S)] and to investigate their association in breast cancer survivors. Levels of estradiol and DHEA(S) were compared between early-stage breast cancer patients with and without cancer-related cognitive impairment (CRCI) during adjuvant chemotherapy. Data were analyzed from 242 patients (mean age ± SD = 50.8 ± 9.2 years) who had completed FACT-Cog v.3.0, blood draws and questionnaires. Regression model was used to fit the magnitude of change in each respective biomarker levels against overall cognitive impairment status while adjusting for clinically important covariates. There was reduction in mean plasma levels of estradiol and DHEAS during and towards the end of chemotherapy (p-values < 0.001). Compared to non-impaired patients, smaller magnitude of decline was observed in DHEA(S) levels in patients reporting CRCI, with significant association between decline in DHEAS levels and acute onset of CRCI at 6 weeks from baseline (adjusted ß of 0.40, p-value of 0.02). In contrast, patients reporting CRCI showed greater magnitude of decline in estradiol compared to non-impaired patients, although this was not found to be statistically significant. There was an association between magnitude of change in biomarker levels with self-reported CRCI which suggests that the hormonal pathway related to DHEAS may be implicated in acute CRCI for breast cancer survivors. Our findings help to improve biological understanding of the pathway from which DHEAS may correlate with cognitive dysfunction and its impact on cancer survivors.

pH-responsive Sulfated Hyaluronic Acid Nanoparticles Targeting Tumor Cells and CAFs for the Treatment of Breast Cancer.

BACKGROUND: Tumor metastasis is a main cause of death in patients with breast cancer. The cross-talk between cancer-associated fibroblasts (CAFs) and tumor cells plays an important role in promoting tumor invasion and metastasis. It is important to develop a novel delivery system to inhibit tumor development by simultaneously targeting both CAFs and tumor cells. OBJECTIVES: The main objective of this research was to prepare nanoparticles to inhibit tumor proliferation and migration by blocking the cross-talk of tumor-CAFs. Additionally, a novel "MCF- 7+NIH/3T3" mixed cell model was established to mimic the tumor microenvironment (TME). METHODS: In this study, the pH-responsive nanoparticles (MIF/DOX-sul-HA NPs) based on sulfated hyaluronic acid (sul-HA) polymers were prepared for co-delivery of doxorubicin (DOX) and mifepristone (MIF). The effects of anti-proliferation and anti-metastasis of MIF/DOX-sul-HA NPs were investigated both in vitro and in vivo. RESULTS: The results showed that MIF/DOX-sul-HA NPs were nearly spherical in shape with narrow particle size distribution and pH-responsive drug release, and could be taken up by both MCF-7 and NIH/3T3 cells. Compared with MCF-7 cells alone, the anti-tumor effect of single DOX was weak in the "MCF-7+NIH/3T3" mixed cell model. MIF/DOX-sul-HA NPs exhibited strong effects of anti-proliferation and anti-metastasis than the free single drug. CONCLUSION: The sul-HA nanoparticles for co-delivery of DOX and MIF could be a promising combined therapy strategy for the treatment of breast cancer.

The Effects of Sacran, a Sulfated Polysaccharide, on Gut Microbiota Using Chronic Kidney Disease Model Rats.

The aim of this study was to investigate the beneficial effects of sacran, a sulfated polysaccharide, on renal damage and intestinal microflora, in 5/6 nephrectomy rats as a model for chronic kidney disease (CKD). 5/6 Nephrectomy rats were divided into sacran treated and non-treated groups and examined for lethality after 4 weeks. The 5/6 nephrectomy rats were also divided into three groups: sacran treated, non-treated and AST-120 treated groups, and treated orally in a concentration-dependent manner for 4 weeks. Renal function was estimated by biochemical and histopathological analyses. Metagenomic analysis of feces from each group after 4 weeks was also performed and changes in intestinal microflora were compared. The administration of sacran to CKD rats at ≥19 mg/d increased their survival. In addition, the sacran-treated group improved CKD-related parameters in a concentration-dependent manner, and the inhibitory effect of 40 mg/d of sacran was comparable to that of AST-120. The changes in the intestinal microflora of the sacran treated group were positively correlated with an increase in the number of Lactobacillus species, which are known to be rich in beneficial bacteria, and the increment of this beneficial bacteria was negatively correlated with the concentration of indoxyl sulfate, a uremic toxin, in plasma. These results strongly suggest that the oral administration of sacran could contribute to the stabilization of intestinal microflora in CKD rats and to the reduction of oxidative stress as well as the inhibition of progression of CKD.

