Xuebijing injection combined with alprostadil in the treatment of diabetic nephropathy: A PRISMA-compliant systematic review and meta-analysis.

BACKGROUND: Diabetes nephropathy (DN), as one of the common complications of diabetes, is characterized by persistent albuminuria, decreased glomerular filtration rate, and elevated arterial blood pressure. At present, Xuebijing injection is widely used in the treatment of DN. However, few systematic reviews and meta-analysis related to Xuebijing injection intervention in DN were published. In order to more systematically and objectively evaluate the clinical efficacy of Xuebijing injection intervention in DN, we conducted systematic reviews and meta-analysis to verify it. OBJECTIVE: The purpose of the research was to systematically evaluate the clinical efficacy of Xuebijing injection combined with alprostadil in the treatment of diabetic nephropathy. METHODS: We searched the China National Knowledge Infrastructure (CNKI), China Biomedical Database (SinoMed), Weipu Database (VIP), Wanfang Database, PubMed, The Cochrane Library, Embase, Web of Science and other databases by computer, and searched the randomized controlled trials of Xuebijing injection combined with alprostadil in the treatment of DN at home and abroad from the establishment of the database to 2022. The main outcome indicators included blood glucose, and the secondary outcome indicators included blood lipid, renal function, urinary protein, and safety. Two evaluators independently screened the literature, extracted the data and evaluated the risk of bias in the included studies. RevMan 5.3 software was used to analyze the data. RESULTS: A total of 14 randomized controlled trials were included, including 1233 cases, 618 cases in the treatment group and 615 cases in the control group. The results of meta-analysis demonstrated that compared with the control group, the treatment group could effectively reduce fasting plasma glucose [mean difference [MD] = -1.90, 95% CI (-2.40, -1.40), P < .00001], glycosylated hemoglobin A1c [MD = -2.38, 95% CI (-2.51, -2.25), P < .00001], 2h postprandial blood glucose [MD = -2.92, 95% CI (-3.95, -1.89), P < .00001], triacylglycerol [MD = -1.08, 95% CI (-1.66, -0.50), P = .0003], total cholesterol [MD = -1.17, 95% CI (-1.39, -0.95), P < .00001], low-density lipoprotein cholesterol [MD = -1.19, 95% CI (-1.60, -0.78), P < .00001], high-density lipoprotein cholesterol [MD = 0.32, 95% CI (0.23, 0.42), P < .00001], serum creatinine [MD = -42.95, 95% CI (-57.46, -28.43), P < .00001], blood urea nitrogen [MD = -2.24, 95%CI (-2.62,-1.86), P < .00001], blood ß2 microglobulin [SMD = -1.49, 95% CI (-1.70, -1.28), P < .00001], urine ß2 microglobulin [SMD = -0.81, 95% CI (-1.04, -0.58), P < .00001], 24-hour urinary protein quantification [MD = -0.20, 95% CI (-0.26, -0.14), P < .00001], urinary albumin excretion rate [SMD = -1.15, 95% CI (-1.38, -0.93), P < .00001]. CONCLUSION: Xuebijing injection combined with alprostadil has more advantages in treating DN compared to routine Western medicine.

The Fe-MAN Challenge: Ferrates-Microkinetic Assessment of Numerical Quantum Chemistry.

Organometallic species, such as organoferrate ions, are prototypical nucleophiles prone to reacting with a wide range of electrophiles, including proton donors. In solution, the operation of dynamic equilibria and the simultaneous presence of several organometallic species severely complicate the analysis of these fundamentally important reactions. This can be overcome by gas-phase experiments on mass-selected ions, which allow for the determination of the microscopic reactivity of the target species. In this contribution, we focus on the reactivity of a series of trisarylferrate complexes toward 2,2,2-trifluoroethanol and 2,2-difluoroethanol. By means of mass-spectrometric measurements, we determined the experimental bimolecular rate constants kexp of the gas-phase protolysis reactions of the trisarylferrate anions FePh3- and FeMes3- with the aforementioned acids. Based on these experiments, we carried out a dual blind challenge, inviting theoretical groups to submit their best predictions for the activation barriers and/or theoretical rate constants ktheo. This provides a unique opportunity to evaluate different computational protocols under minimal bias and sets the stage for further benchmarking of quantum chemical methods and data-driven approaches in the future.

