The Effect and Mechanism of Fufang Banbianlian Injection in the Treatment of Mesangial Proliferative Glomerulonephritis.

OBJECTIVE: Mesangial proliferative glomerulonephritis (MsPGN) is an important cause of chronic kidney disease. Abnormal proliferation of mesangial cells and immune-inflammatory response are its important pathological manifestations. Currently, there is no ideal treatment for this disease. Fufang Banbianlian Injection (FBI) has anti-inflammatory, antioxidant, and immuneenhancing effects, and is mostly used for the treatment of bronchitis, pneumonia, and respiratory tract infections in children. METHODS: A rat model of MsPGN was established and treated with FBI. The efficacy was tested through pathological experiments and urine protein quantification. Network pharmacology methods were used to predict the signaling pathways and key proteins that exert the efficacy of FBI, and were screened through molecular docking experiments. The active substances that work were verified through cell experiments. RESULTS: The results confirmed that intervention with FBI can inhibit the proliferation of glomerular cells and reduce the infiltration of macrophages, thereby reducing the pathological damage of rats with mesangial proliferative nephritis; it has been found to have an obvious therapeutic effect. Molecular docking results have shown kaempferol (Kae), the main component of FBI, to have a good affinity for key targets. The results of in vitro verification experiments showed that FBI and its active ingredient Kae may play a therapeutic role by regulating the NF-κB signaling pathway in mesangial cells, inhibiting its activation and the secretion of proinflammatory cytokines. CONCLUSION: Through network pharmacology, molecular docking, and experimental verification, it was confirmed that FBI and its active ingredient Kae can reduce the molecular mechanism of pathological damage of MsPGN by regulating the NF-κB signaling pathway and providing potential therapeutic drugs for the treatment of this disease.

Global cluster analysis and network visualization in organoids in cancer research: a scientometric mapping from 1991 to 2021.

Objective: In the last three decades, there has been a surge in research on cancer organoids using 3D culture technologies, which has resulted in the development of physiological human cancer models. This study aims to provide an overview of the global trends and frontiers in research on cancer organoids. Methods: A total of 3189 publications on organoids in cancer research from 1991 to 2021 were collected from the Science Citation Index-Expanded (SCIE) of Web of Science (WoS). Bibliometric methods such as the R package "Bibliometrix," Citespace, and VOS viewer software were employed to investigate and visualize bibliographic coupling, co-citation, co-authorship, and co-occurrence trends, as well as publication trends in the field of organoids in cancer research. Results: From 1991 to 2021, there has been a significant increase in publications on cancer organoids, with most articles being from North America, Eastern Asia, and Western Europe. The USA had the highest number of publications, citations, prolific authors, and research funding globally. Cancers was the journal with the most publications, while Nature had the best total link strength. Harvard University were the most contributive institutions. The global research in this field could be classified into five clusters: chemotherapy study, organoids for drug screening, different models, molecular mechanism study, and organoid construction. These areas are expected to remain hotspots for future research. Conclusions: The number of publications on organoids in cancer research is expected to increase based on current global trends.

Complement factor B inhibitor LNP023 improves lupus nephritis in MRL/lpr mice.

