Jinyinqingre Oral Liquid alleviates LPS-induced acute lung injury by inhibiting the NF-κB/NLRP3/GSDMD pathway.

Acute lung injury (ALI) is a prevalent and severe clinical condition characterized by inflammatory damage to the lung endothelial and epithelial barriers, resulting in high incidence and mortality rates. Currently, there is a lack of safe and effective drugs for the treatment of ALI. In a previous clinical study, we observed that Jinyinqingre oral liquid (JYQR), a Traditional Chinese Medicine formulation prepared by the Taihe Hospital, Affiliated Hospital of Hubei University of Medicine, exhibited notable efficacy in treating inflammation-related hepatitis and cholecystitis in clinical settings. However, the potential role of JYQR in ALI/acute respiratory distress syndrome (ARDS) and its anti-inflammatory mechanism remains unexplored. Thus, the present study aimed to investigate the therapeutic effects and underlying molecular mechanisms of JYQR in ALI using a mouse model of lipopolysaccharide (LPS)-induced ALI and an in vitro RAW264.7 cell model. JYQR yielded substantial improvements in LPS-induced histological alterations in lung tissues. Additionally, JYQR administration led to a noteworthy reduction in total protein levels within the BALF, a decrease in MPAP, and attenuation of pleural thickness. These findings collectively highlight the remarkable efficacy of JYQR in mitigating the deleterious effects of LPS-induced ALI. Mechanistic investigations revealed that JYQR pretreatment significantly inhibited NF-κB activation and downregulated the expressions of the downstream proteins, namely NLRP3 and GSDMD, as well as proinflammatory cytokine levels in mice and RAW2647 cells. Consequently, JYQR alleviated LPS-induced ALI by inhibiting the NF-κB/NLRP3/GSDMD pathway. JYQR exerts a protective effect against LPS-induced ALI in mice, and its mechanism of action involves the downregulation of the NF-κB/NLRP3/GSDMD inflammatory pathway.

Targeting of GSDMD sensitizes HCC to anti-PD-1 by activating cGAS pathway and downregulating PD-L1 expression.

BACKGROUND: Gasdermin D (GSDMD) is well known as a downstream of inflammasomes. However, the roles of GSDMD itself in hepatocellular carcinoma (HCC) remain unclear. METHODS: Two independent cohorts of patients with HCC were analyzed to evaluate the pathological relevance of GSDMD/pTBK1/PD-L1. GSDMD knockout (GSDMD-/-) mice, Alb-Cre mice administered with an adeno-associated virus (AAV) vector that expressed the gasdermin-N domain (AAV9-FLEX-GSDMD-N) and their wild-type littermates were used to induce hepatocarcinogenesis or metastatic HCC. Combination of anti-programmed cell death protein-1 (PD-1) and GSDMD inhibitor dimethyl fumarate (DMF) was used to test for improved therapeutic efficacy. RNA sequencing was used to explore the mechanisms how GSDMD promoted HCC progression. RESULTS: The expression of GSDMD and GSDMD-N was upregulated in HCC tissues or metastatic HCC tissues and positive GSDMD expression indicated grim prognosis. Diethylnitrosamine/carbon tetrachloride or thioacetamide-treated GSDMD-/- mice exhibited decreased liver tumors. In contrast, AAV9-FLEX-GSDMD-N promoted hepatocarcinogenesis. RNA sequencing manifested that knockout of GSDMD impacted the cyclic GMP-AMP synthase (cGAS) pathway and immune-associated pathway. GSDMD damped cGAS activation by promoting autophagy via outputting potassium (K+) and promoted programmed death ligand-1 (PD-L1) expression by histone deacetylases/signal transducer and activator of transcription 1 (STAT1)-induced transactivation of PD-L1 via importing calcium (Ca2+). High Mobility Group Box 1/toll-like receptor 4 (TLR4)/caspase-1 pathway contributed to the overexpression and cleavage of GSDMD. Anti-PD-1 combining with DMF largely impaired HCC progression and metastasis. CONCLUSIONS: Targeting GSDMD could promote expression of interferons through inactivation of cGAS pathway and downregulated the PD-L1 expression. Therefore, combined anti-PD-1 and GSDMD inhibitor might serve as an effective treatment option for patients with HCC with GSDMD upregulation.