Mechanistic Insight into Lewis Acid-Catalyzed Cycloaddition of Bicyclo[1.1.0]butanes with Ketene: Bicyclo[1.1.0]butanes Serving as an Electrophile.

Lewis acid-catalyzed cycloaddition between bicyclo[1.1.0]butanes (BCBs) and unsaturated substrates has recently been demonstrated to be a powerful strategy for synthesizing bicyclo[2.1.1]hexanes. However, their reaction mechanisms remain elusive. This computational work explored the recently developed TMSOTf-catalyzed cycloaddition of BCB ketone to ketene and determined the rate-determining step as the activation of BCB ketone. Contrary to the previous proposal of BCB enolate as the active species, this work instead identified the catalytically active species to be a partially Lewis acid-activated BCB cation, which shows a greater electrophilicity and larger orbital interactions with ketene compared to those of the pristine BCB. The most favorable reaction pathway uniquely utilizes this activated BCB species as an electrophile to react with ketene as a nucleophile, while the previously proposed enolate is relatively inactive. Moreover, the in situ-generated TfO anion is revealed to be non-innocent, and its coordination mode and orientation could affect the reaction kinetics.

Diuretic resistance in patients with kidney disease: Challenges and opportunities.

Edema caused by kidney disease is called renal edema. Edema is a common symptom of many human kidney diseases. Patients with renal edema often need to take diuretics.However, After taking diuretics, patients with kidney diseases are prone to kidney congestion, decreased renal perfusion, decreased diuretics secreted by renal tubules, neuroendocrine system abnormalities, abnormal ion transporter transport, drug interaction, electrolyte disorder, and hypoproteinemia, which lead to ineffective or weakened diuretic use and increase readmission rate and mortality. The main causes and coping strategies of diuretic resistance in patients with kidney diseases were described in detail in this report. The common causes of DR included poor diet (electrolyte disturbance and hypoproteinemia due to patients' failure to limit diet according to correct sodium, chlorine, potassium, and protein level) and poor drug compliance (the patient did not take adequate doses of diuretics. true resistance occurs only if the patient takes adequate doses of diuretics, but they are not effective), changes in pharmacokinetics and pharmacodynamics, electrolyte disorders, changes in renal adaptation, functional nephron reduction, and decreased renal blood flow. Common treatment measures include increasing in the diuretic dose and/or frequency, sequential nephron blockade,using new diuretics, ultrafiltration treatment, etc. In clinical work, measures should be taken to prevent or delay the occurrence and development of DR in patients with kidney diseases according to the actual situation of patients and the mechanism of various causes. Currently, there are many studies on DR in patients with heart diseases. Although the phenomenon of DR in patients with kidney diseases is common, there is a relatively little overview of the mechanism and treatment strategy of DR in patients with kidney diseases. Therefore, this paper hopes to show the information on DR in patients with kidney diseases to clinicians and researchers and broaden the research direction and ideas to a certain extent.

Microscopic Reactivity of Phenylferrate Ions toward Organyl Halides.

Despite its practical importance, organoiron chemistry remains poorly understood due to its mechanistic complexity. Here, we focus on the oxidative addition of organyl halides to phenylferrate anions in the gas phase. By mass-selecting individual phenylferrate anions, we can determine the effect of the oxidation state, the ligation, and the nuclearity of the iron complex on its reactions with a series of organyl halides RX. We find that Ph2 Fe(I)- and other low-valent ferrates are more reactive than Ph3 Fe(II)- ; Ph4 Fe(III)- is inert. The coordination of a PPh3 ligand or the presence of a second iron center lower the reactivity. Besides direct cross-coupling reactions resulting in the formation of RPh, we also observe the abstraction of halogen atoms. This reaction channel shows the readiness of organoiron species to undergo radical-type processes. Complementary DFT calculations afford further insight and rationalize the high reactivity of the Ph2 Fe(I)- complex by the exothermicity of the oxidative addition and the low barriers associated with this reaction step. At the same time, they point to the importance of changes of the spin state in the reactions of Ph3 Fe(II)- .

