(5R)-5-hydroxytriptolide for HIV immunological non-responders receiving ART: a randomized, double-blinded, placebo-controlled phase II study.

Background: Therapeutic approaches to HIV-suppressed immunological non-responders (INRs) remain unsettled. We previously reported efficacy of Chinese herbal Tripterygium wilfordii Hook F in INRs. Its derivative (5R)-5-hydroxytriptolide (LLDT-8) on CD4 T cell recovery was assessed. Methods: The phase II, double-blind, randomized, placebo-controlled trial was conducted in adults patients with long-term suppressed HIV infection and suboptimal CD4 recovery, at nine hospitals in China. The patients were 1:1:1 assigned to receive oral LLDT-8 0.5 mg or 1 mg daily, or placebo combined with antiretroviral therapy for 48 weeks. All study staff and participants were masked. The primary endpoints include change of CD4 T cell counts and inflammatory markers at week 48. This study is registered on ClinicalTrials.gov (NCT04084444) and Chinese Clinical Trial Register (CTR20191397). Findings: A total of 149 patients were enrolled from Aug 30, 2019 and randomly allocated to receiving LLDT-8 0.5 mg daily (LT8, n = 51), 1 mg daily (HT8, n = 46), or placebo (PL, n = 52). The median baseline CD4 count was 248 cells/mm3, comparable among three groups. LLDT-8 was well-tolerated in all participants. At 48 weeks, change of CD4 counts was 49 cells/mm3 in LT8 group (95% confidence interval [CI]: 30, 68), 63 cells/mm3 in HT8 group (95% CI: 41, 85), compared to 32 cells/mm3 in placebo group (95% CI: 13, 51). LLDT-8 1 mg daily significantly increased CD4 count compared to placebo (p = 0.036), especially in participants over 45 years. The mean change of serum interferon-γ-induced protein 10 was -72.1 mg/L (95% CI -97.7, -46.5) in HT8 group at 48 weeks, markedly decreased compared to -22.8 mg/L (95% CI -47.1, 1.5, p = 0.007) in placebo group. Treatment-emergent adverse events (TEAEs) were reported in 41 of 46 (89.1%) participants in HT8 group, 43 of 51 (84.3%) in LT8, and 42 of 52 (80.7%) in PL group. No drug-related SAEs were reported. Interpretation: LLDT-8 enhanced CD4 recovery and alleviated inflammation in long-term suppressed INRs, providing them a potential therapeutic option. Fundings: Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, Shanghai Pharmaceuticals Holding Co., Ltd., and the National key technologies R&D program for the 13th five-year plan.

Combined multi-omics and network pharmacology approach reveals the role of Tripterygium Wilfordii Hook F in treating HIV immunological non-responders.

BACKGROUND: The HIV-1 infected immunological non-responders (INRs) are characterized by poor immune reconstitution after long-term treatment. Tripterygium Wilfordii Hook F (TwHF) pill is a traditional Chinese patent drug with extensive immunosuppressive effects and has been clinically proven efficacy in treating INRs. PURPOSE: The therapeutic mechanism of TwHF pills in the treatment of INRs was investigated by the combined multi-omics analysis on clinical samples and network pharmacology approach. METHODS: Clinically, the peripheral blood mononuclear cells (PBMC) samples of TwHF-treated INRs from different time points were collected to conduct the transcriptomic and proteomic profiling. Key effector pathways of TwHF were enriched and analyzed by the ingenuity pathway analysis (IPA). Computationally, the TwHF-related compounds were obtained from traditional Chinese medicine databases, and literature search and structural prediction were performed to identify TwHF-related targets. Integrated with the INR-related targets, the 'TwHF-compounds-targets-INR' network was constructed to analyze core effector targets by centrality measurement. Experimentally, the effects of TwHF compounds on the T cells activation and expression of identified targets were evaluated with in vitro cell culture. RESULTS: 33 INRs were included and treated with TwHF pills for 17 (IQR, 12-24) months. These patients experienced rapid growth in the CD4+ T cell counts and decreased T cell activation. The multi-omics analysis showed that the interferon (IFN)-signaling pathway was significantly inhibited after taking TwHF pills. The network pharmacology predicted the central role of the signal transducer and activator of transcription 1 (STAT1) in the 'TwHF-compounds-targets-INR' network. Further bioinformatic analysis predicted STAT1 would regulate over 58.8% of identified down-regulated genes. Cell experiments validated that triptolide (TPL) would serve as the major bioactivity compound of TwHF pills to inhibit the immune cell activation, the production of IFN-γ, the expression of downstream IFN-stimulated genes, and the phosphorylation of STAT1. CONCLUSION: Our research is the first to systemic verify the mechanisms of TwHF in treating INRs. The IFN signaling pathway and the STAT1 would be the major effector targets of TwHF pills in treating INRs. The TPL would be the major bioactive compound to inhibit the IFN response and the phosphorylation of STAT1. Our observations suggest the basis for further application of TPL analogous in treating INRs.

