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Immune checkpoint inhibitors (ICIs) represent a groundbreaking advance in the treatment of malignancies such as melanoma and non-small cell lung cancer, showcasing substantial therapeutic benefits. Nonetheless, the efficacy of ICIs is limited to a small subset of patients, primarily benefiting those with “hot” tumors characterized by significant immune infiltration. The challenge of converting “cold” tumors, which exhibit minimal immune activity, into “hot” tumors to enhance their responsiveness to ICIs is a critical and complex area of current research. Central to this endeavor is the activation of the cGAS-STING pathway, a pivotal nexus between innate and adaptive immunity. This pathway’s activation promotes the production of type I interferon (IFN) and the recruitment of CD8+ T cells, thereby transforming the tumor microenvironment (TME) from “cold” to “hot”. This review comprehensively explores the cGAS-STING pathway’s role in reconditioning the TME, detailing the underlying mechanisms of innate and adaptive immunity and highlighting the contributions of various immune cells to tumor immunity. Furthermore, we delve into the latest clinical research on STING agonists and their potential in combination therapies, targeting this pathway. The discussion concludes with an examination of the challenges facing the advancement of promising STING agonists in clinical trials and the pressing issues within the cGAS-STING signaling pathway research.

Background and aim: Diabetes-associated cognitive impairment (DCI) is a prevalent complication of diabetes. However, there is a lack of viable strategies for preventing and treating DCI. This study aims to explore the efficacy of baicalin (Bai) in attenuating DCI and elucidating the underlying mechanisms. Experimental procedure: GK rats fed a high-fat and high-glucose diet were utilized to investigate the therapeutic potential of Bai. Cognitive function was assessed using the Morris water maze and novel object recognition tests. To gain insight into the molecular mechanisms underlying Bai’s neuro-protective effects, co-cultured BV2/HT22 cells were established under high-glucose (HG) stimulation. The modes of action of Bai were subsequently confirmed in vivo using the DCI model in db/db mice. Key results: Bai restored cognitive and spatial memory and attenuated neuron loss, along with reducing expressions of Aβ and phosphorylated Tau protein in diabetic GK rats. At the cellular level, Bai exhibited potent antioxidant and anti-inflammatory effects against HG stimulation. These effects were associated with the upregulation of Nrf2 and supressed Keap1 levels. Consistent with these in vitro findings, similar mechanisms were observed in db/db mice. The significant neuroprotective effects of Bai were abolished when co-administered with ATRA, a Nrf2 blocker, in db/db mice, confirming that KEAP1-Nrf2 signaling pathway was responsible for the observed effect. Conclusions and implications: Bai demonstrates a great therapeutic potential for attenuating DCI. The antioxidant defense and anti-inflammatory actions of Bai were mediated through the KEAP1-Nrf2 axis. These findings advance our understanding of potential treatment approaches for DCI, a common complication associated with diabetes.

AbstractElaeagnus oldhamii Maximowicz 1870 is an important medicinal plant mainly distributing in the southeastern coastal region of China. However, the complete chloroplast genome of E. oldhamii has never been studied at present. We obtained the complete chloroplast genome of E. oldhamii, which was 152,283 bp in length, with a typical quadripartite structure that includes a large single-copy region of 82,229 bp, a small single-copy region of 18,256 bp, and 2 inverted repeat (IR) regions of 25,899 bp. The genome contained 128 unique genes with a GC content of 37%, including 83 protein-coding genes, 37 tRNAs, and 8 rRNAs. Phylogenetic analysis suggested that E. oldhamii was closely related to E. glabra and E. macrophylla.

Distant metastasis is a major cause of treatment failure in cancer patients and a key challenge to improving cancer care today. We hypothesized that enhancing anti-cancer immune response and inhibiting circulating tumor cells (CTCs) adhesion and transendothelial migration through synergistic multi-target approaches may effectively prevent cancer metastasis. “Fuyuan Decoction” (FYD) is a traditional Chinese medicine compound that is widely used to prevent postoperative metastasis in cancer patients, but its underlying mechanism remains unclear. In this work, we systematically elucidated the underlying molecular mechanism by which FYD prevents cancer metastasis through multi-compound and multi-target synergies in vitro and in vivo. FYD significantly prevented cancer metastasis at non-cytotoxic concentrations by suppressing the adhesion of CTCs to endothelial cells and their subsequent transendothelial migration, as well as enhancing anti-cancer immune response. Mechanistically, FYD interrupts adhesion of CTCs to vascular endothelium by inhibiting TNF-α-induced CAMs expression via regulation of the NF-κB signaling pathway in endothelial cells. FYD inhibits invasion and migration of CTCs by suppressing EMT, PI3K/AKT and FAK signaling pathways. Moreover, FYD enhances the anti-cancer immune response by significantly increasing the population of Tc and NK cells in the peripheral immune system. In addition, the chemical composition of FYD was determined by UPLC-HRMS, and the results indicated that multiple compounds in FYD prevents cancer metastasis through multi-target synergistic treatment. This study provides a modern medical basis for the application of FYD in the prevention of cancer metastasis, and suggesting that multi-drug and multi-target synergistic therapy may be one of the most effective ways to prevent cancer metastasis.