Intrinsic Radical Species Scavenging Activities of Tea Polyphenols Nanoparticles Block Pyroptosis in Endotoxin-Induced Sepsis.

Sepsis, a life-threating illness caused by deregulated host immune responses to infections, is characterized by overproduction of multiple reactive oxygen and nitrogen species (RONS) and excessive pyroptosis, leading to high mortality. However, there is still no approved specific molecular therapy to treat sepsis. Here we reported drug-free tea polyphenols nanoparticles (TPNs) with intrinsic broad-spectrum RONS scavenging and pyroptosis-blocking activities to treat endotoxin (LPS)-induced sepsis in mice. The RONS scavenging activities originated from the polyphenols-derived structure, while the pyroptosis blockage was achieved by inhibiting gasdermin D (GSDMD) mediating the pore formation and membrane rupture, showing multifunctionalities for sepsis therapy. Notably, TPNs suppress GSDMD by inhibiting the oligomerization of GSDMD rather than the cleavage of GSDMD, thus displaying high pyroptosis-inhibition efficiency. As a result, TPNs showed an excellent therapeutic efficacy in sepsis mice model, as evidenced by survival rate improvement, hypothermia amelioration, and the organ damage protection. Collectively, TPNs present biocompatible candidates for the treatment of sepsis.

Hyperparathyroidism of Renal Disease.

Renal hyperparathyroidism (rHPT) is a common complication of chronic kidney disease characterized by elevated parathyroid hormone levels secondary to derangements in the homeostasis of calcium, phosphate, and vitamin D. Patients with rHPT experience increased rates of cardiovascular problems and bone disease. The Kidney Disease: Improving Global Outcomes guidelines recommend that screening and management of rHPT be initiated for all patients with chronic kidney disease stage 3 (estimated glomerular filtration rate, < 60 mL/min/1.73 m(2)). Since the 1990s, improving medical management with vitamin D analogs, phosphate binders, and calcimimetic drugs has expanded the treatment options for patients with rHPT, but some patients still require a parathyroidectomy to mitigate the sequelae of this challenging disease.

Cinacalcet versus standard treatment for chronic kidney disease: a protocol for a systematic review and meta-analysis.

BACKGROUND: Chronic kidney disease-mineral and bone disorders (CKD-MBD) have been associated with poor health outcomes, including diminished quality and length of life. Standard management for CKD-MBD includes phosphate-restricted diet, active vitamin D, vitamin D analogs, and phosphate binders. Persistently elevated parathyroid hormone (PTH) levels may require the addition of Cinacalcet hydrochloride (cinacalcet) which sensitizes calcium receptors on the parathyroid glands. The objective of this systematic review is to compare the effect of cinacalcet versus standard treatment in patients with CKD-MBD. METHODS/DESIGN: Data sources will include MEDLINE, EMBASE, the Cochrane Register of Controlled Trials, and Web of Science from 1996 to June 2015. Teams of two reviewers will, independently and in duplicate, screen titles and abstracts and potentially eligible full text reports to determine eligibility, and subsequently abstract data and assess risk of bias in eligible trials. We will calculate the effect estimates (risk ratios or mean differences) and 95 % confidence intervals, as well as statistical measures of variability in results across studies using random effect models for patient-important and intermediate outcomes. We will use the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate the quality of evidence about estimates of effect on an outcome-by-outcome basis. We will present our results with a GRADE summary table. DISCUSSION: Our review will explore the effect of cinacalcet versus standard treatment in patients with CKD-MBD. The results of this systematic review will help guide management of this patient population, and identify targets for future research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015020318 http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015020318.

Utilization and costs of medications associated with CKD mineral and bone disorder in dialysis patients enrolled in Medicare Part D.