Coupled influence of pH and dissolved organic carbon on the immobilization of phosphorus by lanthanum-modified zeolite.

Wind-driven waves and currents in shallow lakes frequently trigger the resuspension of sediments in the photic layer, which is characterized with a high pH and high dissolved organic carbon (DOC) concentration. The mechanism of phosphorus-inactivating agents (PIAs) immobilizing phosphorus under the coupled influence of pH and DOC is not clarified, and the applicability of PIAs in eutrophic shallow lakes is thus still doubtful. We found that, under the coupled influence of pH and DOC, the uptake of phosphate by LMZ was affected mainly by pH at low DOC concentrations and by DOC at high DOC concentrations. A high pH (9.3) and high DOC concentration (24.7 mg/L) greatly increased the release of phosphorus from sediment to water. However, the addition of LMZ substantially reduced the P concentrations in water, mainly via capture of dissolved inorganic phosphorus. The results of the reversibility of the adsorption of phosphates and DOC showed that phosphate had much higher affinity than DOC towards LMZ. The phosphate once adsorbed on LMZ was resistant to release when exposed to conditions of either a high pH (9.5), high DOC concentration (250 mg/L) or both; i.e., only <5% of the adsorbed phosphate is releasable. Therefore, we proposed that, to avoid the coupled influence of pH and DOC in the photic layer of eutrophic shallow lakes, LMZ could be applied in multiple low doses in the season when the growth of algae is minimal (a low pH and low DOC concentration).

Effects of cadmium on soil nitrification in the rhizosphere of Robinia pseudoacacia L. seedlings under elevated atmospheric CO2 scenarios.

The individual impacts of elevated CO2 and heavy metals on soil nitrification have been widely reported. However, studies on the combined effects of elevated CO2 and heavy metals on soil nitrification are still limited. Here, a 135-day growth chamber experiment was conducted to investigate the impacts of elevated CO2 and cadmium (Cd) levels on soil nitrification in the rhizosphere of Robinia pseudoacacia L. seedlings. Elevated CO2 combined with Cd pollution generally stimulated ammonia monooxygenase (AMO), hydroxylamine oxidase (HAO), and nitrite oxidoreductase (NXR) activities. Compared to the control, the abundance of ammonia-oxidizing bacteria (AOB) at day 135 and ammonia-oxidizing archaea (AOA) increased significantly (p < 0.05) and the abundance of AOB at days 45 and 90 and that of the nitrite-oxidizing bacteria (NOB) decreased under elevated CO2 + Cd. Elevated CO2 mostly led to a significant (p < 0.05) decrease in soil nitrification intensity in the rhizosphere of R. pseudoacacia exposed to Cd. The effects of Cd, CO2, and their interaction on HAO and NXR activities were significant (p < 0.01). Soil pH, the C/N ratio, water-soluble organic carbon, water-soluble organic nitrogen (WSON), and total carbon were the dominant factors (p < 0.05) affecting nitrifying enzyme activities and nitrification intensity in rhizosphere soils. Elevated CO2 clearly affected AOA, AOB, and NOB community structures and dominant genera by shaping C/N ratio, pH, and Cd and WSON contents in rhizosphere soils under Cd exposure. Overall, the responses of pH, C/N ratio, WSON, and Cd to elevated CO2 led to changes in rhizosphere soil nitrification under the combination of elevated CO2 and Cd pollution.

Effect of algae on phosphorus immobilization by lanthanum-modified zeolite.

Phosphorus-inactivating agents (PIAs) as geoengineering tools in lakes have been investigated extensively, but PIA resuspension in the photic layer occurs frequently in shallow lakes and little is known about the influence of algae on PIA performance. Our results proved that algae increased the dissolved oxygen, pH and dissolved organic carbon concentration substantially. In the absence of sediment, lanthanum modified zeolite (LMZ) as a representative PIA and algae could deplete dissolved inorganic phosphorus (DIP) from water but the former was faster than the latter. When LMZ and algae coexisted, the amount of phosphorus that was captured by LMZ was 3.1 times greater than that taken up by algae. An increase in pH or dissolved organic carbon increased the zero-equilibrium phosphorus concentration (EPC0) of the sediment but LMZ addition could lower the EPC0 and reduce the risk of phosphorus release during the algal blooming season. In the presence of sediment, LMZ reduced the DIP concentration more rapidly and yielded a lower final DIP concentration compared with algae. In conclusion, the influence of algae on the performance of LMZ by (i) taking up DIP to reduce the availability of DIP and convert DIP into a releasable phosphorus form and (ii) increasing the pH and dissolved organic carbon concentration to hinder the adsorption ability of DIP were recognized. The LMZ performed well, even in the presence of algae.