Multistimuli-Responsive and Antifreeze Aggregation-Induced Emission-Active Gels Based on CuNCs.

Multistimuli-responsive fluorescent gelsbased small molecular gelator by supramolecular assembly, possessing excellent dynamic and reversible characteristic, have caused much concern. In this article, aggregation-induced emission-active fluorescence gels (AIE-gels) with chirality were developed by combining Cu nanoclusters (CuNCs) and natural amino acids, l-tryptophan (l-Trp) or d-Tryptophan (d-Trp). In DMSO/H2O mixed solvents, CuNCs can self-assemble to form intertwined fibersbased nanoparticles with numerous pores by introducing Zn2+. Fibers as second networks of heteronetwork structures are characterized with the participation of l-Trp or d-Trp for cross-linking to reinforce mechanical strength and chiral regulation of gel networks. Aggregation-induced emission enhancement (AIEE) of CuNCs endows the gels with excellent fluorescent properties by introducing solvents and gelation process. The fluorescent gels exhibit sufficient fluorescence intensity (FI) at -20 °C to -80 °C and possess sensitive responsibility including gel-sol transition and fluorescence behavior for stimuli of mechanical force, heating, pH, H2O2, and ethylene diamine tetraacetic acid (EDTA).

Environmentally stable, photochromic and thermotropic organohydrogels for low cost on-demand optical devices.

HYPOTHESIS: The color-changing ability of creatures widely existed in nature has inspired the development of adaptive allochroic materials, which can respond to various external stimuli. Integrating multi-stimuli responsiveness and long-term stability in allochroic system are urgent for practical applications under complex circumstances. EXPERIMENTS: The photochromic/thermotropic organohydrogels (PTOs) comprised polyacrylamide and cationic cellulose (JR400) were prepared by facile free-radical polymerization and glycerol displacement. The coexisting covalent bonds and noncovalent interactions collaboratively reinforce the networks, endowing the PTOs with boosted stretchability and toughness. FINDINGS: The photochromic ammonium molybdate (Mo7) and thermo-sensitive poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (EPE) were made into networks. In these cooperative networks, each constituent performed their own function without disruption, including fast photochromism (10 s) and durable thermo-responsiveness. Importantly, the glycerol-water solvent bestowed the distinct anti-freezing (-30 °C) and anti-dehydration performances on the PTOs. Accordingly, the materials could serve as promising rewritable devices for high-resolution and long-term data storage/encryption. Moreover, on-demand PTO windows integrating UV-prevention and solar energy regulation with Tlum (92.96%) and ΔTsol (46.02%) could create comfortable and healthy environments for occupants. This work offers a new design strategy for low-cost, environmentally stable smart optical devices.

Colloidal clusters of icosahedrons and face-centred cubes.

Synthetically colloidal clusters with new functions and well-controlled size distribution can in principle be constructed using colloidal particles. The building units could be integrated into dense-packed and desired structured with novel functions by means of an efficient strategy or binding patterns. Here we synthesized colloidal clusters of icosahedrons and long-range ordered face-centered cubes (FCCs) via emulsion self-assembly using fluorescence upconversion nanoparticles NaGdF4: Yb3+, Er3+ as building blocks. The icosahedrons and FCCs structure may generate spontaneously due to an entropy-driven process. The morphology and structure of colloidal clusters have noticeable transformation from icosahedron-like symmetry to FCC symmetry with the increasing size of clusters. Furthermore, the colloidal clusters could be decorated with cationic polyethyleneimine (PEI) via electrostatic interaction. When copper ions are added, the amino groups of PEI could coordinate with Cu2+ forming low toxic PEI-Cu2+ layers, which can further serve as energy receptors to quench upconversion fluorescence with 980 nm laser excitation. Our results reflect that the colloidal clusters not only can serve as a fluorescence platform of detection and analysis but also may represent advancement in the field of colloidal and interface sciences.

Aggregation Behavior and Antioxidant Properties of Amphiphilic Fullerene C60 Derivatives Cofunctionalized with Cationic and Nonionic Hydrophilic Groups.

