Nicotinamide Riboside Modulates HIF-1 Signaling to Maintain and Enhance Odontoblastic Differentiation in Human Dental Pulp Stem Cells.

Human dental pulp stem cells (hDPSCs) play a vital role in the regeneration of the pulp-dentin complex after pulp disease. While the regeneration efficiency relies on the odontoblastic differentiation capacity of hDPSCs, this is difficult to regulate within the pulp cavity. Although nicotinamide riboside (NR) has been found to promote tissue regeneration, its specific role in pulp-dentin complex regeneration is not fully understood. Here, we aimed to explore the role of NR in the odontoblastic differentiation of hDPSCs and its underlying molecular mechanism. It was found that NR enhanced the viability and retarded senescence in hDPSCs with higher NAD+/NADH levels. In contrast to the sustained action of NR, the multi-directional differentiation of hDPSCs was enhanced after NR pre-treatment. Moreover, in an ectopic pulp regeneration assay in nude mice, transplantation of hDPSCs pretreated with NR promoted the formation of a dentin-like structure surrounded by cells positively expressing DMP-1 and DSPP. RNA-Seq demonstrated inhibition of the HIF-1 signaling pathway in hDPSCs pretreated with NR. The number of HIF-1α-positive cells was significantly decreased in hDPSCs pretreated by NR in vivo. Similarly, NR significantly downregulated the expression of HIF-1α in vitro. The findings suggested that NR could potentially regulate hDPSC odontoblastic differentiation and promote the development of innovative strategies for dental pulp repair.

Research progress on carotenoid production by Rhodosporidium toruloides.

Carotenoids are natural lipophilic pigments, which have been proven to provide significant health benefits to humans, relying on their capacity to efficiently scavenge singlet oxygen and peroxyl radicals as antioxidants. Strains belonging to the genus Rhodosporidium represent a heterogeneous group known for a number of phenotypic traits including accumulation of carotenoids and lipids and tolerance to heavy metals and oxidative stress. As a representative of these yeasts, Rhodosporidium toruloides naturally produces carotenoids with high antioxidant activity and grows on a wide variety of carbon sources. As a result, R. toruloides is a promising host for the efficient production of more value-added lipophilic compound carotenoids, e.g., torulene and torularhodin. This review provides a comprehensive summary of the research progress on carotenoid biosynthesis in R. toruloides, focusing on the understanding of biosynthetic pathways and the regulation of key enzymes and genes involved in the process. Moreover, the relationship between the accumulation of carotenoids and lipid biosynthesis, as well as the stress from diverse abiotic factors, has also been discussed for the first time. Finally, several feasible strategies have been proposed to promote carotenoid production by R. toruloides. It is possible that R. toruloides may become a critical strain in the production of carotenoids or high-value terpenoids by genetic technologies and optimal fermentation processes. KEY POINTS: • Biosynthetic pathway and its regulation of carotenoids in Rhodosporidium toruloides were concluded • Stimulation of abiotic factors for carotenoid biosynthesis in R. toruloides was summarized • Feasible strategies for increasing carotenoid production by R. toruloides were proposed.

Harmine inhibits the proliferation and migration and promotes the apoptosis of colon cancer cells via inhibition of the FAK/AKT and ERK1/2/CREB signaling pathways.

Harmine is present in a variety of medicinal plants, and its effects on colon cancer cells remain unclear. Here, we found that harmine exhibited significant inhibitory effects on the proliferation of colon cancer cells by inhibiting the phosphorylation levels of the FAK/AKT and ERK1/2/CREB. Furthermore, harmine also inhibited the migration of colon cancer cells and suppressed the expression levels of MMP-2, MMP-9, and VEGF. Additionally, harmine-induced apoptosis in colon cancer cells by regulating the expression of Bcl-2 and Bax. In conclusion, our findings suggest that harmine exerts a significant inhibitory effect on the development of colon cancer cells.

[Evidence mapping of traditional Chinese medicine intervention in diabetic retinopathy].