BACKGROUND: Lupus nephritis (LN) is the most common complication of systemic lupus erythematosus (SLE), and the abnormal activation of the alternative complement pathway is associated with the pathogenesis of LN. As an inhibitor of complement factor B (CFB) in the alternative pathway, LNP023 has been used in the treatment of a variety of renal diseases with abnormal complement system involvement, such as paroxysmal nocturnal hemoglobinuria, IgA nephropathy, and membranous nephropathy. The aim of our study was to explore whether LNP023 improved LN in MRL/lpr mice by inhibiting the activation of the alternative complement pathway. METHODS: The mice were divided into a normal control group (Normal group) (n = 6), MRL/lpr model group (n = 6), and LNP023 group (n = 6). The LNP023 group was administered LNP023 for 2 weeks by gavage; the MRL/lpr model group was administered saline for 2 weeks by gavage; and the Normal group was administered saline for 2 weeks by gavage. External signs, renal pathology, renal function, renal immune complex and complement deposition, serum anti-dsDNA, serum ANA concentration, and the expression of core complement factors in the alternative complement pathway were analyzed in the 3 groups of animals. The core targets of LNP023 in the treatment of LN were screened using network pharmacology. The pathogenicity of the core targets in LN was verified by analyzing the mRNA expression of the core targets in the peripheral blood mononuclear cells (PBMCs) of normal individuals, SLE patients, and LN patients. The mRNA and protein expression of core targets in the Normal group, MRL/lpr group, and LNP023 group were analyzed to verify whether LNP023 exerted it LN therapeutic effect through the regulation of core targets. RESULTS: Compared with the MRL/lpr group, the LNP023 group had reduced lupus-like signs, improved renal function, decreased serum anti-dsDNA and ANA concentrations, and reduced renal IgM, IgG, IgG1, C1q, C3, and C4 deposition. Renal pathology showed that LNP023 attenuated pathological damage in the kidneys of MRL/lpr mice. Compared with the MRL/lpr model group, the treatment group had no crescent formation, less immune deposition, no nuclear fragmentation, and less inflammatory cell infiltration. The expression of complement proteins C3, C3b, CR1, CFB, and C5b-9 in kidney tissues and liver was decreased, and the expression of C5 was increased. Network pharmacology screening indicated that AKT, TNF-α, MDM2, UBC, STST3, ESR1, and TP53 were core targets of LNP023 in the treatment of LN. Compared with that in the Normal group, the mRNA expression of the core target in the SLE and LN groups was different; compared with the MRL/lpr group, the LNP023 treatment group showed different mRNA and protein expression levels of AKT, TNF-α, and STST3. CONCLUSION: LNP023 improves LN in MRL/lpr mice. The mechanism is as follows: LNP023 binds to CFB to inhibit the activation of the alternative complement pathway. LNP023 treatment for LN may also play a role in regulating the protein expression of AKT, TNF-α, and STST3.

Naphthalenephenylalanine-phenylalanine-glycine-arginine-glycine-aspartic promotes self-assembly of nephron progenitor cells in decellularized scaffolds to construct bioengineered kidneys.

The shortage of donor kidneys is an important factor restricting kidney transplantation for patients with end-stage renal disease. To overcome this problem, we used decellularized kidney scaffolds and nephron progenitor cells (NPCs) as seed cells to construct bioengineered kidneys (BEKs). To reduce the effect of extracellular matrix (ECM) loss during the decellularization process on the cell growth microenvironment, we used dextrose to minimize collagen loss in decellularized kidney scaffolds. At the same time, to further improve the growth microenvironment of seed cells in the decellularized scaffolds, we modified the decellularized scaffolds with the self-assembling polypeptide Naphthalenephenylalanine-phenylalanine-glycine-arginine-glycine-aspartic (Nap-FFGRGD) to promote the adhesion and proliferation of seed cells in the scaffolds. NPCs were perfused into the decellularized kidney scaffolds and then the BEKs were cultured in vitro and transplanted in vivo. Markers of podocytes and renal tubules expressed in the glomeruli and renal tubules of the BEKs were detected by immunofluorescence staining, respectively were, suggesting that NPCs can continue to differentiate into renal cells and achieve nephron segment-specific re-population through self-assembly. These results indicate that by relying on the microenvironment provided by Nap-FFGRGD modified decellularized scaffolds, NPCs can be used to construct BEKs for transplantation in the future due to the self-assembly properties of organoids.