Comparison of daily oral iron replacement therapy with every other day treatment in female reproductive age patients with iron-deficiency anemia.

Iron-deficiency anemia (IDA) is accepted as the most common cause of anemia in the world. The main goals of iron replacement therapy are to normalize the hemoglobin level and to replace iron stores. Current guidelines for treating iron deficiency recommend daily divided doses of iron to increase absorption. Hepcidin is a key regulator of systemic iron balance and acts in harmony with intracellular iron metabolism. Daily dosing and divided doses may increase serum hepcidin and decrease iron absorption. In this study, it was aimed to compare the effectiveness of daily and every other day oral iron replacement therapy in women of reproductive age with iron-deficiency anemia. We included premenopausal female patients aged between 18 and 50 years with iron-deficiency anemia. Forty patients were given oral iron therapy at a daily dose of 2*80 mg (iron sulfate). Forty-three patients were given iron treatment at a dose of 2*80 mg (iron sulfate) every other day. After 2 months of oral iron therapy, there was a significant improvement in hemoglobin, mean corpuscular volume, serum iron, total iron-binding capacity, and transferrin saturation in both groups. The values of hemoglobin, serum iron, transferrin saturation, and ferritin significantly increased at the end of the treatment for both groups. Although the median hepcidin level on the 15th-day measurement in the every other day treatment group was higher than that in the daily treatment group, there was no significant difference. As a result, the patients' compliance with the treatment can be increased by offering treatment every other day instead of daily, since it provides similar treatment effectiveness.

Sulfated galactoglucan impedes xenografted lung cancer cell growth by blocking angiogenesis via binding BMPRs.

Evidences propound tumor growth may be impeded by blocking angiogenesis. Before we showed that sulfated glucan or arabinogalactan might bind to BMP2 or its receptors to inhibit angiogenesis. Whether sulfated galactoglucan can target both BMPRIA and BMPRII to impede angiogenesis and tumor cells growth is still vague. Here, we prepare galactoglucan and its sulfated derivatives Sul-CDA-0.05. The sulfate groups substituted are at the C-6 of 1, 4-linked α-Glcp and 1, 4-linked α-Galp backbone and at the C-6 of branch chain T-linked α-Glcp. Sul-CDA-0.05 can inhibit angiogenesis in vitro and in vivo. Indeed, Sul-CDA-0.05 impedes xenografted A549 lung tumor cells growth. Mechanism study demonstrates that this polysaccharide may target both BMPRIA and BMPRII to block BMP/Smad/Id1 signaling and attenuate VEGF and its transcription factor. Our evidences suggest that Sul-CDA-0.05 may be a new drug candidate for anti-lung cancer therapy by targeting both BMPRIA and BMPRII.

Effect of Polysaccharide Sulfate-Loaded Poly(lactic-co-glycolic acid) Nanoparticles on Coronary Microvascular Dysfunction of Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM) mainly results from development of coronary microcirculatory dysfunction (CMD). Polysaccharide sulfate (PSS), as one heparin drug, has a variety of biological activities. This study examined the efficacy of a new type of PSS-loaded poly lactic-co-glycolic acid (PLGA) nanoparticles (PSS-NPs) on DCM, in finding a theoretical basis for CMD treatment. After establishment of DCM model, the animals were administrated with PSS, PSS-NPs, normal saline or poly(ethylene glycol)1 (PEG1) through intraperitoneal injection. 8 weeks after injection of streptozotocin (STZ), heart function of rats was assessed by echocardiography. The rat tissues were collected and detected by histological analysis. Quantitative reverse transcription PCR (RT-qPCR) and Western blot analyses determined the levels of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and pro-inflammatory factors. PSS-NPs had a good protective effect on cardiac insufficiency in rats. Administration of PSS-NPs prolonged survival state, and enhanced cardiac function, thereby alleviating the symptoms, and inducing formation of micro vessels. Importantly, it improved the symptoms of DCM patients and their quality of life. Moreover, pro-inflammatory factor levels decreased upon the treatment, accompanied with inactivation of NF-κB signaling pathways, thereby improving DCM. This study demonstrated that the PSS-NPs significantly relieved DCM and restored cardiac function in rats through NF-κB signaling pathways, providing a theoretical basis for development of PSS-NPs, and new treatment ideas for CMD of DCM.