This study aims to assess the quality of evidence for the treatment of diabetic retinopathy with traditional Chinese medicine based on the systematic reviews/Meta-analyses of relevant studies. CNKI, Wanfang, VIP, SinoMed, PubMed, Web of Science, EMbase, and Cochrane Library were searched for the systematic reviews/Meta-analyses of traditional Chinese medicine interventions in diabetic retinopathy published from the inception to November 2023. A Measurement Tool to Assess Systematic Reviews 2(AMSTAR2) scale was used to assess the methodological quality of the included studies. An evidence map was built to present the information on intervention measures, the number of studies included in the systematic reviews/Meta-analyses, research conclusions, and methodological quality assessment results. A total of 51 studies were included. Traditional Chinese medicine interventions accounted for a large proportion of the intervention measures, followed by Chinese patent medicines. The treatment methods mainly included tonifying deficiency, activating blood, and resolving stasis. According to the AMSTAR2 scale assessment results, the descriptions of funding information for included studies, lists of excluded articles, and preliminary research protocols were particularly lacking. The evidence map showed that 48, 2, and 1 studies concluded with beneficial effects, possible beneficial effects, and unclear effects, respectively. On the whole, traditional Chinese medicine demonstrated definite efficacy in the treatment of diabetic retinopathy, while the evidence pre-sents moderate to low quality. It is suggested that higher-quality studies remain to be carried out to provide more evidence.

Functional Dental Pulp Regeneration: Basic Research and Clinical Translation.

Pulpal and periapical diseases account for a large proportion of dental visits, the current treatments for which are root canal therapy (RCT) and pulp revascularisation. Despite the clinical signs of full recovery and histological reconstruction, true regeneration of pulp tissues is still far from being achieved. The goal of regenerative endodontics is to promote normal pulp function recovery in inflamed or necrotic teeth that would result in true regeneration of the pulpodentinal complex. Recently, rapid progress has been made related to tissue engineering-mediated pulp regeneration, which combines stem cells, biomaterials, and growth factors. Since the successful isolation and characterisation of dental pulp stem cells (DPSCs) and other applicable dental mesenchymal stem cells, basic research and preclinical exploration of stem cell-mediated functional pulp regeneration via cell transplantation and cell homing have received considerably more attention. Some of this effort has translated into clinical therapeutic applications, bringing a ground-breaking revolution and a new perspective to the endodontic field. In this article, we retrospectively examined the current treatment status and clinical goals of pulpal and periapical diseases and scrutinized biological studies of functional pulp regeneration with a focus on DPSCs, biomaterials, and growth factors. Then, we reviewed preclinical experiments based on various animal models and research strategies. Finally, we summarised the current challenges encountered in preclinical or clinical regenerative applications and suggested promising solutions to address these challenges to guide tissue engineering-mediated clinical translation in the future.

[Traditional Chinese therapy of tonifying the kidney and invigorating blood circulation reduces sperm DNA damage and improves natural pregnancy in infertile males].

OBJECTIVE: To study the effect of the traditional Chinese therapy of tonifying the kidney and invigorating blood circulation (TKIB) on male infertility. METHODS: Forty-two infertile males with abnormal DNA fragmentation index (DFI) were randomly allocated into a TKIB (n = 22) and a control group (n = 20), the former treated by TKIB with an oral Chinese medicinal prescription while the latter with oral tamoxifen tablets and vitamin E capsules, both for 3 months. Before and after treatment, we obtained the semen parameters and sperm DFI from the patients and followed them up for the outcomes of natural pregnancy. RESULTS: Compared with the baseline, the patients in both the TKIB and control groups showed significant increases after medication in sperm concentration (ï¼»36.82 ± 29.16ï¼½ and ï¼»34.56 ± 37.03ï¼½ vs ï¼»50.00 ± 39.16ï¼½ and ï¼»40.72 ± 47.37ï¼½ ×106/ml, P<0.05), the percentage of progressively motile sperm (PMS) (ï¼»20.62 ± 9.10ï¼½% and ï¼»21.25 ± 9.11ï¼½% vs ï¼»36.82 ± 13.45ï¼½% and ï¼»26.18 ± 10.60ï¼½%, P<0.05) and the percentage of morphologically normal sperm (MNS) (ï¼»1.28 ± 1.00ï¼½% and ï¼»1.48 ± 0.91ï¼½% vs ï¼»3.44 ± 1.33ï¼½% and ï¼»2.57 ± 1.32ï¼½%, P<0.05), but remarkably decreased sperm DFI (ï¼»29.07 ± 11.52ï¼½% and ï¼»24.43 ± 8.46ï¼½% vs ï¼»15.51 ± 11.31ï¼½% and ï¼»18.53 ± 10.44ï¼½%, P<0.05). The patients of the TKIB group exhibited an even higher total sperm motility and percentages of PMS and MNS than those of the control group (P<0.05) but no statistically significant difference from the latter in sperm concentration or DFI (P>0.05). Besides, the former achieved higher rates of natural pregnancy (18.2%) and live birth (18.2%) than the controls (15% and 10%) though neither with statistically significant difference (P>0.05). CONCLUSIONS: The traditional Chinese therapy of tonifying the kidney and invigorating blood circulation can reduce sperm DNA damage and improve the outcomes of natural pregnancy in infertile men.