Amphiphilic derivatives of fullerene C60 are attractive from viewpoints of supramolecular chemistry and biomedicine. The establishment of relationships among the molecular structure, aggregation behavior and properties such as scavenging radicals of the amphiphilic C60 derivatives is the key to push these carbon nanomaterials to real applications. In this work, six monosubstituted C60 derivatives were synthesized by a one-step quaternization of their neutral precursors, which bear Percec monodendrons terminated with oligo(poly(ethylene oxide)) (o-PEO) chain(s). The main difference among the C60 derivatives lies in the number and substituted position of the o-PEO chain(s) within the Percec monodendron. Derivative with a 4-substitution of the o-PEO chain still showed limited solubility in water. Other derivatives possessing two or three o-PEO chains exhibited much improved solubilities and rich aggregation behavior in water. It was found that the formation of aggregates is regulated both by the number and the substituted pattern of the o-PEO chains. Typical morphologies include nanosheets, nanowires, vesicles, nanotubes, and nanorods. Although the structures of the C60 derivatives are different from those of traditional surfactants, their aggregation behavior can be also well explained by applying the theory of critical packing parameter. Interestingly, the capabilities of the C60 derivatives to scavenge the hydroxyl radicals (OH·-) followed the same order of their solubility in water, where the compound bearing three o-PEO chains with a 2,3,4-substitution got the champion quenching efficiency of ∼97.79% at a concentration of 0.15 mg·mL-1 (∼0.11 mmol·L-1).

Microgels in biomaterials and nanomedicines.

Microgels are colloidal particles with crosslinked polymer networks and dimensions ranging from tens of nanometers to micrometers. Specifically, smart microgels are fascinating capable of responding to biological signals in vivo or remote triggers and making the possible for applications in biomaterials and biomedicines. Therefore, how to fundamentally design microgels is an urgent problem to be solved. In this review, we put forward our important fundamental opinions on how to devise the intelligent microgels for cancer therapy, biosensing and biological lubrication. We focus on the design ideas instead of specific implementation process by employing reverse synthesis analysis to programme the microgels at the original stage. Moreover, special insights will be, for the first time, as far as we know, dedicated to the particles completely composed of DNA or proteins into microgel systems. These are discussed in detail in this review. We expect to give readers a broad overview of the design criteria and practical methodologies of microgels according to the application fields, as well as to propel the further developments of highly interesting concepts and materials.

Identification of FAM111A as an SV40 host range restriction and adenovirus helper factor.

The small genome of polyomaviruses encodes a limited number of proteins that are highly dependent on interactions with host cell proteins for efficient viral replication. The SV40 large T antigen (LT) contains several discrete functional domains including the LXCXE or RB-binding motif, the DNA binding and helicase domains that contribute to the viral life cycle. In addition, the LT C-terminal region contains the host range and adenovirus helper functions required for lytic infection in certain restrictive cell types. To understand how LT affects the host cell to facilitate viral replication, we expressed full-length or functional domains of LT in cells, identified interacting host proteins and carried out expression profiling. LT perturbed the expression of p53 target genes and subsets of cell-cycle dependent genes regulated by the DREAM and the B-Myb-MuvB complexes. Affinity purification of LT followed by mass spectrometry revealed a specific interaction between the LT C-terminal region and FAM111A, a previously uncharacterized protein. Depletion of FAM111A recapitulated the effects of heterologous expression of the LT C-terminal region, including increased viral gene expression and lytic infection of SV40 host range mutants and adenovirus replication in restrictive cells. FAM111A functions as a host range restriction factor that is specifically targeted by SV40 LT.

