Green technology innovation and regional carbon emissions: analysis based on heterogeneous treatment effect modeling.

The impact of green technology innovation on regional carbon emissions has been a contentious issue in academic research. In this study, we attempt to analyze the influence of green technology innovation on regional carbon emissions using panel data from 28 Chinese provinces for the period of 2007-2020. Utilizing a heterogeneous treatment effect model, we systematically examine the effects of green technology innovation on regional carbon emissions. Firstly, we conduct a feature selection analysis on the factors influencing regional carbon emissions using causal inference methods based on machine learning. Subsequently, we explore the conditional and marginal treatment effects of green technology innovation on regional carbon emissions using the heterogeneous treatment effect model. Finally, we investigate the dynamic effects of green technology innovation on regional carbon emissions across different periods. Empirical results indicate that firstly, green technology innovation indirectly reduces regional carbon emissions by promoting energy efficiency improvement; secondly, the impact of green technology innovation on carbon emissions exhibits significant regional heterogeneity, with the largest effect observed in the eastern region, followed by the western region and the smallest effect in the central region; thirdly, at a significance level of 5%, green technology innovation has a direct inhibitory effect on carbon emissions in certain regions.

Influence of sampling location and processing on the assembly and network of Polygoni Multiflori Radix surface microbiome.

The raw and processed roots of Polygonum multiflorum Thunb is a popular traditional Chinese medicine. However, Polygoni Multiflori Radix is easily contaminated by toxigenic fungi and mycotoxins during harvesting, processing, and transportation, thereby posing a health risk for consumers. This study aims to investigate the presence of fungi on the surface of raw and processed Polygoni Multiflori Radix collected from four producing areas using high-throughput sequencing. Results showed that the phyla Ascomycota and Basidiomycota, the genera Xeromyces, Cystofilobasidium, Eurotium, and Aspergillus were the dominant fungus, and significant differences are presented in four areas and two processed products. Three potential mycotoxin-producing fungi were detected, namely Trichosporon cutaneum, Aspergillus restrictus, and Fusarium oxysporum. The α-diversity and network complexity showed significant differences in four areas. Chao 1 and Shannon were highest in Yunnan (YN), then incrementally decreased from SC (Sichuan) to AH (Anhui) and GD (Guangdong) areas. Meanwhile, α-diversity was also strongly influenced by processing. Chao 1 and Shannon indices were higher in the raw group, however, the network complexity and connectivity were higher in the processed group. In conclusion, the assembly and network of the surface microbiome on Polygoni Multiflori Radix were influenced by sampling location and processing. This work provides details on the surface microbiome of Polygoni Multiflori Radix samples, which could ensure the drug and consumers' safety.

Generation of an induced pluripotent stem cell line (SDASi001-A) from a Schimke immune-osseous dysplasia patient with SMARCAL1 mutations.

A human induced pluripotent stem cell (iPSC) line (SDASi001-A) was generated from patient with Schimke immune-osseous dysplasia (SIOD), carrying heterozygous mutations in SMARCAL1 gene. Peripheral blood mononuclear cells (PBMCs) were reprogrammed using non-integrating delivery of OCT4, SOX2, KFL4, BCL-XL and c-MYC. The iPSC line expresses pluripotency markers, displays a normal karyotype, and has the ability to differentiate into cells of three germ layers in vitro. This iPSC line represents a valuable cell model for SIOD in humans.

Fungal microbiome related to mycotoxin contamination in medicinal and edible seed Semen Persicae.