[Study on safflower yellow for injection based on cell degranulation and acute anaphylactoid model].

This paper was aimed to establish screening methods of anaphylactoid reaction caused by safflower yellow for injection based on RBL-2 H3 cell degranulation model and mice model for acute anaphylactoid reaction,and evaluate the hypersensitivity caused by safflower yellow for injection from different batches. An in vitro cell model was used to keep the cells stimulated for an hour with different batches of safflower yellow for injection as the drug group,serum-free MEM medium as negative control group and 30 mg·L-1 C48/80 as positive control group respectively. The supernatant was then absorbed,and neutral red staining technique was used to detect the effect of safflower yellow injection on the degranulation of RBL-2 H3 cells with the positive cell rate of degranulation as the indicator.An in vivo model was established to validate the experimental results,and mice model for acute anaphylactoid reaction and ELISA method were adopted to detect the plasma histamine content,and screen the hypersensitivity caused by safflower yellow for injection at the animal level by using plasma histamine content as a test index. The results of the neutral red staining experiments showed that the positive control C48/80 could cause cell degranulation,and most of the cells were deeply stained. There was significant difference in positive cell rate between different batches of safflower yellow and positive control group. In the mice model for acute anaphylactoid reaction,it was found that the positive control C48/80 significantly increased the histamine content in the plasma of mice,while the safflower yellow in each batch did not cause a significant increase in plasma histamine( P<0. 000 1). The mechanism of anaphylactoid reaction is relatively complicated. This study was mainly based on the release of histamine and other active substances by degranulation of mast cells. No significant degranulation reaction of RBL-2 H3 cells induced by safflower yellow for injection was detected,nor was the plasma histamine level significantly increased in mice from the in vitro and in vivo aspects.

[Study on wavelength overlapping HPLC fingerprint and multi-component content determination of Danshen].

This project was launched to and establish the wavelength overlapping HPLC fingerprint for Danshen and determine the contents of 7 component in Danshen. The chromatographic fingerprints were built by using Agilent Eclipse Plus C_(18)( 4. 6 mm×100 mm,3. 5 µm) as stationary phase and 0. 1% formic acid solution( A)-acetonitrile( B) as mobile phase with gradient elution( 0-5 min,10%-20% B; 5-20 min,20%-30% B; 20-25 min,30%-50% B; 25-40 min,50%-65% B; 40-45 min,65%-80% B; 45-46 min,80%-10% B; 46-50 min,10% B) at a flow rate of 1 mL·min~(-1). The column temperature was maintained at 30 ℃ and the detection wavelength was set at 250,280,310 and 340 nm. The technique of wavelength overlapping fingerprint was established and the contents of 7 indicative compounds have been determined in this method. The results of wavelength overlapping HPLC fingerprint showed all-around information of the fingerprints at 250,280,310 and 340 nm,and the similarity among 17 batches of Danshen was over 0. 828-0. 936. In wavelength overlapping HPLC fingerprint,15 common peaks were selected as the common peaks,and 7 contents of them were indentified as rosmarinic acid,salvianolic acid B,salvianolic acid A,phenolic acid,dihydrotanshinone Ⅰ,tanshinone Ⅰ and tanshinone ⅡA. The results of methodological study demonstrated that the method met the requirements of the determination. The method established in this study is simple,convenient and durable,which can provide a scientific basis for the quality control of Danshen.

