Albumin-to-Globulin Ratio Combined with Neutrophil-to-Lymphocyte Ratio as a Prognostic Predictor in Multiple Myeloma with Renal Impairment.

Background: The albumin-to-globulin ratio (AGR) and neutrophil-to-lymphocyte ratio (NLR) have been recently regarded as promising prognostic factors in various malignancies. The present study investigated the prognostic value of combining the AGR and NLR (ANS) for risk assessments in multiple myeloma (MM) with renal impairment (RI). Methods: From 2011 to 2018, 79 patients with MM and RI were enrolled in this study. Receiver operating curves (ROCs) were constructed to determine optimal AGR and NLR thresholds for predicting overall survival (OS) and progression-free survival (PFS) during follow up. The prognostic values of AGR, NLR, and ANS were evaluated with Cox regression and Kaplan-Meier methods. We also created a predictive nomogram for prognostic evaluations of OS and PFS, and the predictive accuracy was assessed with a concordance index (c-index). Results: The ROC curves analyses showed that the optimal cut-off levels were 2.27 for NLR and 1.57 for AGR. A high NLR and a high ANS were significantly associated with worse OS and PFS. However, a high NLR combined with a low AGR was associated with worse OS. Multivariate analyses demonstrated that both the NLR and ANS were independent predictors for both OS and PFS and that a low AGR was an independent predictor of a reduced OS. The nomogram accurately predicted OS (c-index: 0.785) and PFS (c-index: 0.786) in patients with MM and RI. Conclusion: ANS may serve as a potential prognostic biomarker in patients with MM and RI. The proposed nomograms may facilitate prognostic predictions for patients with MM and RI.

Long-term phosphorus fertilization reveals the phosphorus limitation shaping the soil micro-food web stability in the Loess Plateau.

The intricate decomposition pathways within soil micro-food webs are vital for cycling soil organic carbon and nutrients, influencing the quality, productivity, and sustainability of soil systems. However, the impact of diverse phosphorus addition on these organic decomposition pathways still needs to be explored. In an 8-year experiment, phosphorus (P) fertilizer was added at varying levels (0 kg ha-1, CK; 60 kg ha-1, P60; 120 kg ha-1, P120; and 180 kg ha-1, P180), to investigate the response of the soil micro-food web. The results revealed a significant effect of phosphorus addition on soil microorganisms and nematodes, with P60 exerting a greater influence than other treatments. At P60, the Shannon index of nematodes and fungi surpassed other treatments, indicating higher diversity, while the Shannon index of bacteria was lower. The Chao1 index of bacteria and fungi at P60 was higher, contrasting with the lower index for nematodes. Metabolic footprints of bacterivores and omnivores-predators (BFMF and OPMF) were higher at P60, while metabolic footprints of fungivores and plant parasites (FFMF and PPMF) were lower, signifying altered energy flow. Functional metabolic footprints and energy flow analysis unveiled a stable soil micro-food web structure at P60, with enhanced energy conversion efficiency. Network analysis illustrated positive correlations between fungi, fungivorous nematodes (FF), and omnivorous-predatory nematodes (OP) at P60, while P120 and P180 showed positive correlations among bacteria, bacterivorous nematodes (BF), and OP. Path analysis underscored the higher contribution rate of BF-C, FF-C, and OP-C to soil organic carbon at P60 compared with P120 and P180. These findings suggest that nutrient interactions between fungi and nematodes regulate soil micro-food web decomposition under low phosphorus concentrations. In contrast, interactions between bacteria and nematodes dominate at high phosphorus concentrations. The study indicates that adding phosphorus has nuanced bottom-up effects, intricately shaping the structure and activity of the pathways and underscoring the need for a comprehensive understanding of nutrient dynamics in soil ecosystems.

Spatial-Temporal Correlations between Soil pH and NPP of Grassland Ecosystems in the Yellow River Source Area, China.