Effects of elevated CO2 on arbuscular mycorrhizal fungi associated with Robinia pseudoacacia L. grown in cadmium-contaminated soils.

As symbionts capable of reciprocal rewards, arbuscular mycorrhizal fungi (AMF) can alleviate heavy metal toxicity to host plants and are easily influenced by elevated CO2 (ECO2). Although the individual effects of ECO2 and cadmium (Cd) on AMF have been widely reported, the response of AMF to ECO2 + Cd receives little attention. We evaluated the combined effects of ECO2 and Cd on AMF in the rhizosphere soil and roots of Robinia pseudoacacia L. seedlings. Under ECO2 + Cd relative to Cd, AMF gene copies and richness in rhizosphere soils increased (p < 0.05) and the diversity reduced (p < 0.05) at 4.5 mg Cd kg-1 dry soil; whereas root AMF abundance at 4.5 mg Cd kg-1 dry soil and the diversity and richness reduced (p < 0.05). Elevated CO2 caused obvious differences in the dominant genera abundance between rhizosphere soils and roots upon Cd exposure. Responses of C, water-soluble organic nitrogen (WSON), pH, and diethylene triamine penta-acetic acid (DTPA)-Cd in rhizosphere soils and root N to ECO2 shaped dominant genera in Cd-polluted rhizosphere soils. Levels of DTPA-Cd, WSON, C and pH in rhizosphere soils and C/N ratio, N, and Cd in roots to ECO2 affected (p < 0.05) dominant genera in roots under Cd exposure. AMF richness and diversity were lower in roots than in rhizosphere soils. Elevated CO2 altered AMF communities in rhizosphere soils and roots of R. pseudoacacia seedlings exposed to Cd. AMF associated with R. pseudoacacia may be useful/interesting to be used for improving the phytoremediation of Cd under ECO2.

Interactions of phosphate and dissolved organic carbon with lanthanum modified bentonite: Implications for the inactivation of phosphorus in lakes.

Lanthanum-modified bentonite (LMB) is a widely used phosphorus-inactivating agent in lakes. However, dissolved organic carbon (DOC) exists ubiquitously in lakes, and its influence on phosphate binding is still not adequately understood. Our results showed that both phosphate and DOC can be adsorbed by LMB. The Langmuir adsorption maxima of phosphate and DOC were 9.06 mg P/g and 5.31 mg C/g, respectively, generating a C/P molar ratio ∼1.5. When phosphate and DOC coexisted at this ratio, the adsorption of phosphate was not influenced by DOC and vice versa. However, the phosphate capture by LMB was significantly reduced by raising the ratio above ∼9, and the reduction was increased with increasing the ratio. Once adsorbed by LMB, phosphate was essentially not desorbed by DOC, while adsorbed DOC can be mostly liberated by phosphate. It is deemed that phosphate can interact preferentially with La on LMB. However, DOC can still be adsorbed by LMB, even after LMB was saturated with phosphate, which was attributed to (i) the high coordination capacity of La; (ii) the interaction of DOC with the hydroxyl group(s) of the adsorbed phosphate via hydrogen bonding; and (iii) the interaction of DOC with the La sites unoccupied by phosphate. We proposed that LMB can be applied in the season (time) when the DOC/P ratio in lakes is low enough to facilitate the adsorption of phosphate, which will no longer be released into water, even after the C/P ratio is raised later.

A consecutive 4-year elevated air temperature shaped soil bacterial community structure and metabolic functional groups in the rhizosphere of black locust seedlings exposed to lead pollution.