Intralesional purified protein derivative versus zinc sulfate 2% in the treatment of pediatric warts: Clinical and dermoscopic evaluation.

BACKGROUND: Warts are common in children and can be difficult to treat. Many treatments for warts are destructive and painful in contrast to intralesional immunotherapy using different types of antigens. AIM: To evaluate the efficacy, safety, and tolerability of intralesional purified protein derivative (PPD) versus intralesional zinc sulfate 2% in the treatment of pediatric warts. METHODS: This randomized clinical trial included 120 children with multiple warts divided into two equal groups. Group Ⅰ received intralesional 10 IU (0.1 ml) of PPD, group Ⅱ received intralesional zinc sulfate 2% in the largest wart every 2 weeks till improvement or for a maximum five treatment sessions. The follow-up period was 6 months after the last treatment session. RESULTS: The overall response was equal in both groups (81.7%), but the response of the injected wart was higher in the zinc sulfate group (93.4%) versus PPD group (83.3%) with no significant difference. The highest cure rates were after the 5th session in the PPD group and the 1st session in the zinc sulfate group with slightly lower numbers of sessions needed for cure in the zinc sulfate group (3 sessions) versus the PPD group (4 sessions). The zinc sulfate group showed statistically significant higher rates of complications (pain, inflammation, necrosis, and scar) than PPD group. The zinc sulfate group showed non-significant higher rates of recurrence during the follow-up period. CONCLUSION: Both intralesional PPD and zinc sulfate 2% are effective in pediatric warts with higher safety profile of PPD.

Single- and multiple-dose safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ASP0367, or bocidelpar sulfate, a novel modulator of peroxisome proliferator-activated receptor delta in healthy adults: Results from a phase 1 study.

INTRODUCTION/AIMS: ASP0367, or bocidelpar sulfate, is an orally administered small molecule that potently and selectively modulates peroxisome proliferator-activated receptor δ (PPARδ) to address mitochondrial dysfunction occurring in diseases including primary mitochondrial myopathy and Duchenne muscular dystrophy. The objectives of this first-in-human trial were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of ASP0367 in healthy participants. METHODS: In this double-blind phase 1 study, adult participants were randomized to single or multiple ascending oral doses of ASP0367 or placebo. The study duration was 1 and 14 days, respectively. Pharmacokinetic parameters under fed conditions were also evaluated. RESULTS: A total of 64 (single-dose cohort) and 37 (multiple-dose cohort) participants were included in the study. After single doses of 1 to 120 mg, ASP0367 was rapidly absorbed, with median time to maximum plasma concentration (tmax ) of 1.50 to 2.24 hours under fasting conditions; ASP0367 concentrations declined in a multiphasic manner after reaching maximum plasma concentration. Under fed conditions, tmax was delayed 1.7 hours. After multiple once-daily doses, mean half-life of ASP0367 10 to 75 mg ranged from 14.1 to 17.5 hours; steady state was reached after 4 days. Negligible accumulation was observed after repeated dosing. No participants receiving ASP0367 discontinued treatment, and all treatment-emergent adverse events were mild to moderate in severity; none were considered drug-related. No clinically significant changes were observed on laboratory or electrocardiographic evaluation. Treatment- and dose-dependent upregulation of six PPARδ target genes was observed with single and multiple doses of ASP0367. DISCUSSION: ASP0367, or bocidelpar sulfate, was well tolerated; rapid absorption, roughly dose-proportional bioavailability, and effects on PPARδ target genes were demonstrated in healthy adult participants.