Medicinal and edible seed Semen Persicae is susceptible to mycotoxin and fungal contamination. However, the occurrence of mycotoxin contamination and fungal infection is still unclear. In this paper, ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry and high-throughput sequencing were conducted to determine the mycotoxin contents and fungal abundances of Semen Persicae. 42.86% of samples were positive for aflatoxin B1 (26.48-48.37 µg/kg) and 28.57% of samples were positive for aflatoxin B2 (1.47-4.82 µg/kg). Ochratoxin A and fumonisin B1 were only detected in one sample (91.02 and 34.61 µg/kg, respectively). Chao 1 and Shannon indices were significantly higher in the Dalian of Liaoning, Baotou of Innermongolia and Langfang of Hebei regions than in other groups. Ascomycota, Basidiomycota, Wallemia, Candica, Saccharomyces and Aspergillus were the predominant fungi and they were significantly region-specific. Simultaneously, the diversity, composition and co-occurrence network complexity in the mycotoxin-free group were significantly higher than those in the mycotoxin-contaminated group. Spearman correlation analysis showed aflatoxins, ochratoxin A and fumonisins contents were positively and significantly correlated with the abundances of Aspergillus, Rhodotorula, Wallemia and Candida. In conclusion, this study reported the prevalence of mycotoxin contamination and the great diversity of fungi associated with Semen Persicae for the first time, providing an early warning for subsequent potential mycotoxin biosynthesis.

Sampling locations and processing methods shape fungi microbiome on the surface of edible and medicinal Arecae semen.

Introduction: Arecae semen, which is derived from the dried ripe seed of Areca catechu L., has been commonly used as one of the major traditional Chinese medicines (TCMs). Three types of crude herbal preparations, namely, raw Arecae semen (AS), Arecae semen tostum (SAS), and Arecae semen carbonisata (FAS), are available for different clinical applications in TCMs. Although aflatoxin contamination in Arecae semen has been reported preliminarily, only a few studies have been conducted on fungal contamination. Methods: In this study, the presence of fungi on the surface of three Arecae semen (AS, SAS, and FAS) that collected from four provinces were investigated using high-throughput sequencing and internal transcribed spacer 2. Results: Results showed that the phyla Ascomycota (75.45%) and Basidiomycota (14.29%) and the genera Wallemia (7.56%), Botryosphaeria (6.91%), Davidiella (5.14%), and Symbiotaphrina (4.87%) were the dominant fungi, and they presented significant differences in four areas and three processed products (p < 0.05). The α-diversity and network complexity exhibited significant differences in the four sampling locations (p < 0.05), with higher in Yunnan (Chao 1, 213.45; Shannon, 4.61; average degree, 19.96) and Hainan (Chao 1, 198.27; Shannon, 4.21; average degree, 22.46) provinces. Significant differences were noted in the three processed samples; and SAS group had highest α-diversity (Chao 1, 167.80; Shannon, 4.54) and network complexity (average degree, 18.32). Conclusions: In conclusion, the diversity and composition of microbiome on the surface of Arecae semen were shaped by sampling location and processing methods. This work provides details on the surface microbiome of Arecae semen samples and highlights the importance of roles of origin and processing methods in microbiomes, ensuring drug efficacy and food safety.

Modules in robust but low-efficiency phyllosphere fungal networks drive saponin accumulation in leaves of different Panax species.

BACKGROUND: The phyllosphere mycobiome plays a crucial role in plant fitness and ecosystem functions. The complex microbial ecological networks (MEN) formed by these fungi remain poorly understood, particularly with regard to their organization strategy and their contributions to plant secondary metabolites such as saponin. RESULTS: In this study, we constructed six MENs from leaf epiphytic and endophytic mycobiomes of three Panax species distributed in the northeast and southwest ends of mainland China. Hub nodes were absent in these MENs, which were significantly more complex, robust, and less efficient compared to random graphs (P < 0.05), indicating a hub-independent high-robustness strategy to maintain structural homeostasis. The important roles of specific MEN modules in shaping leaf saponin profiles of each Panax species were proved by multiple machine learning algorithms. Positive regulation modules (PRMs) of total saponin content were further identified, which exhibited more deterministic ecological assembly and comprised of highly connected nodes as well as higher proportion of plant-associated fungal guilds compared to other network members, indicating their tight links with host plant. The significant and direct effects (P < 0.05) of PRMs on total saponin accumulation were validated by well-fitted structural equation models (χ2 < 0.3, P > 0.5). Taxonomic analysis revealed that Pleosporales and Chaetothyriales were significantly overrepresented by positive regulation taxa (PRT) of total saponin content (FDR < 0.05). Across PRT identified in three Panax species, Epicoccum and Coniothyrium were conservatively present, while species-specific taxa such as Agaricales were also found, indicating the conservatism and specificity of plant-fungi interactions associated with leaf saponin accumulation in Panax genus. CONCLUSIONS: These findings provide a foundation for understanding mechanisms maintaining the steady state of phyllosphere mycobiome in healthy plant, and offer clues for engineering phyllosphere mycobiome to improve the accumulation of bioactive secondary metabolites on the basis of network modules.