Out-of-Band Radiation and Spatio-Temporal Characterization of Gd Target Laser Plasma Sources.

In this paper, an Nd∶YAG laser with 10ns pulse width and output wavelength of 1 064 nm was employed to ablate Gd metal target and Gd-doped glass target for plasma generation. The out-of-band (OOB) radiation of extreme ultraviolet sources with the two target configurations was comparatively studied. It has been found that the continuous radiation emitted by the plasma is the main component of the out-of-band radiation. The spectral distribution of the continuum emission matches that of blackbody radiation with a temperature of about 5 eV. And it is also found that the intensity of OOB radiation can be considerably decreased by using Gd-doped glass target. Optical Emission Spectroscopy (OES) has been used to analyze the temporal and spatial behaviors of electron temperature (Te) and density (Ne) of the Gd-doped glass target plasma, and experimental results show that temporal evolution of electron temperature and density of the plasma are found to be decayed exponentially with the increasing of delay time. At 125 ns after laser irradiation, electron temperature and density were 4 eV and 1.2×1018 cm-3 respectively, and then decreased to 1.5 eV and 8×1017 cm-3 with delaying time of 250 ns. On the other hand, spatial evolution of electron temperature and density show that both of them first increase and then decrease in the region of 1~10 mm from the target surface. The electron temperature and electron density achieves the maximum of 2.6 eV and 8.5×1017 cm-3, respectively, when the probe location away from the target surface 6 mm.

Stanniocalcin-1 Promotes PARP1-Dependent Cell Death via JNK Activation in Colitis.

Stanniocalcin-1 (STC1) is upregulated by inflammation and modulates oxidative stress-induced cell death. Herein, the function of STC1 in colitis and stress-induced parthanatos, a newly identified type of programmed necrotic cell death dependent on the activation of poly-ADP ribose polymerase-1 (PARP1) is investigated. Results show that STC1 expression is markedly increased in the inflamed colonic mucosa of Crohn's disease (CD) patients and chemically-induced mice colitis models. Evaluation of parthanatos severity and pro-inflammatory cytokine expression shows that intestinal-specific Stc1 knockout (Stc1INT-KO ) mice are resistant to dextran sulfate sodium (DSS)-induced colitis and exhibit lower disease severity. STC1-overexpressing cells show an increased degree of parthanatos and proinflammatory cytokine expression, whereas STC1-knockout cells show a decreased degree of parthanatos. Co-immunoprecipitation, mass spectrometry, and proteomic analyses indicate that STC1 interacts with PARP1, which activates the JNK pathway via PARP1-JNK interactions. Moreover, inhibition of PARP1 and JNK alleviates parthanatos and inflammatory injuries triggered by STC1 overexpression. Finally, following restoration of Stc1 and Parp1 expression by adeno-associated viruses, and overexpression of Stc1 and Parp1 aggravated DSS-induced colitis in Stc1INT-KO mice. In conclusion, STC1 mediates oxidative stress-associated parthanatos and aggravates inflammation via the STC1-PARP1-JNK interactions and subsequent JNK pathway activation in CD pathogenesis.

Lysosomal dysfunction-derived autophagy impairment of gingival epithelial cells in diabetes-associated periodontitis with altered protein acetylation.