In recent years, ecological concerns such as vegetation destruction, permafrost deterioration, and river drying have been paid much more attention to on the Yellow River Basin in China. Soil pH is regarded to be the fundamental variable among soil properties for vegetation growth, while net primary productivity (NPP) is also an essential indicator to reflect the healthy growth of vegetation. Due to the limitation of on-site samples, the spatial−temporal variations in soil pH and NPP, as well as their intrinsic mechanisms, remain unknown, especially in the Yellow River source area, China. Therefore, it is imperative to investigate the coupling relationship between soil pH and NPP of the area. The study coupled MODIS reflectance data (MOD09A1) with on-site soil pH to estimate spatial−temporal variations in soil pH, explore the response of NPP to soil pH, and assess the extent to which they contribute to grassland ecosystems, thus helping to fill knowledge gaps. Results indicated that the surface spectral reflectance for seven bands could express the geographic pattern of soil pH by applying a multiple linear regression equation; NPP exhibited an increasing trend while soil pH was the contrary in summer from 2000 to 2021. In summer, NPP was negatively correlated with soil pH and there was a lag effect in the response of NPP to soil pH, revealing a correlation between temperate steppes > montane meadows > alpine meadows > swamps in different grassland ecosystems. In addition, contribution indices for temperate steppes and montane meadows were positive whereas they were negative for swamps and alpine meadows, which are apparent findings. The contribution index of montane and alpine meadows was greater than that of temperate steppes and swamps. The approach of the study can enable managers to easily identify and rehabilitate alkaline soil and provides an important reference and practical value for ecological restoration and sustainable development of grassland ecosystems in alpine regions.

Prognostic value of fibrinogen to albumin ratios among critically ill patients with acute kidney injury.

Fibrinogen to albumin ratios (FAR) have shown to be a promising prognostic factor for improving the predictive accuracy in various diseases. This study explores FAR's prognostic significance in critically ill patients with acute kidney injury (AKI). All clinical data were extracted from the Multiparameter Intelligent Monitoring in Intensive Care Database III version 1.4. All patients were divided into four groups based on FAR quartiles. The primary endpoint was in-hospital mortality. A generalized additive model was applied to explore a nonlinear association between FAR and in-hospital mortality. The Cox proportional hazards models were used to determine the association between FAR and in-hospital mortality. A total of 5001 eligible subjects were enrolled. Multivariate analysis demonstrated that higher FAR was an independent predictor of in-hospital mortality after adjusting for potential confounders (HR, 95% CI 1.23, 1.03-1.48, P = 0.025). A nonlinear relationship between FAR and in-hospital mortality was observed. FAR may serve as a potential prognostic biomarker in critically patients with AKI and higher FAR was associated with increased risk of in-hospital mortality among these patients.

Effect of chronic renal failure medium on the ubiquitin­proteasome pathway of arterial muscle cells.

The ubiquitin­proteasome pathway (UPP) is involved in the occurrence and development of atherosclerosis through inhibitor of κB (IκB) degradation which activates nuclear factor-κB (NF­κB). However, the correlation between UPP and vascular complications of uramia remains unknown. The aim of the present study was to determine whether the UPP is activated in aortic smooth muscle cells (ASMCs) when cultured with uremic serum and to examine the role of the UPP on the dysfunction of ASMCs in uremia. ASMCs were cultured with pooled normal sera or chronic renal failure sera. The mRNA expression levels for ubiquitin (Ub) and Ub-activating enzyme (E1) were analyzed using reverse transcription PCR and levels of the ubiquitinated proteins E1 and IκBα were measured using western blot analysis. The enzymatic activities of three 20S proteasomes were examined using specific fluorogenic peptide substrates. Compared with normal serum, chronic renal serum increased E1 mRNA and protein expression of rabbit ASMCs (both P<0.01). In addition, the mRNA expression of Ub also increased and the expression of IκBα was observed to decrease significantly (both P<0.01). Ubiquitinated proteins in the normal and chronic renal failure groups were not found to be significantly different, but the activity of proteasomes increased significantly (P<0.01). Chronic renal failure medium induced the activation of the UPP in ASMCs.

Uraemic serum induces dysfunction of vascular endothelial cells: role of ubiquitin-proteasome pathway.

The ubiquitin-proteasome pathway (UPP) has been indicated to contribute to dysfunction of endothelial cells (ECs). Nevertheless, the relationship between UPP and vascular complications of uraemia remains unknown. We aimed to determine whether the UPP is activated in vascular ECs when cultured with uraemic serum, and to examine the role of the UPP on dysfunction of ECs in uraemia. Rabbit aortic endothelial cells (RAECs) were cultured with normal serum or different concentrations of uraemic serum. The expression of the ubiquitin-activating enzyme (E1), an indicator of the UPP, was detected by real-time RT-PCR and Western blot; proteasome activity was determined by fluorescence spectrophotometry; and nuclear factor-κB (NF-κB) activity and expression, as well as tumour necrosis factor-α (TNF-α) expression, were also detected. We found that the expression of E1 and the activities of three kinds of proteasomes were increased significantly in RAECs after incubation with uraemic serum. Proliferation of RAECs was increased significantly by incubation with 3-15% uraemic serum but decreased markedly when incubated with uraemic serum above 15% (increased apoptosis). Incubation of RAECs with uraemic serum induced increased NF-B DNA-binding activity and nuclear translocation of NF-κB, decreased nitric oxide production and increased expression of TNF-α, which is the final effector of inflammatory activation of cells. All of these responses in RAECs were suppressed by the specific proteasome inhibitor, MG132. The inhibition of inflammatory responses by MG132 was further supported by a parallel experiment with pyrrolidine dithiocarbamate, a specific inhibitor of κNF-B. These findings suggest that the UPP was activated in RAECs by administration of uraemic serum, and played a pivotal role in the dysfunction of vascular ECs, such as inflammatory activation.