[Research summary of chemical constituents and pharmacological effects of Panax notoginseng and predictive analysis on its Q-markers].

Panax notoginseng contains triterpene saponins, flavonoids, amino acids, polysaccharides, volatile oil and other active components, which have the effects of promoting blood circulation, stopping bleeding, removing blood stasis, etc. This study summarized the herbal research, chemical constituents and main pharmacological activities of P. notoginseng, and based on the theory of Q-markers of traditional Chinese medicine, predicted and analyzed the Q-markers of P. notoginseng from the aspects of plant kinship, efficacy, drug properties, measurability of chemical components, etc. It was found that ginsenosides Rg_1, Re, and Rb_1 with specific content ratio, ginsenosides Rb_2, Rb_3, Rc, Rd, Rh_2, and Rg_3, notoginseng R_1, dencichine and quercetin could be used as potential Q-markers of P. notoginseng, which facilitated the formulation of quality standards reflecting the efficacy of P. notoginseng.

Jujuboside A ameliorates cognitive deficiency in delirium through promoting hippocampal E4BP4 in mice.

OBJECTIVE: Delirium (acute brain syndrome) is a common and serious neuropsychiatric disorder characterized by an acute decline in cognitive function. However, there is no effective treatment clinically. Here we investigated the potential effect of jujuboside A (JuA, a natural triterpenoid saponin) on cognitive impairment in delirium. METHODS: Delirium models of mice were established by injecting lipopolysaccharide (LPS) plus midazolam and implementing a jet lag protocol. Novel object recognition test and Y maze test were used to evaluate the effects of JuA on delirium-associated cognitive impairment. The mRNA and protein levels of relevant clock factors and inflammatory factors were measured by qPCR and Western blotting. Hippocampal Iba1+ intensity was determined by immunofluorescence staining. KEY FINDINGS: JuA ameliorated delirium (particularly delirium-associated cognitive impairment) in mice, which was proved by the behavioural tests, including a preference for new objects, an increase of spontaneous alternation and improvement of locomotor activity. Furthermore, JuA inhibited the expression of ERK1/2, p-p65, TNFα and IL-1ß in hippocampus, and repressed microglial activation in delirious mice. This was attributed to the increased expression of E4BP4 (a negative regulator of ERK1/2 cascade and microglial activation). Moreover, loss of E4bp4 in mice abrogated the effects of JuA on delirium as well as on ERK1/2 cascade and microglial activation in the hippocampus of delirious mice. Additionally, JuA treatment increased the expression of E4BP4 and decreased the expression of p-p65, TNFα and IL-1ß in LPS-stimulated BV2 cells, supporting a protective effect of JuA on delirium. CONCLUSIONS: JuA protects against delirium-associated cognitive impairment through promoting hippocampal E4BP4 in mice. Our findings are of great significance to the drug development of JuA against delirium and related disorders.

Occurrence of fungi and mycotoxins in herbal medicines and rapid detection of toxin-producing fungi.

Contamination from external hazardous materials may greatly influence the safety and efficacy of herbal medicines. This paper aimed to evaluate the levels of contamination by mycotoxins and toxigenic fungi in herbal medicines and establish a rapid method for detecting toxin-producing fungi. Herein, 62.92%, 36.25%, and 64.17% of herbal medicines were contaminated by aflatoxins (AFs), ochratoxins, and fumonisins, respectively. Aspergillus (43.77%), Fusarium (5.17%), and Cladosporium (4.46%) were the three predominant genera. Spearman's correlation results showed that Aspergillus and Fusarium were significantly and positively correlated with mycotoxin content (R > 0.5, P < 0.05). In addition, 323 fungal strains were isolated from herbal medicines, and 20 species were identified, mainly belonging to Aspergillus and Penicillium. Analysis of potential mycotoxin-producing fungi showed that Aspergillus flavus can produce AFs, and Aspergillus ochraceus and Aspergillus niger can produce ochratoxin A (OTA). Multiplex real-time polymerase chain reaction showed that A. flavus harbored AF synthesis genes (aflR), and A. ochraceus and A. niger harbored OTA synthesis genes (aoksl). With these synthesis genes, 67.07% and 37.20% of 164 herbal medicines were positive for toxigenic genes. Furthermore, an excellent correlation was found between the above gene copies and mycotoxin content (R2 = 0.99). Our results confirmed the high detection rate of mycotoxins in herbal medicines and identified pivotal AF- and OTA-producing fungi. In conclusion, this paper provided the contamination status of fungi and mycotoxins in herbal medicines and established a rapid method for detecting toxigenic fungi.