BACKGROUND: Information is limited regarding utilization patterns and costs for chronic kidney disease-mineral and bone disorder (CKD-MBD) medications in Medicare Part D-enrolled dialysis patients. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Annual cohorts of dialysis patients, 2007-2010. PREDICTORS: Cohort year, low-income subsidy status, and dialysis provider. OUTCOMES: Utilization and costs of prescription phosphate binders, oral and intravenous vitamin D analogues, and cinacalcet. MEASUREMENTS: Using logistic regression, we calculated adjusted odds of medication use for low-income subsidy versus non-low-income subsidy patients and for patients from various dialysis organizations, and we report per-member-per-month and average out-of-pocket costs. RESULTS: Phosphate binders (∼83%) and intravenous vitamin D (77.5%-79.3%) were the most commonly used CKD-MBD medications in 2007 through 2010. The adjusted odds of prescription phosphate-binder, intravenous vitamin D, and cinacalcet use were significantly higher for low-income subsidy than for non-low-income subsidy patients. Total Part D versus CKD-MBD Part D medication costs increased 22% versus 36% from 2007 to 2010. For Part D-enrolled dialysis patients, CKD-MBD medications represented ∼50% of overall net Part D costs in 2010. LIMITATIONS: Inability to describe utilization and costs of calcium carbonate, an over-the-counter agent not covered under Medicare Part D; inability to reliably identify prescriptions filled through a non-Part D reimbursement or payment mechanism; findings may not apply to dialysis patients without Medicare Part D benefits or with Medicare Advantage plans, or to pediatric dialysis patients; could identify only prescription drugs dispensed in the outpatient setting; inability to adjust for MBD laboratory values. CONCLUSIONS: Part D net costs for CKD-MBD medications increased at a faster rate than costs for all Part D medications in dialysis patients despite relatively stable use within medication classes. In a bundled environment, there may be incentives to shift to generic phosphate binders and reduce cinacalcet use.

Balancing nutrition and serum phosphorus in maintenance dialysis.

Elevated serum phosphorus levels are common in patients with chronic kidney disease and are associated with heart and vascular disease, conditions that in turn are associated with increased mortality. Accurately managing phosphorus intake by restricting dietary protein alone can prove challenging because protein from different sources can contain varying amounts of available phosphorus. Additives used in processed foods frequently are high in inorganic phosphorus, which is readily absorbed, compounding this difficulty. Recent evidence suggests that dietary protein restriction in some cases may do more harm than good in some patients treated with maintenance hemodialysis because protein restriction can lead to protein-energy wasting, which is associated with increased mortality. Accordingly, phosphorus binders are important for managing hyperphosphatemia in dialysis patients. Managing hyperphosphatemia in patients with late-stage chronic kidney disease requires an individualized approach, involving a combination of adequate dietary advice, phosphate-binder use, and adjustments to dialysis prescription. We speculate that increased use of phosphate binders could allow patients to eat more protein-rich foods and that communicating this to patients might increase their perception of their need for phosphate binders, providing an incentive to improve adherence. The aim of this review is to discuss the challenges involved in maintaining adequate nutrition while controlling phosphorus levels in patients on maintenance hemodialysis therapy.

Gastrointestinal phosphate handling in CKD and its association with cardiovascular disease.

Increases in serum concentrations of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) and ultimately phosphate and decreases in 1,25-dihydroxyvitamin D level are thought to play a central role in the progressive nature of kidney disease and the development of cardiovascular disease in patients with chronic kidney disease. The initial changes in PTH and FGF-23 levels are adaptive to maintain serum phosphate concentration and phosphate load within defined levels by increasing urinary excretion of phosphate. Less well appreciated is the unanticipated finding that absorption of phosphate from the gastrointestinal tract is not downregulated in chronic kidney disease. This maladaptive response maintains higher levels of phosphate absorption, thereby contributing to the phosphate burden. Moreover, in response to a low-phosphate diet, as often is prescribed to such patients, gut phosphate absorption may be enhanced, undermining the potential beneficial effects of this intervention. Given the poor response to limiting phosphate intake and the use of phosphate binders, we suggest that research efforts be oriented toward better understanding of the factors that affect phosphate absorption in the gastrointestinal tract and the development of agents that directly inhibit phosphate transporters in the small intestine and/or their associated binding proteins.

Derangements in phosphate metabolism in chronic kidney diseases/endstage renal disease: therapeutic considerations.