Analysis of the association of ANO3/MUC15, COL4A4, RRBP1, and KLK1 polymorphisms with COPD susceptibility in the Kashi population.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a complex, multifactorial, polygenic disease. The rate of occurrence of COPD in the Kashi population (Uyghur) is significantly higher than that observed nationwide. The identification of COPD-related genes in the Chinese Uyghur population could provide useful insights that could help us understand this phenomenon. Our previous whole-exome sequencing study of three Uyghur families with COPD demonstrated that 72 mutations in 55 genes might be associated with COPD; these included rs15783G > A in the anoctamin 3 (ANO3) gene/mucin 15 (MUC15) gene, rs1800517G > A in the collagen type IV alpha 4 chain (COL4A4) gene, rs11960G > A in the ribosome binding protein 1 (RRBP1) gene, and rs5516C > G in the kallikrein 1 (KLK1) gene. This case-control study aimed to further validate the association of the four mutations with COPD in the Chinese Uyghur population. METHODS: Sanger sequencing was used for the genotyping of four polymorphisms (ANO3/MUC15 rs15783, COL4A4 rs1800517, RRBP1 rs11960, and KLK1 rs5516) in 541 unrelated Uyghur COPD patients and 534 Uyghur healthy controls. We then conducted stratified analyses based on the smoking status and airflow limitation severity, to explore the correlation between selected gene polymorphisms and COPD. RESULTS: ANO3/MUC15 rs15783 and KLK1 rs5516 polymorphisms could significantly reduce COPD risk (p < 0.05), but COL4A4 rs1800517 and RRBP1 rs11960 polymorphisms were not correlated with COPD in the entire population. In a stratified analysis of smoking status, non-smokers with the ANO3/MUC15 rs15783G/G genotype (OR = 0.63, p = 0.032) or COL4A4 rs1800517 allele G (OR = 0.80, p = 0.023) had a reduced risk of COPD. Smokers with the RRBP1 rs11960A/G genotype had a lower risk of COPD (OR = 0.41, p = 0.025). The KLK1 rs5516G > C polymorphism was associated with a decreased risk of COPD (OR < 1, p < 0.05), irrespective of the smoking status of individuals. No significant association with COPD severity was observed in individuals with these four polymorphisms (p > 0.05). CONCLUSION: We identified four previously unreported mutations (ANO3/MUC15 rs15783, COL4A4 rs1800517, RRBP1 rs11960, and KLK1 rs5516) that might decrease the COPD risk in individuals with different smoking statuses in the Chinese Uyghur population. Our findings provide new light for the genetic risk factors associated with the occurrence of COPD.

SMAD3 rs36221701 T>C polymorphism impacts COPD susceptibility in the Kashi population.

Small mother against decapentaplegic (SMAD) family member 3 (SMAD3) is well correlated with the inflammatory response of chronic obstructive pulmonary disease (COPD). A previous study indicated that the single nucleotide polymorphism (SNP) rs36221701 of SMAD3 was related to the risk of inflammatory disease. Hence, given the pathogenesis of COPD is intently associated with smoking and gene polymorphism, this study aims to analyze the relationship between SMAD3 rs36221701 and COPD susceptibility, and to explore whether the interaction is related to smoking status. We studied the association between the rs36221701 and rs34307601 of SMAD3 and COPD susceptibility, a total of 541 COPD patients and 534 controls of the Uyghur population were recruited at the First People's Hospital and the village of Kashi. The interrelation of the two SNPs with the risk of COPD was determined by calculating odds ratio (OR) and 95% confidence interval (95% CI). We found a significant association between the rs36221701 and COPD risk in the non-smoking population. TC genotype showed a significant decreased association with COPD risk (OR = 0.59, 95% CI = 0.41-0.83, P < 0.05), but CC genotype can increased the COPD risk (OR > 1, P < 0.05). In addition, COPD susceptibility was not related to the genetic variations in the rs34307601 (P > 0.05). In conclusion, we confirmed that the SMAD3 rs36221701 may be associated with COPD susceptibility in the Chinese Uyghur population, especially among non-smokers. Our data provide new light for the relationship between SMAD3 gene polymorphisms and COPD susceptibility in the Chinese Uyghur population.

Primary mirror segmentation for large optical telescopes: an inverse map projection approach.

Large segmented-mirror telescopes are powerful tools used in modern astronomy. Segmentation of the primary mirror is important for support design, mirror fabrication, and construction cost reduction. A curvature study showed that a primary mirror with a solid angle of less than π/6 can be well divided by projecting identical hexagonal tilings onto a curved surface. Three approaches, based on map projection, are presented. The conformal method, preserving the angle locally, provides optimal regularity. The equal-area algorithm generates a partition having zero area variation. The equidistant projection minimizes the circumscribed diameter of the segments. These approaches are unified by a newly proposed compromise approach, which provides the necessary adjustment range for individual preferences. The performances of the three approaches are numerically verified using the Thirty Meter Telescope model. This study verifies the effectiveness of the scaling rule and sheds light on the mechanism of primary mirror segmentation.

Prevalence and Risk Factors of Chronic Obstructive Pulmonary Disease in Kashi Region, Northwestern China.