Backfill of cemented waste rock into underground mined-out areas is an effective way to eliminate solid wastes and potential hazards in mines. To understand the backfill strength distribution law throughout the stope, similarity simulation experiments were conducted for direct-irrigating cemented waste rock backfill, and OpenCV and neural network were employed to analyze particle segregation and the spatial distribution of backfill strength. Results show that distinct gravitational segregation leads to an uneven and heterogeneous distribution of natural graded waste rocks in a similar model. Backfill strength near sidewalls and bottom of the model surpasses that of other areas. In the vertical direction, the average backfill strength increases with depth, ranging from 1.15 MPa at the topmost layer to 1.91 MPa at the bottommost layer. Horizontally, the average backfill strength near model boundaries is consistently higher than that at the model center, irrespective of the layer depth and orientation. Neural network prediction on spatial backfill strength proves reliable, exhibiting an average relative error of 4.12%, compared to the traditional surface fitting with a 10.20% error. Verification tests affirm the capability of the neural network model to accurately predict the anisotropic and nonlinear distribution of backfill strength in a large stope.

Pharmacological drug interactions are among the most common causes of medication errors. Many different methods have been proposed to extract drug–drug interactions from the literature to reduce medication errors over the last few years. However, the performance of these methods can be further improved. In this paper, we present a Pharmacological representation-based Long Short-Term Memory (LSTM) network named Phar-LSTM. In this method, a novel embedding strategy is proposed to extract pharmacological representations from the biomedical literature, and the information related to the target drug is considered. Then, an LSTM-based multi-task learning scheme is introduced to extract features from the different but related tasks according to their corresponding pharmacological representations. Finally, the extracted features are fed to the SoftMax classifier of the corresponding task. Experimental results on the DDIExtraction 2011 and DDIExtraction 2013 corpuses show that the performance of Phar-LSTM is competitive compared with other state-of-the-art methods. Our Python implementation and the corresponding data of Phar-LSTM are available by using the DOI 10.5281/zenodo.8249384.

Profiting from the sustained clinical improvement and prolonged patient survival, immune checkpoint blockade of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has emerged as a revolutionary cancer therapy approach. However, the anti-PD-1/PD-L1 antibodies only achieve a clinical response rate of approximately 20%. Herein, we identified a novel combination strategy that Chinese medicine ginseng-derived ginsenoside Rh2 (Rh2) markedly improved the anti-cancer efficacy of anti-PD-L1 antibody in mice bearing MC38 tumor. Rh2 combined with anti-PD-L1 antibody (combo treatment) further triggered the infiltration, proliferation and activation of CD8+ T cells in the tumor microenvironment (TME). Depletion of CD8+ T cells by mouse CD8 blocking antibody abolished the anti-cancer effect of combo treatment totally. Mechanistically, combo treatment further increased the expression of CXCL10 through activating TBK1-IRF3 signaling pathway, explaining the increased infiltration of T cells. Employing anti- CXC chemokine receptor 3 (CXCR3) blocking antibody prevented the T cells infiltration and abolished the anti-cancer effect of combo treatment. Meanwhile, combo treatment increased the percentage of M1-like macrophages and raised the ratio of M1/M2 macrophages in TME. By comparing the anti-cancer effect of combo treatment among MC38, CT26 and 4T1 tumors, resident T cells were considered as a prerequisite for the effectiveness of combo treatment. These findings demonstrated that Rh2 potentiated the anti-cancer effect of PD-L1 blockade via promoting the T cells infiltration and activation, which shed a new light on the combination strategy to enhance anti-PD-L1 immunotherapy by using natural product Rh2.

Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease that has no viable treatment. Curcumin (Cur) and resveratrol (Res) are two natural products that have been studied for their potential to ameliorate MAFLD. However, while these compounds have been investigated individually, their combined use and the potential for a synergistic or augmented effect remain unexplored. This study aims to investigate the effect of curcumin (Cur) and resveratrol (Res) as a potential combination therapy on MAFLD. Cur, Res and Cur+Res were tested in palmitic acid (PA)-induced-HepG2 cells. MAFLD model was established using Goto-Kakizaki rats. The animals were treated with vehicle control (model group), Cur (150 mg/kg), Res (150 mg/kg), Cur+Res (150 mg/kg, 8:2, w/w), or metformin (Met, positive control, 400 mg/kg/day) via oral gavage for 4 weeks. Wistar rats were used as the control group. Network pharmacology was conducted to elucidate the molecular actions of Cur and Res, followed by q-PCR and immunoblotting in vivo. Cur+Res exhibited synergistic effects in reducing triglyceride, total cholesterol and lipid accumulation in PA-induced HepG2 cells. The combination also markedly attenuated hepatic steatosis in the MAFLD rats. Network pharmacology illustrated that the interaction of Cur and Res was associated with the modulation of multiple molecular targets associated with the PI3K/AKT/mTOR and HIF-1 signaling pathways. Experimental results confirmed that Cur+Res nomalised the gene targets and protein expressions in the PI3K/AKT/mTOR and HIF-1 signaling pathways, including PI3K, mTOR, STAT-3, HIF-1α, and VEGF. The present study demonstrated an advanced effect of Cur and Res in combination to attenuate MAFLD, and the mechanism is at least partly associated with the modulation of the PI3K/AKT/mTOR and HIF-1 signaling pathways.

Abstract Background The morning glories (Convolvulaceae) are distributed worldwide and produce economically important crops, medicinal herbs, and ornamentals. Members of this family are diverse in morphological characteristics and trophic modes, including the leafless parasitic Cuscuta (dodders). Organelle genomes were generally used for studying plant phylogeny and genomic variations. Notably, plastomes in parasitic plants always show non-canonical features, such as reduced size and accelerated rates. However, few organelle genomes of this group have been sequenced, hindering our understanding of their evolution, and dodder mitogenome in particular. Results We assembled 22 new mitogenomes and 12 new plastomes in Convolvulaceae. Alongside previously known ones, we totally analyzed organelle genomes of 23 species in the family. Our sampling includes 16 leafy autotrophic species and 7 leafless parasitic dodders, covering 8 of the 12 tribes. Both the plastid and mitochondrial genomes of these plants have encountered variations that were rarely observed in other angiosperms. All of the plastomes possessed atypical IR boundaries. Besides the gene and IR losses in dodders, some leafy species also showed gene and intron losses, duplications, structural variations, and insertions of foreign DNAs. The phylogeny reconstructed by plastid protein coding sequences confirmed the previous relationship of the tribes. However, the monophyly of ‘Merremieae’ and the sister group of Cuscuta remained uncertain. The mitogenome was significantly inflated in Cuscuta japonica, which has exceeded over 800 kb and integrated massive DNAs from other species. In other dodders, mitogenomes were maintained in small size, revealing divergent evolutionary strategies. Mutations unique to plants were detected in the mitochondrial gene ccmFc, which has broken into three fragments through gene fission and splicing shift. The unusual changes likely initially happened to the common ancestor of the family and were caused by a foreign insertion from rosids followed by double-strand breaks and imprecise DNA repairs. The coding regions of ccmFc expanded at both sides after the fission, which may have altered the protein structure. Conclusions Our family-scale analyses uncovered unusual scenarios for both organelle genomes in Convolvulaceae, especially in parasitic plants. The data provided valuable genetic resources for studying the evolution of Convolvulaceae and plant parasitism.

Metastasis is the leading cause of cancer-related death and a critical challenge in improving cancer treatment today. Circulating tumor cells (CTCs) adhesion to and across the vascular endothelium are critical steps in the establishment of micrometastatic foci away from the primary tumor. Therefore, we believe that interrupting CTCs adhesion to endothelium and transendothelial migration may efficiently prevent cancer metastasis. Fucoxanthin (Fx) is an algal carotenoid widely distributed in brown algae, macroalgae, and diatoms. Previous studies have found that Fx has various pharmacological activities, including antidiabetic, antioxidant, anti-inflammatory, anti-obesity, antimalarial, anticancer, and so on. However, it remains unclear whether Fx has a preventive effect on cancer metastasis. Here, we found that Fx interrupts breast cancer cells MCF-7 adhesion to endothelium and transendothelial migration, thus inhibiting CTCs-based pulmonary metastasis in vivo. The hetero-adhesion assay showed that Fx significantly inhibited the expression of inflammatory factor-induced cell adhesion molecules (CAMs) and the resulting adhesion between MCF-7 cells and endothelial cells. The wound-healing and transwell assays showed that Fx significantly inhibited the motility, invasion, and transendothelial migration abilities of MCF-7 cells. However, the same concentration of Fx did not significantly alter the cell viability, cell cycle, apoptosis, and ROS of breast cancer cells, thus excluding the possibility that Fx inhibits MCF-7 cell adhesion and transendothelial migration through cytotoxicity. Mechanistically, Fx inhibits the expression of CAMs on endothelial cells by inhibiting the NF-кB signaling pathway by down-regulating the phosphorylation level of IKK-α/β, IкB-α, and NF-кB p65. Fx inhibits transendothelial migration of MCF-7 cells by inhibiting Epithelial-to-mesenchymal transition (EMT), PI3K/AKT, and FAK/Paxillin signaling pathways. Moreover, we demonstrated that Fx significantly inhibits the formation of lung micrometastatic foci in immunocompetent syngeneic mouse breast cancer metastasis models. We also showed that Fx enhances antitumor immune responses by substantially increasing the subsets of cytotoxic T lymphocytes in the peripheral immune system. This new finding provides a basis for the application of Fx in cancer metastatic chemoprevention and suggests that interruption of the CTCs adhesion to endothelium and transendothelial migration may serve as a new avenue for cancer metastatic chemoprevention.