The changes in phosphate (PO(4)) metabolism across the spectrum of chronic kidney disease (CKD) and specific strategies to address these abnormalities by reducing PO(4) loads are discussed in this review. This review also addresses briefly the evidence for specific PO(4) serum targets in CKD and endstage renal disease (ESRD) and the potential for other biomarkers such as fibroblast growth factor-23 (FGF-23) to define disease and monitor the effectiveness of therapy. As renal function declines, single nephron excretion of PO(4) must increase to maintain PO(4) balance. Abnormalities in PO(4) metabolism occur early in CKD. Compensatory changes in renal PO(4) handling are sufficient to maintain a normal serum PO(4) level in early stages of CKD, but in more advanced CKD, these processes no longer suffice and overt hyperphosphatemia develops. The resulting increased PO(4) burden contributes directly to development of secondary hyperparathyroidism. The FGF-23 increases early in CKD, likely in response to abnormal PO(4) metabolism, and mediates processes that help restore serum PO(4) levels to normal in CKD stage 3 and in early stage 4. The increased PO(4) burden and subsequent overt hyperphosphatemia are associated with increased mortality and morbidity. Dietary PO(4) restriction, modification of dialysis prescriptions, and administration of oral PO(4) binders can restore PO(4) balance. As CKD progresses, population-based studies demonstrate that diet alone is typically not able to prevent or treat hyperphosphatemia. Dialysis modalities that are currently used often fail to remove sufficient PO(4) to prevent hyperphosphatemia in patients with an inadequately controlled dietary PO(4) load. This is particularly likely among patients without significant residual renal function. Thus, in the majority of ESRD patients, PO(4) binders remain the mainstay of therapy for hyperphosphatemia. All currently available PO(4) binders can restore serum PO(4) to the required level when administered appropriately and in conjunction with dietary PO(4) restrictions. PO(4) binders differ regarding their potential side-effects and impact on long-term patient-centered outcomes. Which of the PO(4) binders might result in the most favorable survival and cardiovascular morbidity profiles and which remain uncertain, remains a subject of considerable clinical investigation. Compelling observational and more limited randomized controlled trial (RCT) evidence support the view that PO(4) binders might differ in their effects on mortality and/or morbidity. The limited evidence from RCTs is mostly congruent with the findings from large observational studies. In particular, evidences from both epidemiologic and RCT support the view that excess calcium administration may independently increase the risk of cardiovascular disease in individuals with normal renal function and in patients with CKD and ESRD. Additional RCT evidence might help determine the degree at which any increased risk from oral calcium exposure can be mitigated with the use of noncalcium-based PO(4) binders. Judicious control of PO(4) early in CKD, possibly monitored by measures of FGF-23, could potentially reduce the risk of development of renal secondary hyperparathyroidism and all of the adverse clinical consequences of poorly controlled CKD-mineral and bone disorder. The mainstays of therapy are likely to include a balance of dietary restriction and PO(4) binders to reduce PO(4) input, and in ESRD patients, dialysis modalities to augment PO(4) output.

The bone and mineral disorder of children undergoing chronic peritoneal dialysis.

The mineral and bone disorder of chronic kidney disease remains a challenging complication in pediatric end-stage renal disease. Here, we assessed symptoms, risk factors and management of this disorder in 890 children and adolescents from 24 countries reported to the International Pediatric Peritoneal Dialysis Network Registry. Signs of this disease were most common in North American patients. The prevalence of hyperphosphatemia increased with age from 6% in young infants to 81% in adolescents. Serum parathyroid hormone (PTH) was outside the guideline targets in the majority of patients and associated with low calcium, high phosphorus, acidosis, dialysis vintage and female gender. Serum calcium was associated with dialytic calcium exposure, serum phosphorus with low residual renal function and pubertal status. PTH levels were highest in Latin America and lowest in Europe. Vitamin D and its active analogs were most frequently administered in Europe; calcium-free phosphate binders and cinacalcet in North America. Clinical and radiological symptoms markedly increased when PTH exceeded 300 pg/ml, the risk of hypercalcemia increased with levels below 100 pg/ml, and time-averaged PTH concentrations above 500 pg/ml were associated with impaired longitudinal growth. Hence, the symptoms and management of the mineral and bone disorder of chronic kidney disease in children on peritoneal dialysis showed substantial regional variation. Our findings support a PTH target range of 100-300 pg/ml in the pediatric age group.