Juvenile dermatomyositis and nephrotic syndrome: A case report and a mini literature review.

Background: Renal involvement is rarely reported in juvenile dermatomyositis and may be caused by the toxic effects of myoglobinuria or an autoimmune reaction. We report a case of dermatomyositis and nephrotic syndrome in a child to explore the association between juvenile dermatomyositis and renal involvement. Case presentation: An 8-year-old girl with skin rash, edema, proximal muscle weakness predominantly involving the lower extremities, low-grade fever, and foamy urine was admitted to our hospital. Her laboratory tests met the criteria of nephrotic syndrome. She had elevated creatine kinase and lactate dehydrogenase and was diagnosed with juvenile dermatomyositis after electromyography and muscle MRI. Anti-NXP2 antibodies were positive. Her proteinuria was relieved soon after treatment with prednisone and methotrexate, but her muscle strength progressively decreased. The disease was relieved after pulse methylprednisolone treatment and mycophenolate mofetil, but recurred after drug reduction with mild proteinuria. Adalimumab was used for treatment and helped reduce the doses of glucocorticoid and mycophenolate mofetil. Conclusion: Juvenile dermatomyositis may be one of the rare causes of nephrotic syndrome. The mechanism involved in JDM combined with renal injury may be multifactorial. Autoantibodies may play important roles in both muscle and renal damage.

Effect of vaginal delivery on adverse pregnancy outcomes after cesarean section in scar uterus.

The purpose of this study was to investigate the impact of vaginal delivery on adverse pregnancy outcomes after cesarean section for the cicatricial uterus. Eighty patients with scarred uterus after cesarean section admitted to our hospital from October 2019 to May 2021 were selected for the study. Among them, 44 cases were eligible for vaginal delivery. Thirty-eight cases of cesarean delivery were selected as the control group and 42 cases of vaginal delivery were selected as the observation group according to the mode of delivery. Baseline data, 24-h blood loss, length of hospital stay, hospital costs, 5-minute Apger score, and adverse pregnancy outcomes were compared between the two groups. When comparing the age, gestational age, number of pregnancies, and duration of cesarean delivery between the two groups (t = 1.333, 0.989, 0.597, 0.752, P > 0.05), the scar thickness in the observation group was higher than that in the control group. The 24-h postpartum bleeding and hospitalization cost was lower in the observation group than in the control group, the hospitalization time was shorter than in the control group, and the 5-minute Apger score was higher than in the control group (t = 21.744, 15.029, 11.524, 7.342, P < 0.05). The incidence of maternal and neonatal complications was compared between the two groups (23.68% vs 7.14%, 7.89% vs 0.00%, correction 2 = 1.083, 1.605, P > 0.05). The incidence of adverse pregnancy outcomes was 7.14% in the observation group, which was significantly lower than the 31.57% in the control group. The difference was statistically significant (correction 2 = 4.060, P < 0.05).

Development of a Highly Sensitive Hybrid LC/MS Assay for the Quantitative Measurement of CTLA-4 in Human T Cells.