[Potential effect of uremic medium on cell proliferation and apoptosis and the activation of nuclear factor-kappa B pathway of aortic endothelial cells in rabbit culture].

OBJECTIVE: To investigate the potential effect of uremic medium on cell proliferation and apoptosis of aortic endothelial cell (AEC), two key processes in the development of atherosclerosis, in rabbit culture. And to understand the effects of uremic medium on the activation of nuclear factor-kappa B (NF-κB) pathway and cytokines expression of AEC. METHODS: Rabbit AEC were cultured with growth media supplemented with pooled sera from normal rabbits or those with chronic renal failure. The 80% confluent AEC were incubated for 24 h with media supplemented with pools of control or uremic sera. Cell proliferation was assessed by a MTT assay and cell cycle detected by flow cytometry. Hoechst33342 assay and flow cytometry were used to investigate the apoptotic effect of uremic medium in AEC. The expression of mRNA and protein levels for NF-κB, IκBα were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. NF-κB P65 nuclear translocation was analyzed by immunofluorescence. The activity of NF-κB was measured by electrophoretic mobility shift assay (EMSA). Concentrations of TNF-α and IL-6 in culture supernatants were evaluated by ELISA, and the expression of protein for TNF-α in cell lysates by Western blot. RESULTS: Uremic medium induced proliferation in the lower concentration range of 3%-10% while promoted apoptosis in the higher concentrations (> 10%). Uremic serum increased NF-κB mRNA (0.35 ± 0.05 vs 0.26 ± 0.02, P < 0.01) and protein (1.67 ± 0.15 vs 0.41 ± 0.05, P < 0.01) expression, decreased IκBα mRNA (0.13 ± 0.03 vs 0.24 ± 0.04, P < 0.01) and protein (0.29 ± 0.06 vs 0.65 ± 0.08, P < 0.01) expression. Uremic serum enabled NF-κB p65 nuclear translocation and increased NF-κB DNA binding activity. An increased secretion of cytokines IL-6 and TNF-α. in AEC was observed after a treatment of 10% uremic sera in a time dependent manner. The expression of TNF-α in AEC exposed to 10% uremic sera also increased significantly (0.37 ± 0.04 vs 0.14 ± 0.03, P < 0.01). CONCLUSION: Uremic medium induces the activation of AEC. A lower level of uremic medium accelerates the proliferation of AEC while a higher level induces the apoptosis of AEC. The increased proliferation may be related to a higher NF-κB activity and the expression of inflammation cytokines. Although the enhanced atherosclerosis can not be explained on the basis of an apoptotic process, the proliferative status can contribute to intimal proliferation, an earlier step in the development of atherosclerosis.

Preventive effect of a proteasome inhibitor on the formation of accelerated atherosclerosis in rabbits with uremia.

Inflammation plays a central role in the pathogenesis of atherosclerosis. This study investigated whether the proteasome inhibitor has the same preventive effect on the formation of accelerated atherosclerosis in rabbits with uremia compared with a NF-kappaB inhibitor. New Zealand white rabbits were subjected to five-sixths nephrectomy (chronic renal failure [CRF]) or to a sham operation. Rats in each group were randomly assigned into three subgroups (n = 24 in each group) and treated with repeated intramuscular injections of proteasome inhibitor MG132 or NF-kappaB inhibitor PDTC for a specified period. Compared with sham rabbits, CRF rabbits displayed typical atherosclerotic changes (endothelial cell damage, intimal thickens, and appearance of foam cells). CRF rabbits had significantly higher levels of proteasome activity, NF-kappaB mRNA, protein, and DNA binding activity as well as tumor necrosis factor-a and proliferative cell nuclear antigen protein expression in aortic wall cells. CRF rabbits also showed lower levels of IkappaBalpha. Compared with CRF rabbits, CRF rabbits treatment with proteasome inhibitor MG132 showed restoration of IkappaBalpha mRNA and protein expression and decreased NF-kappaB DNA binding activity and tumor necrosis factor-a expression. Treatment with either proteasome inhibitor MG132 or NF-kappaB inhibitor PDTC could reverse these pathologic changes in the aortic wall cells of CRF rabbits. A comparison between the inhibitory effects of the two treatments revealed no statistical difference. These results suggest that ubiquitin-proteasome activation play a pivotal role in the pathogenesis of uremia-accelerated atherosclerosis. The ubiquitin-proteasome signaling pathway in aortic cells may therefore be an important target for preventing uremia-accelerated atherosclerosis.