Diabetes-associated periodontitis (DP) presents severe inflammation and resistance to periodontal conventional treatment, presenting a significant challenge in clinical management. In this study, we investigated the underlying mechanism driving the hyperinflammatory response in gingival epithelial cells (GECs) of DP patients. Our findings indicate that lysosomal dysfunction under high glucose conditions leads to the blockage of autophagy flux, exacerbating inflammatory response in GECs. Single-cell RNA sequencing and immunohistochemistry analyses of clinical gingival epithelia revealed dysregulation in the lysosome pathway characterized by reduced levels of lysosome-associated membrane glycoprotein 2 (LAMP2) and V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C) in subjects with DP. In vitro stimulation of human gingival epithelial cells (HGECs) with a hyperglycemic microenvironment showed elevated release of proinflammatory cytokines, compromised lysosomal acidity and blocked autophagy. Moreover, HGECs with deficiency in ATP6V0C demonstrated impaired autophagy and heightened inflammatory response, mirroring the effects of high glucose stimulation. Proteomic analysis of acetylation modifications identified altered acetylation levels in 28 autophagy-lysosome pathway-related proteins and 37 sites in HGECs subjected to high glucose stimulation or siATP6V0C. Overall, our finding highlights the pivotal role of lysosome impairment in autophagy obstruction in DP and suggests a potential impact of altered acetylation of relevant proteins on the interplay between lysosome dysfunction and autophagy blockage. These insights may pave the way for the development of effective therapeutic strategies against DP.

Providing biomimetic microenvironment for pulp regeneration via hydrogel-mediated sustained delivery of tissue-specific developmental signals.

Regenerative endodontic therapy is a promising approach to restore the vitality of necrotic teeth, however, pulp regeneration in mature permanent teeth remains a substantial challenge due to insufficient developmental signals. The dentin is embryologically and histologically similar to the pulp, which contains a cocktail of pulp-specific structural proteins and growth factors, thus we proposed an optimizing strategy to obtain dentin matrix extracted proteins (DMEP) and engineered a DMEP functionalized double network hydrogel, whose physicochemical property was tunable by adjusting polymer concentrations to synchronize with regenerated tissues. In vitro models showed that the biomimetic hydrogel with sustained release of DMEP provided a beneficial microenvironment for the encapsulation, propagation and migration of human dental pulp stem cells (hDPSCs). The odontogenic and angiogenic differentiation of hDPSCs were enhanced as well. To elicit the mechanism hidden in the microenvironment to guide cell fate, RNA sequencing was performed and 109 differential expression of genes were identified, the majority of which enriched in cell metabolism, cell differentiation and intercellular communications. The involvement of ERK, p38 and JNK MAPK signaling pathways in the process was confirmed. Of note, in vivo models showed that the injectable and in situ photo-crosslinkable hydrogel was user-friendly for root canal systems and was capable of inducing the regeneration of highly organized and vascularized pulp-like tissues in root segments that subcutaneously implanted into nude mice. Taken together, this study reported a facile and efficient way to fabricate a cell delivery hydrogel with pulp-specific developmental cues, which exhibited promising application and translation potential in future regenerative endodontic fields.

Antimicrobial Peptide- and Dentin Matrix-Functionalized Hydrogel for Vital Pulp Therapy via Synergistic Bacteriostasis, Immunomodulation, and Dentinogenesis.

The preservation of vital pulps is crucial for maintaining the physiological functions of teeth; however, vital pulp therapy (VPT) of pulpitis teeth remains a substantial challenge due to uncontrolled infection, excessive inflammation, and limited regenerative potential. Current pulp capping agents have restricted effects in the infectious and inflammatory microenvironment. To address this, a multifunctional hydrogel (TGH/DM) with antibacterial, immunomodulatory, and mineralization-promoting effects is designed. The antimicrobial peptide (AMP) and demineralized dentin matrix are incorporated into the hydrogel, achieving sustainable delivery of AMP and a cocktail of growth factors. In vitro results show that TGH/DM could kill endodontic microbiota, ameliorate inflammatory responses of human dental pulp stem cells (hDPSCs), and prompt odontogenic differentiation of inflammatory hDPSCs via activation of peroxisome proliferator-activated receptor gamma. In vivo results suggest that TGH/DM is capable of inducing M2 phenotype transformation of macrophages in mice and fostering the regeneration of the dentin-pulp complex in inflamed pulps of beagle dogs. Overall, this study first proposes the synergistic regulation of AMP and tissue-specific extracellular matrix for the treatment of pulpitis, and the advanced hydrogel provides a facile and effective way for VPT.

Design and synthesis of dabigatran etexilate derivatives with inhibiting thrombin activity for hepatocellular carcinoma treatment.