Effect of phosphate binders on oxidative stress and inflammation markers in hemodialysis patients.

It has been suggested that phosphate binders may reduce the inflammatory state of hemodialysis (HD) patients. However, it is not clear whether it has any effect on oxidative stress. The objective of this study was to evaluate the effect of sevelamer hydrochloride (SH) and calcium acetate (CA) on oxidative stress and inflammation markers in HD patients. Hemodialysis patients were randomly assigned to therapy with SH (n=17) or CA (n=14) for 1 year. Before the initiation of therapy (baseline) and at 12 months, we measured in vitro reactive oxygen species (ROS) production by stimulated and unstimulated polymorphonuclear neutrophils and serum levels of tumor necrosis factor alpha, interleukin-10, C-reactive protein, and albumin. There was a significant reduction of spontaneous ROS production in both groups after 12 months of therapy. There was a significant decrease of Staphylococcus aureus stimulated ROS production in the SH group. There was a significant increase in albumin serum levels only in the SH group. In the SH group, there was also a decrease in the serum levels of tumor necrosis factor alpha and C-reactive protein. Our results suggest that compared with CA treatment, SH may lead to a reduction in oxidative stress and inflammation. Therefore, it is possible that phosphate binders exert pleiotropic effects on oxidative stress and inflammation, which could contribute toward decreasing endothelial injury in patients in HD.

Novel therapeutic agents and strategies for the management of chronic kidney disease mineral and bone disorder.

Abnormalities in the serum concentrations of calcium, phosphate, parathyroid hormone and vitamin D develop with declining renal function, leading in turn to renal osteodystrophy. Observational data now suggest that these disturbances in bone and mineral metabolism play an important role in the development of vascular calcification and subsequent cardiovascular disease, contributing to the high burden of cardiovascular disease within this population. A new nomenclature-"chronic kidney disease mineral and bone disorder"-has been introduced to describe this broader clinical syndrome and reflect the new emphasis that has been placed upon its management. This article describes the current therapeutic options for this condition, focusing particularly on the novel medications and strategies that have recently been introduced, and highlighting promising therapeutic possibilities for the future.

Salivary phosphorus and phosphate content of beverages: implications for the treatment of uremic hyperphosphatemia.

BACKGROUND: Hyperphosphatemia provides relevant and dangerous evidence of end-stage renal disease (ESRD) in patients undergoing periodic hemodialysis. The relationship between hyperphosphatemia and cardiovascular calcification, with the consequences of high morbidity and mortality after cardiovascular events, is well-defined. Hyperphosphatemia is treated by dietary limitation of phosphorus ingestion and by phosphate binders, but only half of ESRD patients fall within the range of K/DOQI guidelines. OBJECTIVE AND METHODS: We summarize the results of our studies on salivary phosphate secretion in hemodialysis (HD) and chronic kidney disease (CKD) patients, and on the habit of HD patients to drink beverages with a high or low phosphate content. We also examine the correlation between hyperphosphoremia and the phosphate content of common beverages consumed by HD patients. RESULTS AND CONCLUSIONS: Higher levels of salivary phosphate secretion were found in HD and in CKD patients, along with a relationship between serum phosphorus levels and a high phosphate content of beverages in HD patients.

Phosphate binders in chronic kidney disease and end-stage renal disease: a patient-centered approach.

Disorders of calcium and phosphorus metabolism are associated with significant morbidity and mortality in patients with advanced chronic kidney disease. These patients typically require oral phosphate binders to maintain phosphorus homeostasis, but the choice of which among several agents to use has been actively investigated and debated. Recent debate has been polarized between those who favor calcium-based binders for their proven efficacy and relatively low cost and those who favor sevelamer for its putative beneficial effects on inflammatory biomarkers and vascular calcification. This review summarizes the current state of the art of prescribing phosphate binders, ranging from large-scale clinical trials to focused mechanistic studies, and proposes that the available evidence does not conclusively prove the relative superiority of any one binder.

Phosphate metabolism in the setting of chronic kidney disease: significance and recommendations for treatment.