OBJECTIVE: To investigate the prevalence and the risk factors of COPD in the Uyghur population in the Kashi region. METHODS: From August 2018 to March 2019, we recruited participants of Uyghur ethnicity and aged ≥40 years old from the Kashi region using a combined cluster sampling and random sampling method. We collected potential risk factors using questionnaire, and conduced lung function using a portable pulmonary function instrument. RESULTS: A total of 2963 participants were included in this analysis, of whom 1268 were males and 1695 were females. There were 504 participants with COPD, generating a prevalence of 17.01%. With the increase of age, the prevalence of COPD in different genders increased significantly. The results of different regions were χ2= 627.89, p < 0.01, indicating significant differences in the prevalence in different regions. Among them, based on the existing survey data, it is speculated that Shache county has the highest crude prevalence, but the sample size needs to be further expanded. The participants with high age, smoking, lower BMI, high waist circumference, systolic blood pressure, fried cooking and barbecue share more COPD than those who partake of fruits and vegetables in this study. CONCLUSION: The prevalence of COPD among the Uyghur population in the Kashi region is higher than the national rural average. Among them, high age, smoking, low BMI, high waist circumference, high systolic blood pressure, cooking methods that may be stir-fried and deep-fried barbecue are risk factors for COPD, and vegetable and fruit intake may be a protective factor for COPD.

Whole-Exome Sequencing Implicates the USP34 rs777591A > G Intron Variant in Chronic Obstructive Pulmonary Disease in a Kashi Cohort.

Genetic factors are important factors in chronic obstructive pulmonary disease (COPD) onset. Plenty of risk and new causative genes for COPD have been identified in patients of the Chinese Han population. In contrast, we know considerably little concerning the genetics in the Kashi COPD population (Uyghur). This study aims at clarifying the genetic maps regarding COPD susceptibility in Kashi (China). Whole-exome sequencing (WES) was used to analyze three Uyghur families with COPD in Kashi (eight patients and one healthy control). Sanger sequencing was also used to verify the WES results in 541 unrelated Uyghur COPD patients and 534 Uyghur healthy controls. WES showed 72 single nucleotide variants (SNVs), two deletions, and small insertions (InDels), 26 copy number variants (CNVs), and 34 structural variants (SVs), including g.71230620T > A (rs12449210T > A, NC_000,016.10) in the HYDIN axonemal central pair apparatus protein (HYDIN) gene and g.61190482A > G (rs777591A > G, NC_000002.12) in the ubiquitin-specific protease 34 (USP34) gene. After Sanger sequencing, we found that rs777591"AA" under different genetic models except for the dominant model (adjusted OR = 0.8559, 95%CI 0.6568-1.115, p > .05), could significantly reduce COPD risk, but rs12449210T > A was not related to COPD. In stratified analysis of smoking status, rs777591"AA" reduced COPD risk significantly among the nonsmoker group. Protein and mRNA expression of USP34 in cigarette smoke extract-treated BEAS-2b cells increased significantly compared with those in the control group. Our findings associate the USP34 rs777591"AA" genotype as a protector factor in COPD.

The effect and mechanism of action of carbocysteine on airway bacterial load in rats chronically exposed to cigarette smoke.

BACKGROUND AND OBJECTIVE: Carbocysteine (S-carboxymethylcysteine) is a mucoactive drug with in vitro free radical scavenging and anti-inflammatory properties. Several clinical trials have indicated that carbocysteine reduces exacerbation rates in COPD. In the present study, the effect of carbocysteine on the airway load of Haemophilus influenzae was assessed in rats chronically exposed to cigarette smoke (CS). In addition, the effects of carbocysteine on airway mucus hypersecretion and mucociliary clearance (MCC) associated with the adherence and clearance of H. influenzae were investigated. METHODS: Wistar rats were randomly divided into control, carbocysteine vehicle, CS exposure and carbocysteine treatment groups. After 12 weeks, rats were selected for quantitative inoculation of H. influenzae. BAL fluid and lungs were collected aseptically after 3 h for quantitative culture of H. influenzae. MCC was measured by quantifying the clearance of (99m)Tc-Sc. Goblet cell metaplasia and the presence of mucoid matter were evaluated by Alcian blue/periodic acid-Schiff staining. Mucin 5AC (Muc5AC) expression was detected by western blotting and real-time reverse transcription-PCR. RESULTS: Exposure to CS increased airway H. influenzae load, aggravated mucus hypersecretion and delayed MCC. Treatment with carbocysteine decreased airway H. influenzae load, and attenuated airway mucus hypersecretion, with improved MCC associated with adherence and clearance of H. influenzae. CONCLUSIONS: These results suggest that carbocysteine may be beneficial in patients with COPD by increasing the clearance of bacteria and decreasing bacterial load.