Hepatocellular carcinoma (HCC) is one of the most fatal solid malignancies worldwide. Evidence suggests that thrombin stimulates tumor progression via fibrin formation and platelet activation. Meanwhile, we also found a correlation between thrombin and HCC through bioinformatics analysis. Dabigatran is a selective, direct thrombin inhibitor that reversibly binds to thrombin. Dabigatran was used as the lead agent in this study, and 19 dabigatran derivatives were designed and synthesized based on docking mode. The thrombin-inhibitory activity of the derivative AX-2 was slightly better than that of dabigatran. BX-2, a prodrug of AX-2, showed a fairly strong inhibitory effect on thrombin-induced platelet aggregation, and effectively antagonized proliferation of HCC tumor cells induced by thrombin at the cellular level. Furthermore, BX-2 reduced tumor volume, weight, lung metastasis, and secondary tumor occurrence in nude mouse models. BX-2 combined with sorafenib increased sorafenib efficacy. This study lays the foundation for discovering new anti-HCC mechanism based on thrombin. BX-2 can be used as an anti-HCC drug lead for further research.

Therapeutic potential of the secreted Kazal-type serine protease inhibitor SPINK4 in colitis.

Mucus injury associated with goblet cell (GC) depletion constitutes an early event in inflammatory bowel disease (IBD). Using single-cell sequencing to detect critical events in mucus dysfunction, we discover that the Kazal-type serine protease inhibitor SPINK4 is dynamically regulated in colitic intestine in parallel with disease activities. Under chemically induced colitic conditions, the grim status in Spink4-conditional knockout mice is successfully rescued by recombinant murine SPINK4. Notably, its therapeutic potential is synergistic with existing TNF-α inhibitor infliximab in colitis treatment. Mechanistically, SPINK4 promotes GC differentiation using a Kazal-like motif to modulate EGFR-Wnt/ß-catenin and -Hippo pathways. Microbiota-derived diacylated lipoprotein Pam2CSK4 triggers SPINK4 production. We also show that monitoring SPINK4 in circulation is a reliable noninvasive technique to distinguish IBD patients from healthy controls and assess disease activity. Thus, SPINK4 serves as a serologic biomarker of IBD and has therapeutic potential for colitis via intrinsic EGFR activation in intestinal homeostasis.

Targeting cariogenic pathogens and promoting competitiveness of commensal bacteria with a novel pH-responsive antimicrobial peptide.

Novel ecological antimicrobial approaches to dental caries focus on inhibiting cariogenic pathogens while enhancing the growth of health-associated commensal communities or suppressing cariogenic virulence without affecting the diversity of oral microbiota, which emphasize the crucial role of establishing a healthy microbiome in caries prevention. Considering that the acidified cariogenic microenvironment leads to the dysbiosis of microecology and demineralization of enamel, exploiting the acidic pH as a bioresponsive trigger to help materials and medications target cariogenic pathogens is a promising strategy to develop novel anticaries approaches. In this study, a pH-responsive antimicrobial peptide, LH12, was designed utilizing the pH-sensitivity of histidine, which showed higher cationicity and stronger interactions with bacterial cytomembranes at acidic pH. Streptococcus mutans was used as the in vitro caries model to evaluate the inhibitory effects of LH12 on the cariogenic properties, such as biofilm formation, biofilm morphology, acidurance, acidogenicity, and exopolysaccharides synthesis. The dual-species model of Streptococcus mutans and Streptococcus gordonii was established in vitro to evaluate the regulation effects of LH12 on the mixed species microbial community containing both cariogenic bacteria and commensal bacteria. LH12 suppressed the cariogenic properties and regulated the bacterial composition to a healthier condition through a dual-functional mechanism. Firstly, LH12-targeted cariogenic pathogens in response to the acidified microenvironment and suppressed the cariogenic virulence by inhibiting the expression of multiple virulence genes and two-component signal transduction systems. Additionally, LH12 elevated H2O2 production of the commensal bacteria and subsequently improved the ecological competitiveness of the commensals. The dual-functional mechanism made LH12 a potential bioresponsive approach to caries management.