Immunoregulatory effects of sinomenine on the T-bet/GATA-3 ratio and Th1/Th2 cytokine balance in the treatment of mesangial proliferative nephritis.

Sinomenine has been used to treat autoimmune diseases for centuries. However, the mechanism underlying its therapeutic effects remains unknown. Increasing recognition of the importance of the Th1/Th2 imbalance in nephritis has raised the questions of whether there is a Th1/Th2 imbalance in patients with mesangial proliferative nephritis (MsPGN) and whether sinomenine can modulate the Th1/Th2 imbalance. In this study, 25 MsPGN patients were treated with sinomenine and followed for 3 months. The expression of T-bet and GATA-3 mRNA in peripheral blood mononuclear cells (PBMCs) and the serum levels of interferon-gamma (IFN-gamma), interleukin (IL)-4, and IL-10 were studied at month 0, month 1, and month 3. The intra-renal expression of T-bet and GATA-3 was studied via immunohistochemistry. Results reveal that PBMCs from MsPGN patients expressed high levels of T-bet mRNA and low levels of GATA-3 mRNA, and the T-bet/GATA-3 ratio in MsPGN patients was significantly higher than that in healthy donors. Meanwhile, MsPGN patients were found to have simultaneously elevated IFN-gamma values and decreased IL-10 values. Immunohistochemistry revealed increased T-bet and decreased GATA-3 expression in renal tissues from MsPGN patients. Moreover, sinomenine was found to cause a decrease in T-bet mRNA expression, resulting in a drop in the T-bet/GATA-3 ratio. Sinomenine was also found to elicit a decrease in the serum levels of IFN-gamma. These results suggest that a shift toward the Th1 pathway of Th cell activation occurs in MsPGN patients, and that sinomenine has the potential to counter this shift in the Th1/Th2 balance and thereby produce therapeutic effects.

[Protective effects of metanephric mesenchymal cells on acute renal tubular damage: experiment with rats].

OBJECTIVE: To study the protective effects of metanephric mesenchymal cells (MMCs) on acute renal tubular damage and explore its possible mechanism. METHODS: MMCs were isolated and cultured from 13-day-old embryonic rats and labeled with 5-bromodeoxyuridine. Seventy-two male SD rats were randomly divided into 3 equal groups: MMC group, receiving MMC injection instantaneously when ischemia/reperfusion (I/R) renal injury was induced, I/R group, undergoing I/R to establish acute renal tubular damage models, and sham operation group. Six rats from each group were killed at different time points: 24 h, 48 h, 72 h, and 96 h later. Blood sample was collected from the vena cava inferior, to examine the serum creatinine (SCr) and blood urea nitrogen (BUN). Specimens of kidney underwent microscopy. Apoptosis was conformed by TUNEL assay. Immunohistochemistry was used to detect the protein expression of Bcl-2 and Bax. The distribution of MMCs labeled with 5-bromodeoxyuridine in kidney was observed by immunofluorescence technique. RESULTS: The SCr and BUN levels in different time points of the MMC group were both significantly lower than those of the I/R group (both P <0.05), HE staining showed that pathological damage of the MMC group was less than that of the I/R group (P <0.05). TUNEL results investigated that the number of apoptosis renal tubular epithelial cells of the MMC group was (13.4 +/- 3.2/HPF), significantly less than that of the I/R group [(25.4 +/- 5.2/HPF)]. In comparison with the I/R group, there were more Bcl-2 positive cells and fewer Bax positive cells in the MMC group. BrdU-labeled MMCs began to occur in the renal tissue (60 +/- 6/HP) In the 72 h subgroup of MMC group, and number of BrdU-labeled MMCs, the 96 h subgroup was (143 +/- 8/HP), significantly higher than that of the 72 h subgroup (P<0.05). CONCLUSION: MMCs have the ability to protect renal function in acute renal tubular damage in rats, migrate and repopulate in the I/R injured renal tubules, and inhibits renal tubular epithelial cell apoptosis. The mechanism may be involved in regulating the expression of Bcl-2 and Bax.