Global warming may influence the bioavailability and mobility of heavy metals by stimulating or inhibiting plant growth, thereby influencing rhizosphere soil chemistry and microbial characteristics. Black locust has been widely planted in China as a promising species for afforestation programs, farmland shelterbelt projects, and soil restoration in mined areas because of its rapid growth and adaptability to environmental stressors. Here, we examined soil bacterial community structure and predicted bacterial metabolic function in the rhizosphere of black locust exposed to elevated temperature (+1.99 °C) and Pb for 4 years. Elevated temperature significantly (p < 0.05) reduced total carbon (TC), total nitrogen (TN), and total sulfur (TS) contents in above-ground parts but increased TC and TN contents in roots and seedling height under Pb exposure. Elevated temperature significantly (p < 0.05) increased Pb availability and raised pH, TC, TN, TS and water-soluble organic carbon (WSOC) contents, and the C:H ratio in rhizosphere soils under Pb exposure. The interactive effects between Pb and temperature on pH, TC, TH, TS, WSOC, and the C:H ratio were significant (p < 0.05). Elevated temperature significantly (p < 0.05) reduced the diversity and the richness of bacterial community, altered genus-level bacterial community composition, and improved (p < 0.05) the relative abundances of some bacteria involving in terpenoids and polyketides and xenobiotics biodegradation metabolism under Pb exposure. Canonical correspondence analysis indicated that pH, WSOC, C:N ratio, and soluble Pb were significant (p < 0.05) factors on the relative abundance of bacterial genera, such as Ochrobactrum and Sphingomnas. Overall, long-term elevated temperature resulted in changes in rhizosphere soil characteristics and Pb availability, thus affecting the bacterial community structure and metabolic functional groups. The conclusion helps us understand the response mechanism of soil bacteria in the rhizosphere to heavy metals under global warming scenarios.

The recovery of phosphorus from source-separated urine by repeatedly usable magnetic Fe3O4@ZrO2 nanoparticles under acidic conditions.

The separation of urine at source for phosphorus (P) recovery is attractive taking into account the high P concentration and small volume. However, the treatment of urine is still challenging due to its unpleasant odor and hygiene problems. Because the above problems could be solved by acidification to keep the pH of urine below 4, we propose a novel strategy to recover P from acidified urine using tailored hydrous zirconia-coated magnetite nanoparticles (Fe3O4@ZrO2). This strategy involves the selective adsorption of phosphate by easily separable and reusable Fe3O4@ZrO2, the desorption of adsorbed phosphate, and the precipitation of desorbed phosphate as calcium phosphate fertilizer. The results indicated that at pH 4, the P in synthetic urine was selectively adsorbed and could be exhausted using Fe3O4@ZrO2. Nearly all (>97.5%) of the sequestered P on the Fe3O4@ZrO2 nanoparticles was stripped using ≥1 M NaOH solution and ~100% of the stripped P was then successfully transformed into calcium phosphate, upon adding CaCl2 at pH >12 and a Ca/P molar ratio of 3. The liquid/solid (Fe3O4@ZrO2 particles) mixture could be conveniently separated for reuse using an external magnetic field. The reusability of the Fe3O4@ZrO2 nanoparticles in the extraction of P from synthetic urine was confirmed using five cycles of the adsorption-desorption process and their performance validated using real urine samples. The mechanism of phosphate adsorption was investigated using XPS, FTIR and zeta potential measurements, showing that phosphate was chemically adsorbed on the surface through direct coordination to zirconium atom via ligand exchange.

Immobilization and Release Behavior of Phosphorus on Phoslock-Inactivated Sediment under Conditions Simulating the Photic Zone in Eutrophic Shallow Lakes.

Phosphorus-inactivating agents (PIAs) have increasingly been applied and extensively investigated to control internal phosphorus loading in lakes. However, little is known about the behavior of PIA-amended sediment in terms of phosphorus immobilization and release when the sediment is resuspended in the photic layer, whose environment differs from the lake bed. Lanthanum-modified bentonite (LMB) is a popular PIA product. In this study, the 33 day core incubation experiment under dark conditions showed that capping sediment with LMB efficiently decreased the concentration of total phosphorus, total dissolved phosphorus, and dissolved inorganic phosphorus (DIP) by 90, 87, and 99%, respectively. Resuspension into overlying water under light conditions at high pH, high dissolved organic carbon, and in the presence of algae significantly impedes the performance of LMB. However, the adoption of a higher LMB dose improved the performance, including a reduction in the phosphorus level and control of algal growth. The dynamics of the phosphorus migration when the LMB-inactivated sediment was resuspended into the photic zone mainly involves the release of DIP from the sediment and the uptake of DIP by algae and LMB. In conclusion, a higher dose is needed in the PIA (particularly Phoslock) application in shallow productive lakes where sediment resuspension occurs frequently.

Inactivation of phosphorus in the sediment of the Lake Taihu by lanthanum modified zeolite using laboratory studies.