Evaluation and optimization of ecological landscape pattern for urban agglomeration in the Pearl River Delta, China.

The evaluation and optimization of landscape ecological pattern has important implications for the accurate improvement of forest quality and high-quality urban development in the Pearl River Delta urban agglomeration. Based on the "one map" data and digital elevation model data of forest resource management in 2021, we evaluated and optimized landscape ecological pattern of the Pearl River Delta urban agglomeration by morphological spatial pattern analysis and minimum cumulative resistance model. The results showed that there were 435861 patches in the Pearl River Delta urban agglomeration that could be used as ecological source area, covering an area of 7346.60 km2 and accounting for 13.4% of the Pearl River Delta area. Thirty patches were selected as the ecological source area of the study area by using the area and patch importance index, covering an area of 2792.59 km2 and accounting for 5.1% of the Pearl River Delta area. The overall natural environment of the Pearl River Delta urban agglomeration was excellent. The ecological resistance level was small. The peripheral ecological resistance was low. The core ecological resistance was high. There was still a large room for adjustment of stand types and landscape patterns, which should be optimized by adjusting the composition and spatial distribution of tree species. The ecological network of the Pearl River Delta urban agglomeration was optimized with 30 ecological sources, 103 key ecological corridors, and 95 ecological nodes. The improvement rates of the optimized probability of connectivity index and integral index of connectivity index were 297.5% and 695.1%, respectively. The optimization results could effectively connect the ecological sources and spread the ecological service functions of ecological sources.

Design, Synthesis, and Bioactivity Investigation of Cyclic Lipopeptide Antibiotics Containing Eight to Nine Amino Acids.

The current global issue of antibiotic resistance is serious, and there is an urgent requirement of developing novel antibiotics. Octapeptins have recently regained interest because of their activities against resistant Gram-negative bacteria. We synthesized four natural octapeptins and 33 derivatives with diverse polarity, amphiphilicity, and acid-base properties by solid-phase synthesis and investigated their in vitro antibacterial activity and renal cytotoxicity. We also assessed the structure-activity relationship and structure-toxicity relationship of the cyclic lipopeptide compounds. Some compounds showed increased activity against Gram-negative and/or Gram-positive bacteria, with improved renal cytotoxicity. C-02 showed remarkable in vitro antibacterial activity and low renal cytotoxicity. We found that C-02 showed high antibacterial activity against Escherichia coli in vivo and manifested its effects preliminarily by increasing outer membrane permeability. Therefore, C-02 might be a new antibiotic lead compound with not only high efficacy but also low renal cytotoxicity.

Recent developments on BMPs and their antagonists in inflammatory bowel diseases.

Inflammatory bowel diseases (IBDs), including ulcerative colitis, and Crohn's disease, are intestinal disorders characterized by chronic relapsing inflammation. A large proportion of patients with IBD will progress to develop colitis-associated colorectal cancer due to the chronic intestinal inflammation. Biologic agents that target tumour necrosis factor-α, integrin α4ß7, and interleukin (IL)12/23p40 have been more successful than conventional therapies in treating IBD. However, drug intolerance and loss of response are serious drawbacks of current biologics, necessitating the development of novel drugs that target specific pathways in IBD pathogenesis. One promising group of candidate molecules are bone morphogenetic proteins (BMPs), members of the TGF-ß family involved in regulating morphogenesis, homeostasis, stemness, and inflammatory responses in the gastrointestinal tract. Also worth examining are BMP antagonists, major regulators of these proteins. Evidence has shown that BMPs (especially BMP4/6/7) and BMP antagonists (especially Gremlin1 and follistatin-like protein 1) play essential roles in IBD pathogenesis. In this review, we provide an updated overview on the involvement of BMPs and BMP antagonists in IBD pathogenesis and in regulating the fate of intestinal stem cells. We also described the expression patterns of BMPs and BMP antagonists along the intestinal crypt-villus axis. Lastly, we synthesized available research on negative regulators of BMP signalling. This review summarizes recent developments on BMPs and BMP antagonists in IBD pathogenesis, which provides novel insights into future therapeutic strategies.