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a check point protein expressed on the surface of T cells and plays a central role in regulating the immune response. In recent years, CTLA-4 has become a popular target for cancer immunotherapy in which blocking CTLA-4 can restore T-cell function and enhance the immune response against cancer. Currently, there are many CTLA-4 inhibitors in a variety of modalities, including cell therapies, which are being developed in both preclinical and clinical stages to further harness the potential of the target for the treatment of certain types of cancer. In drug discovery research, measuring the level of CTLA-4 in T cells is important for drug discovery and development because it provides key information for quantitative assessment of the pharmacodynamics, efficacy, and safety of the CTLA-4-based therapies. However, to our best knowledge, there is still no report of a sensitive, specific, accurate, and reliable assay for CTLA-4 measurement. In this work, an LC/MS-based method was developed to measure CTLA-4 in human T cells. The assay demonstrated high specificity with an LLOQ of 5 copies of CTLA-4 per cell when using 2.5 million T cells for analysis. As shown in the work, the assay was successfully used to measure CTLA-4 levels in subtype T-cell samples from individual healthy subjects. The assay could be applied in supporting the studies of CTLA-4-based cancer therapies.

[Traditional Chinese medicine microbiomics and its research strategies].

The tight relationships between microbiome and traditional Chinese medicine(TCM)have been widely recognized. New technologies, results, and theories are emerging in the field of microbiomics in recent years with the advances in high-throughput sequencing and multi-omics technologies. Based on the previous research, the present study has proposed the concept of TCM microbiomics(TCMM), which is an interdisciplinary subject aiming at elucidating the functions and applications of microbiome in the areas of herb resources, herb processing, herb storage, and clinical effects by using modern technology of biology, ecology, and informatics. This subject essentially contains the structures, functions, interactions, molecular mechanisms, and application strategies of the microbiome associated with the quality, safety, and efficacy of TCM. Firstly, the development of the TCMM concept was summarized, with the profound understanding of TCMM on the complexity and entirety of microbiome being emphasized. Then, the research contents and applications of TCMM in promoting the sustainable development of herb resources, improving the standardization and diversification of herb fermentation, strengthening the safety of herb storage, and resolving the scientific connotation of theories and clinical efficacy of TCM are reviewed. Finally, the research strategies and methods of TCM microbiomics were elaborated from basic research, application research, and system research. TCMM is expected to promote the integrative development of TCM with frontier science and technology, thereby expanding the depth and scope of TCM study and facilitating TCM modernization.

Identification of histone acetyltransferase genes responsible for cannabinoid synthesis in hemp.

BACKGROUND: Histone acetyltransferases (HATs) play an important role in plant growth and development, stress response, and regulation of secondary metabolite biosynthesis. Hemp (Cannabis sativa L.) is famous for its high industrial, nutritional, and medicinal value. It contains non-psychoactive cannabinoid cannabidiol (CBD) and cannabinol (CBG), which play important roles as anti-inflammatory and anti-anxiety. At present, the involvement of HATs in the regulation of cannabinoid CBD and CBG synthesis has not been clarified. METHODS: The members of HAT genes family in hemp were systematically analyzed by bioinformatics analysis. In addition, the expression level of HATs and the level of histone acetylation modification were analyzed based on transcriptome data and protein modification data. Real-time quantitative PCR was used to verify the changes in gene expression levels after inhibitor treatment. The changes of CBD and CBG contents after inhibitor treatment were verified by HPLC-MS analysis. RESULTS: Here, 11 HAT genes were identified in the hemp genome. Phylogenetic analysis showed that hemp HAT family genes can be divided into six groups. Cannabinoid synthesis genes exhibited spatiotemporal specificity, and histones were acetylated in different inflorescence developmental stages. The expression of cannabinoid synthesis genes was inhibited and the content of CBD and CBG declined by 10% to 55% in the samples treated by HAT inhibitor (PU139). Results indicated that CsHAT genes may regulate cannabinoid synthesis through altering histone acetylation. CONCLUSIONS: Our study provides genetic information of HATs responsible for cannabinoid synthesis, and offers a new approach for increasing the content of cannabinoid in hemp.

Structural basis of SecA-mediated protein translocation.