The Parkinson's disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase that stimulates kinase activity.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the leading cause of autosomal dominant Parkinson's disease (PD). LRRK2, a member of the ROCO protein family, contains both Ras GTPase-like (Roc) and kinase (MAPKKK) domains, as well as other functional motifs. Here, we have identified LRRK2 as the first mammalian ROCO protein that is an authentic and functional GTPase, defined by the ability to bind GTP and undergo intrinsic GTP hydrolysis. Furthermore, the Roc domain is sufficient for this native GTPase activity and binds and hydrolyzes GTP indistinguishably from the Ras-related small GTPase, Rac1. The PD-associated mutation, R1441C, located within the Roc domain, leads to an increase in LRRK2 kinase activity and a decrease in the rate of GTP hydrolysis, compared to the wild-type protein, in an in vitro assay. This finding suggests that the R1441C mutation may help stabilize an activated state of LRRK2. Additionally, LRRK2-mediated phosphorylation is stimulated upon binding of non-hydrolyzable GTP analogs, suggesting that LRRK2 is an MAPKKK-activated intramolecularly by its own GTPase. Since GTPases and MAPKKKs are upstream regulators of multiple signal transduction cascades, LRRK2 may play a central role in integrating pathways involved in neuronal cell signaling and the pathogenesis of PD.

Leucine-rich repeat kinase 2: relevance to Parkinson's disease.

Human leucine-rich repeat kinase 2 (LRRK2) is a novel kinase belonging to the ROCO protein superfamily (Ras of complex proteins (Roc) with a C-terminal of Roc domain). This large complex protein of 280kDa contains several functional domains including leucine-rich repeats, Ras-related GTPase, mitogen-activated protein kinase kinase kinase (MAPKKK), and WD40 repeats. While definitive functions of LRRK2 have yet to be described, the domain structure of LRRK2 suggests that it plays an important role in the regulation of signal transduction cascades through its dual enzymatic activities of GTPase and MAPKKK. Moreover, mutations in LRRK2 have been found to be thus far the most frequent cause of late-onset familial and idiopathic Parkinson's disease. Further investigations should allow for the elucidation of how pathogenic mutations trigger changes in the structure and function of LRRK2 that lead to aberrant signal transduction and neurodegeneration in Parkinson's disease.

Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission.

Minor histocompatibility antigens (mHAs) are known targets of donor T cells after allogeneic hematopoietic stem cell transplantation (HSCT). In contrast, B-cell responses to mHAs have not been extensively characterized and the clinical significance of antibodies to mHAs is unknown. We tested 121 patients who underwent HSCT and 134 healthy donors for immunoglobulin G (IgG) antibodies against 5 mHAs encoded by genes on the Y chromosome (DBY, UTY, ZFY, RPS4Y, and EIF1AY). Antibodies to at least one H-Y protein developed in 52% of male patients with female donors compared with 8.7% of male patients with male donors (P < .0001), and in 41.4% of healthy females compared with 7.8% of healthy males (P < .0001). H-Y antibodies develop 4 to 12 months after transplantation and persist for long periods. The clinical significance of H-Y antibodies was characterized in 75 male patients with hematologic malignancies who received stem cells from female donors (F --> M HSCT). The presence of H-Y antibodies correlated with chronic graft-versus-host disease (GVHD) by univariate (odds ratio [OR] = 15.5; P < .0001) and multivariable logistic regression analysis (OR = 56.5; P < .0001). Antibody response to Y-chromosome encoded histocompatibility antigens (H-Y antigens) was also associated with maintenance of disease remission (P < .0001). B cells may provide a new target for immune intervention in chronic GVHD.

Minor histocompatibility antigen DBY elicits a coordinated B and T cell response after allogeneic stem cell transplantation.

We examined the immune response to DBY, a model H-Y minor histocompatibility antigen (mHA) in a male patient with chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplant from a human histocompatibility leukocyte antigen (HLA)-identical female sibling. Patient peripheral blood mononuclear cells were screened for reactivity against a panel of 93 peptides representing the entire amino acid sequence of DBY. This epitope screen revealed a high frequency CD4(+) T cell response to a single DBY peptide that persisted from 8 to 21 mo after transplant. A CD4(+) T cell clone displaying the same reactivity was established from posttransplant patient cells and used to characterize the T cell epitope as a 19-mer peptide starting at position 30 in the DBY sequence and restricted by HLA-DRB1*1501. Remarkably, the corresponding X homologue peptide was also recognized by donor T cells. Moreover, the T cell clone responded equally to mature HLA-DRB1*1501 male and female dendritic cells, indicating that both DBY and DBX peptides were endogenously processed. After transplant, the patient also developed antibodies that were specific for recombinant DBY protein and did not react with DBX. This antibody response was mapped to two DBY peptides beginning at positions 118 and 536. Corresponding DBX peptides were not recognized. These studies provide the first demonstration of a coordinated B and T cell immune response to an H-Y antigen after allogeneic transplant. The specificity for recipient male cells was mediated by the B cell response and not by donor T cells. This dual DBX/DBY antigen is the first mHA to be identified in the context of chronic GVHD.