Release of phosphorus (P) from sediment to overlying water has to be dealt with to address algal blooms in eutrophic lakes. In this study, the sediment from the Lake Taihu was amended with lanthanum modified zeolite (LMZ) to reduce P release under different pH, temperature and anaerobic conditions. LMZ performed well, to decreasing P concentration in Lake Taihu water in the presence of sediment. The EPC0 value, the critical P concentration at which there was neither P adsorption nor P release, was lowered by adding LMZ, suggesting that amendment with LMZ could diminish the risk of P release from the sediment. From the Langmuir isotherm model, the adsorption capacity of phosphate by LMZ was estimated to be 64.1 mgP/g. The LMZ-amended sediment had a higher content of stable P forms (HCl-P and Res-P) and a lower content of P forms with a high (NH4Cl-P and BD-P) or medium-high (NaOH-P and Org-P) risk of release, when compared with the original sediment. The fractionation simulates conditions which release potentially mobile P which can then be simply re-bound to LMZ. At high pH (>9.0), anaerobic condition or high temperature promoted the liberation of P from sediment. However, P release could be greatly inhibited by LMZ. In addition, although Mn2+ and NH4+ ions were released from sediment under the anaerobic condition, the release could also be hindered by adding LMZ. LMZ is a promising P inactivation agent to manage eutrophication in the sediment of Lake Taihu.

A biodegradable biomass-based polymeric composite for slow release and water retention.

Slow-release fertilizer has been proven to be more effective than traditional fertilizer for providing a long-term stable nutrient supply. Although such fertilizers have been widely investigated, their water-retention properties and biodegradability have not been fully analysed. Composites of fertilizers and polymers provide opportunities to prepare new types of fertilizer with enhanced properties for real applications. Chicken feather protein-graft-poly(potassium acrylate)-polyvinyl alcohol semi-interpenetrating networks forming a super absorbent resin combined with nitrogen (N) and phosphorus (P) (CFP-g-PKA/PVA/NP semi-IPNs SAR) was prepared. The chemically bonded or physically embedded fertilizer compound could be released form the resin matrix to the surrounding soil under irrigation. The synthesis mechanism, morphology, and chemical and mechanical structure of the synthesized composites were investigated. The reactant doses were optimized through response surface methodology (RSM). A 30-day field trial of the prepared SAR was applied to detect the influence of sample particle size, soil salinity, pH, and moisture content on the slow-release behaviour of N and P. The maximum release values of N and P from the composites were 69.46% N and 65.23% P. A 120-day soil burying experiment and 30-day Aspergillus niger (A. niger) inoculation were performed, and the biodegradability and change in microstructure were monitored. The addition of SAR to soil could also improve the water-retention ability of the soil.

Detecting neuronal dysfunction of hand motor cortex in ALS: A MRSI study.

BACKGROUND: Although hand motor cortex (HMC) has been constantly used for identification of primary motor cortex in magnetic resonance spectroscopy (MRS) studies of amyotrophic lateral sclerosis (ALS), neurochemical profiles of HMC have never been assessed independently. As HMC has a constant location and the clinic-anatomic correlation between hand motor function and HMC has been established, we hypothesize that HMC may serve as a promising region of interest in diagnosing ALS. PATIENTS AND METHODS: Fourteen ALS patients and 14 age- and gender-matched healthy controls (HC) were recruited in this study. An optimized magnetic resonance spectroscopic imaging (MRSI) method was developed and for each subject bilateral HMC areas were scanned separately (two-dimensional multi-voxel MRSI, voxel size 0.56 cm3). N-acetyl aspartate (NAA)-creatine (Cr) ratio was measured from HMC and the adjacent postcentral gyrus. RESULTS: Compared with HC, NAA/Cr ratios from HMC and the postcentral gyrus were significantly reduced in ALS. However, in each group the difference of NAA/Cr ratios between HMC and the postcentral gyrus was not significant. Limb predominance of HMC was not found in either ALS or HC. In ALS, there was a significant difference in NAA/Cr ratio between the most affected HMC and the less affected HMC. A positive relationship between NAA/Cr ratio of HMC and the severity of hand strength (assessed by finger tapping speed) was demonstrated. CONCLUSION: Neuronal dysfunction of HMC can differentiate ALS patients from HC when represented as reduced NAA/Cr ratio. Postcentral gyrus could not serve as normal internal reference tissue in diagnosing ALS. Asymmetrical NAA/Cr ratios from bilateral HMC may serve as a promising diagnostic biomarker of ALS at the individual level.