Secretory proteins are cotranslationally or posttranslationally translocated across lipid membranes via a protein-conducting channel named SecY in prokaryotes and Sec61 in eukaryotes. The vast majority of secretory proteins in bacteria are driven through the channel posttranslationally by SecA, a highly conserved ATPase. How a polypeptide chain is moved by SecA through the SecY channel is poorly understood. Here, we report electron cryomicroscopy structures of the active SecA-SecY translocon with a polypeptide substrate. The substrate is captured in different translocation states when clamped by SecA with different nucleotides. Upon binding of an ATP analog, SecA undergoes global conformational changes to push the polypeptide substrate toward the channel in a way similar to how the RecA-like helicases translocate their nucleic acid substrates. The movements of the polypeptide substrates in the SecA-SecY translocon share a similar structural basis to those in the ribosome-SecY complex during cotranslational translocation.

Association between glomerular C4d deposition, proteinuria, and disease severity in children with IgA nephropathy.

BACKGROUND: C4d may be used as a marker to evaluate the condition and prognosis of adults with IgA nephropathy, but there have been few studies of children with IgA nephropathy. METHODS: C4d immunohistochemical staining was performed on samples from children with IgA nephropathy with C1q-negative immunofluorescence. The clinical and pathological treatment and prognostic characteristics of children in the C4d-positive and -negative groups were compared. RESULTS: A total of sixty-five children with IgA nephropathy were included in the study and were followed up for an average of 37 months. C4d was mainly deposited along the capillary loops. The urinary protein-to-creatinine ratio (UPCR) in the C4d-positive group was significantly higher than that in the C4d-negative group (3.97 vs. 0.81, P < 0.001), and the average integrated optical density value of each child was positively correlated with the UPCR (r = 0.441, P < 0.001). There was a significant difference in the proportions of children with mesangial hypercellularity (M1) (68.97% vs. 44.44%, P = 0.048) and segmental glomerulosclerosis (S1) (65.52% vs. 33.33%, P = 0.010) between the C4d-positive group and the C4d-negative group. The proportion of children who received immunosuppressants in the C4d-positive group was higher than that in the C4d-negative group (86.21% vs. 36.11%, P < 0.001). There was no significant difference in the proportion of children developing kidney failure between the two groups. CONCLUSION: C4d was found to be associated with proteinuria, segmental lesions, and immunosuppressant treatment. Activation of the lectin pathway may reflect the severity of clinical and pathological manifestations of IgA nephropathy in children. A higher resolution version of the Graphical abstract is available as Supplementary information.

An evaluation method for product design solutions for healthy aging companionship.

Background: With the development trend of healthy aging and intelligent integration, escort products have become a new means of healthy aging. Healthy old-age care pays attention to the convenience and informatization of life. To meet the needs, designers often design multiple accompanying product solutions, and it is very important to use reasonable evaluation methods to decide on the optimal solution. Purposes: A new comprehensive evaluation method is proposed to reduce the subjectivity and one-sidedness of the selection process of intelligent escort product design solutions, and to make the decision more objective and reasonable. Such decisions can enhance the experience and naturalness of the elderly using intelligent products. Methods: First, a large number of user interviews were analyzed using the grounded theory, gradually refine through theoretical coding, and abstracted with the design scheme evaluation index. Second, the idea of game-theoretic weighting is used to optimize a linear combination of subjective and objective weights to determine the final weights of each evaluation indicator. Finally, the evaluation and selection are completed based on the solution ranking determined by the approximate ideal solution ranking method (TOPSIS). It is applied for the selection of the elderly escort robot design, and the usability test is conducted using the PSSUQ to verify the selection results. Results: A new comprehensive evaluation method can better complete the preferential selection of product design solutions for healthy aging escorts, and reduce the subjectivity and one-sidedness of the evaluation. Conclusion: This method compensates for the reliance on personal experience in the selection of options, and improve the subjectivity of the evaluation index determination process and the deviation of index weighting. Improving the objectivity and scientificity of decision-making reduces the blindness of design and production. It also provides a theoretical reference for the research scholars of healthy aging companion products.

Core rhizosphere microbiome of Panax notoginseng and its associations with belowground biomass and saponin contents.