Phosphorus is an essential mineral that plays a crucial role in cell structure and metabolism. In living organisms, phosphorus exists surrounded by four oxygen atoms to form phosphate (PO(4)). Within cells, PO(4) regulates enzymatic activity and serves as an essential component of nucleic acids, adenosine triphosphate, and phospholipid membranes. Outside cells, PO(4) primarily resides in bone and teeth as hydroxyapatite. A small amount of inorganic PO(4) circulates in serum, with levels balanced by gastrointestinal intake, renal excretion, and a set of specific hormones. Under normal conditions, PO(4) is excreted through the kidneys. Among patients with end stage renal disease (ESRD) receiving chronic dialysis, circulating PO(4) levels typically rise to levels well above the normal laboratory range. Higher serum PO(4) levels are strongly associated with arterial calcification and mortality in this setting. Among predialysis patients with chronic kidney disease (CKD), phosphaturic hormones enhance renal PO(4) excretion to maintain serum PO(4) levels within the high-normal laboratory range. Recently, high-normal serum PO(4) levels have been associated with cardiovascular (CV) events and mortality among individuals who have CKD and among those who have normal kidney function. This review discusses PO(4) metabolism in the context of CKD, examines associations of PO(4) levels with adverse outcomes in the CKD setting, and suggests treatment strategies for moderating serum PO(4) levels.

Phosphorus homeostasis in normal health and in chronic kidney disease patients with special emphasis on dietary phosphorus intake.

Elevated serum phosphorus has been identified as a cardiovascular risk factor in chronic kidney disease (CKD) patients and a clear understanding of phosphorus homeostasis is very important for practicing nephrologists. At any particular point, serum phosphorus levels reflect the balance between movements of this mineral from and into the intestine, bone, intracellular space, and kidneys. We briefly review here all these exchanges with a particular emphasis on dietary phosphorus intake. Despite all the oral phosphorus binders currently available in the market, dietary restriction of this mineral remains a cornerstone for the prevention and treatment of hyperphosphatemia. An effective restriction of dietary intake of phosphorus requires prescription of a moderate protein intake (0.9-1.0 g/kg/day) and restricted consumption of highly processed fast and convenience foods. Phosphorus added during food processing is an important source of this mineral because of its magnitude and high bioavailabilty. Moreover, as food manufacturers are not required to label the amount of phosphorus added during food processing, a significant amount of the current daily phosphorus intake remains unaccounted when estimating phosphorus intake in CKD patients. The recent development of low phosphorus-containing food products represents a very useful addition for CKD patients.

The cost-utility of cinacalcet in addition to standard care compared to standard care alone for secondary hyperparathyroidism in end-stage renal disease: a UK perspective.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is a common side effect of end-stage renal disease (ESRD) and is associated with increased risk of fracture and cardiovascular events (CV). Current standard treatment includes dietary control, phosphate binders and vitamin D. However, many patients do not have their parathyroid hormone (PTH), calcium and phosphate levels controlled by this regimen. Cinacalcet is the first of a new class of calcimimetic drugs which suppress PTH production. Although there is convincing evidence of the impact of cinacalcet on serum biomarkers, the long-term clinical implications of treatment are less clear. The aim of this study is to estimate the cost-utility of cinacalcet as an addition to standard treatment of SHPT compared with standard treatment alone. METHODS: A Markov model was developed to estimate the incremental cost-utility of cinacalcet. Uncertainty was explored through extensive sensitivity analysis. RESULTS: Compared with standard treatment, cinacalcet incurs average additional lifetime costs of pound21,167 per person and confers an additional 0.34 quality adjusted life years, resulting in an incremental cost-effectiveness ratio of pound61,890 (approximately euro89,000) per quality-adjusted life-year (QALY). Extensive one-way sensitivity analysis showed that cinacalcet was only likely to be considered cost-effective if the relative risk of mortality for people with very high levels of PTH was 2.2 compared with people whose PTH reached target levels, or if drug costs were considerably reduced. Probabilistic sensitivity analysis showed cinacalcet was very unlikely to be cost-effective at usual levels of willingness to pay in the National Health Service (NHS). CONCLUSION: Unless the cost of cinacalcet is considerably reduced, it is unlikely to be considered a cost-effective treatment for people with SHPT.