Effects of Microbiota-Driven Therapy on Circulating Indoxyl Sulfate and P-Cresyl Sulfate in Patients with Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Indoxyl sulfate (IS) and p-cresyl sulfate (PCS), protein-bound uremic toxins, exacerbate the deterioration of renal function and increase the risk of cardiovascular events in chronic kidney disease (CKD) patients. The effects of microbiota-driven therapy (probiotics, prebiotics, or synbiotics) on decreasing circulating IS and PCS concentrations are controversial; thus, we performed the present systematic review and meta-analysis to assess the effects of microbiota-driven therapy on circulating IS and PCS concentrations in CKD patients. PubMed, EMBASE, and Cochrane Library databases were systematically searched from inception to 22 July, 2021, and randomized controlled trials (RCTs) investigating the effects of microbiota-driven therapy on circulating IS and PCS concentrations in CKD patients were included. In all, 14 RCTs with 513 participants were eligible for the meta-analysis. The effects of microbiota-driven therapy on the circulating IS and PCS concentrations were evaluated with weighted mean differences (WMDs) measured by a fixed-effects model or a random-effects model. Compared with placebo, microbiota-driven therapy had no statistically significant effect on the circulating IS concentration (WMD: -1.64 mg/L; 95% CI: -3.46, 0.18 mg/L; P = 0.077) but it decreased the circulating PCS concentration (WMD: -2.42 mg/L; 95% CI: -3.81, -1.04 mg/L; P = 0.001). In the subgroup analyses, prebiotic (n = 6) and synbiotic (n = 3) supplementation significantly decreased the circulating PCS concentration, whereas probiotic (n = 3) supplementation did not. Meta-regression showed that the effects of microbiota-driven therapy were not associated with the supplementation time or the year of publication. Moreover, there was no significant evidence of publication bias. This review found that microbiota-driven therapy decreased the circulating PCS concentration in CKD patients. Additional large, well-designed RCTs with improved methodology and reporting are necessary to assess the effects of microbiota-driven therapy on circulating IS and PCS concentrations in the long term. This systematic review was registered at www.crd.york.ac.uk/prospero/ as CRD42021269146.

Sulfated Polysaccharides from Enteromorpha prolifera Attenuate Lipid Metabolism Disorders in Mice with Obesity Induced by a High-Fat Diet via a Pathway Dependent on AMP-Activated Protein Kinase.

BACKGROUND: Obesity-related metabolic diseases have recently evoked worldwide attention. Studies have demonstrated that Enteromorpha polysaccharide (EP) exerts lipid-lowering effects, but the underlying mechanism remains unclear. OBJECTIVES: We investigated whether EP regulates lipid metabolism disorders in mice with high-fat diet (HFD)-induced obesity via an AMP-activated protein kinase (AMPK)-dependent pathway. METHODS: Six-week-old male C57BL/6J mice (18 ± 2 g) were fed a normal diet (ND; 10% energy from fats) or an HFD (60% energy from fats) for 6 weeks to induce obesity and treated intragastrically with EP (200 mg/kg body weight) or distilled water (10 mL/kg body weight) for 8 weeks. Biochemical indicators, AMPK-dependent pathways, and lipid metabolism-related genes were evaluated to assess the effects of EP on HFD-induced lipid metabolism disorders. The essential role of AMPK in the EP-mediated regulation of lipid metabolism was confirmed using HFD-fed male Ampka2-knockout mice (aged 6 weeks; 17 ± 2 g) treated or not treated with the above-mentioned dose of EP. The data were analyzed by t-tests, 2-factor and 1-way ANOVAs. RESULTS: Compared to the ND, the HFD resulted in a greater body weight (24.3%), perirenal fat index (2.2-fold), and serum total cholesterol (24.66%) and LDL cholesterol (1.25-fold) concentrations (P < 0.05) and dysregulated the AMPK-dependent pathway and the expression of most lipid metabolism-related genes (P < 0.05). Compared to the HFD, EP treatment resulted in a lower perirenal fat index (31.22%) and LDL cholesterol concentration (23.98%) and partly reversed the dysregulation of the AMPK-dependent pathway and the altered expression of lipid metabolism-related genes (P < 0.05). Ampka2 knockout abolished the above-mentioned effects of EP in obese mice and the EP-mediated effects on the expression of lipid metabolism-related genes (P > 0.05). CONCLUSIONS: These findings suggest that EP can ameliorate lipid metabolism disorders in mice with HFD-induced obesity via an AMPK-dependent pathway.