Antibody response to DBY minor histocompatibility antigen is induced after allogeneic stem cell transplantation and in healthy female donors.

Minor histocompatibility antigens (mHAs) recognized by donor T cells play a central role as immunologic targets of graft-versus-host disease (GVHD) and graft versus leukemia after allogeneic hematopoietic stem cell transplantation (HSCT). Men who have undergone sex-mismatched allogeneic HSCT are at high risk for GVHD because of immune responses directed against mHAs encoded by genes on the Y chromosome (termed H-Y antigens). We hypothesized that the immunogenicity of mHAs results in a coordinated response involving B cells as well as T cells. To test this, we measured antibody responses to a well-characterized H-Y antigen, dead box RNA helicase Y (DBY), and its homolog, DBX, in 150 HSCT patients. Using Western blot and enzyme-linked immunosorbent assay (ELISA), we found that 50% of male patients who received stem cell grafts from female donors developed antibody responses to recombinant DBY protein. Antibodies to DBY were also detected in 17% of healthy women, but not in healthy men. Antibody responses were directed primarily against areas of amino acid disparity between DBY and DBX. These studies demonstrate that the immune response to mHA includes the generation of specific antibodies and suggests that the serologic response to these antigens may also be useful in the identification of new mHAs.

Silicon-based metalloprotease inhibitors: synthesis and evaluation of silanol and silanediol peptide analogues as inhibitors of angiotensin-converting enzyme.

Silanols are best known as unstable precursors of siloxane (silicone) polymers, substances generally considered stable and inert, but have the potential to mimic a hydrated carbonyl and inhibit protease enzymes. While previous testing of simple silanediol and silanetriol species as inhibitors of hydrolase enzymes found them ineffective, this study reports polypeptide mimics with a central methylsilanol [SiMeOH] or silanediol [Si(OH)(2)] group and their assessment as effective transition state analogue inhibitors of the well-studied metalloprotease angiotensin-converting enzyme (ACE). Central to the synthesis strategy, phenylsilanes were employed as acid-hydrolyzable precursors of the silanol group. The N-benzoyl Leu-[SiMeOH]-Gly benzyl amides proved to be stable and readily characterized. In contrast, the Leu-[Si(OH)(2)]-Gly structure was difficult to characterize, possibly because of self-association. Capping the silanediol with chlorotrimethylsilane gave a well-defined trisiloxane, demonstrating that the silanediol was monomeric. The Leu-[Si]-Gly structures were converted to Leu-[Si]-Ala analogues by enolate alkylation. Coupling of the silanol precursors with proline tert-butyl ester gave N-benzoyl Leu-[Si]-Gly-Pro and N-benzoyl Leu-[Si]-Ala-Pro tripeptide analogues. Treatment of these with triflic acid formed the corresponding methylsilanols and silanediols, all of which were monomeric. The silanediol tripeptide mimics inhibited ACE with IC(50) values as low as 14 nM. Methylsilanols, in contrast, were poor inhibitors, with IC(50) values above 3000 nM. These data, including comparisons with inhibition data from carbon analogues, are consistent with binding of the silanediols by chelation of the ACE active site zinc, whereas the methylsilanols ligate poorly.

Silanediols: A New Class of Potent Protease Inhibitors.

Transition state analogues of the peptide hydrolysis intermediate can take the form of complex silanediols such as 1, which inhibits angiotensin-converting enzyme (ACE) at nanomolar concentrations. In contrast, earlier investigation of enzyme inhibition with simple silanediols and silanetriols showed them to be inactive.