The core rhizosphere microbiome is critical for plant fitness. However, its contribution to the belowground biomass and saponin contents of Panax notoginseng remains unclear. High-throughput sequencing of amplicon and metagenome was performed to obtain the microbiome profiles and functional traits in P. notoginseng rhizosphere across a large spatial scale. We obtained 639 bacterial and 310 fungal core OTUs, which were mainly affected by soil pH and organic matter (OM). The core taxa were grouped into four ecological clusters (i.e. high pH, low pH, high OM and low OM) for sharing similar habitat preferences. Furthermore, structural equation modelling (SEM) and correlation analyses revealed that the diversity and composition of core microbiomes, as well as the metagenome-derived microbial functions, were related to belowground biomass and saponin contents. Key microbial genera related to the two plant indicators were also identified. In short, this study explored the main driving environmental factors of core microbiomes in the P. notoginseng rhizosphere and revealed that the core microbiomes and microbial functions potentially contributed to the belowground biomass and saponin contents of the plant. This work may enhance our understanding of interactions between microbes and perennial plants and improve our ability to manage root microbiota for the sustainable production of herbal medicine.

Therapeutic effects of shaogan fuzi decoction in rheumatoid arthritis: Network pharmacology and experimental validation.

Shaogan Fuzi Decoction (SGFD), one of the classical prescriptions of Chinese Medicine, has a long history in the treatment of rheumatoid arthritis (RA), but definitive studies on its efficacy and mechanism of action are lacking. This study aims to elucidate the pharmacodynamic role of SGFD against RA and the potential mechanisms based on a combination of network pharmacology and experimental verification. The RA model in rats was induced by intradermal injection of bovine type Ⅱ collagen and incomplete Freund's adjuvant at the tail root. SGFD was administered once a day by oral gavage for 4 weeks. After SGFD administration, rat's arthritis index (AI) score and paw swelling decreased to some extent, and synovial inflammation, vascular hyperplasia, and cartilage destruction of the ankle joint were improved. Simultaneously, thymus and spleen index and serum levels of C-reactive protein (CRP) were lowered. Network pharmacology revealed that quercetin, kaempferol, naringenin, formononetin isorhamnetin and licochalcone A were the potentialiy active components, and IL6, TP53, TNF, PTGS2, MAPK3 and IL-1ß were potential key targets for SGFD in the treatment of RA. Ingredients-targets molecular docking showed that the components had the high binding activity to these target proteins. The mechanism of SGFD for RA involves various biological functions and is closely correlated with TNF signaling pathway, Osteoclast differentiation, T cell receptor signaling pathway, mitogen-activated protein kinase (MAPK) signaling pathway, NF-κB signaling pathway, toll-like receptor signaling pathway, and so on. Western blot and ELISA showed that the expression of toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB) p65, phosphorylated c-Jun N-terminal kinase (p-JNK), p-p38, phosphorylated extracellular regulated kinase (p-ERK) and TNF-α was significantly upregulated in the synovium of RA rats, and the levels of serum inflammatory factors were significantly increased. SGFD inhibits the activation of the TLR4/NF-κB/MAPK pathway and the expression/production of pro-inflammatory cytokines. In summary, SGFD could improve the symptoms and inflammatory response in collagen-induced arthritis (CIA) rat model. The mechanism might be related to the regulation of TLR4/MAPKs/NF-κB signaling pathway and the reduction of inflammatory factor release, which partially confirms the results predicted by network pharmacology.

Accurate de novo design of membrane-traversing macrocycles.

We use computational design coupled with experimental characterization to systematically investigate the design principles for macrocycle membrane permeability and oral bioavailability. We designed 184 6-12 residue macrocycles with a wide range of predicted structures containing noncanonical backbone modifications and experimentally determined structures of 35; 29 are very close to the computational models. With such control, we show that membrane permeability can be systematically achieved by ensuring all amide (NH) groups are engaged in internal hydrogen bonding interactions. 84 designs over the 6-12 residue size range cross membranes with an apparent permeability greater than 1 × 10-6 cm/s. Designs with exposed NH groups can be made membrane permeable through the design of an alternative isoenergetic fully hydrogen-bonded state favored in the lipid membrane. The ability to robustly design membrane-permeable and orally bioavailable peptides with high structural accuracy should contribute to the next generation of designed macrocycle therapeutics.