Endothelial dysfunction is an early pathological event in diabetic angiopathy which is the most common complication of diabetes. This study aims to investigate individual and combined actions of Curcumin (Cur) and Baicalein (Bai) in protecting vascular function. The cellular protective effects of Cur, Bai and Cur+Bai (1:1, w/w) were tested in H2O2 (2.5 mM) impaired EA. hy926 cells. Wistar rats were treated with vehicle control as the control group, Goto-Kakizaki rats (n=5 each group) were treated with vehicle control (model group), Cur (150 mg/kg), Bai (150 mg/kg), or Cur+Bai (75 mg/kg Cur + 75 mg/kg Bai, OG) for 4 weeks after a four-week high-fat diet to investigate the changes on blood vessel against diabetic angiopathy. Our results showed that Cur+Bai synergistically restored the endothelial cell survival and exhibited greater effects on lowering the fasting blood glucose and blood lipids in rats comparing to individual compounds. Cur+Bai repaired the blood vessel structure in the aortic arch and mid thoracic aorta. The network pharmacology analysis showed that Nrf2 and MAPK/JNK kinase were highly relevant to the multi-targeted action of Cur+Bai which has been confirmed in the in vitro and in vivo studies. In conclusion, Cur+Bai demonstrated an enhanced activity in attenuating endothelial dysfunction against oxidative damage and effectively protected vascular function in diabetic angiopathy rats.

Diabetes-induced cognitive impairment (DCI) presents a major public health risk among the aging population. Previous clinical attempts on known therapeutic targets for DCI, such as depleted insulin secretion, insulin resistance, and hyperglycaemia have delivered poor patient outcomes. However, recent evidence has demonstrated that the gut microbiome plays an important role in DCI by modulating cognitive function through the gut–brain crosstalk. The bioactive compound tanshinone IIA (TAN) has shown to improve cognitive and memory function in diabetes mellitus models, though the pharmacological actions are not fully understood. This study aims to investigate the effect and underlying mechanism of TAN in attenuating DCI in relation to regulating the gut microbiome. Metagenomic sequencing analyses were performed on a group of control rats, rats with diabetes induced by a high-fat/high-glucose diet (HFD) and streptozotocin (STZ) (model group) and TAN-treated diabetic rats (TAN group). Cognitive and memory function were assessed by the Morris water maze test, histopathological assessment of brain tissues, and immunoblotting of neurological biomarkers. The fasting blood glucose (FBG) level was monitored throughout the experiments. The levels of serum lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunoassays to reflect the circulatory inflammation level. The morphology of the colon barrier was observed by histopathological staining. Our study confirmed that TAN reduced the FBG level and improved the cognitive and memory function against HFD- and STZ-induced diabetes. TAN protected the endothelial tight junction in the hippocampus and colon, regulated neuronal biomarkers, and lowered the serum levels of LPS and TNF-α. TAN corrected the reduced abundance of Bacteroidetes in diabetic rats. At the species level, TAN regulated the abundance of B. dorei, Lachnoclostridium sp. YL32 and Clostridiodes difficile. TAN modulated the lipid metabolism and biosynthesis of fatty acids in related pathways as the main functional components. TAN significantly restored the reduced levels of isobutyric acid and butyric acid. Our results supported the use of TAN as a promising therapeutic agent for DCI, in which the underlying mechanism may be associated with gut microbiome regulation.

Dendrobium mixture (DM) is a patent Chinese herbal formulation consisting of Dendrobii Caulis, Astragali Radix, Rehmanniae Radix as the main ingredients. DM has been shown to alleviate diabetic related symptoms attributed to its anti-hyperglycaemic and anti-inflammatory activities. However, the effect on diabetic induced cognitive dysfunction has not been investigated. This study aims to investigate the effect of DM in improving diabetic cognitive impairment and associated mechanisms.Our study confirmed the anti-hyperglycaemic effect of DM and showed its capacity to restore the cognitive and memory function in high fat/high glucose and streptozotocin-induced diabetic rats. The neuroprotective effect was manifested as improved learning and memory behaviours, restored blood-brain barrier tight junction, and enhanced expressions of neuronal survival related biomarkers. DM protected the colon tight junction, and effectively lowered the circulated proinflammatory mediators including tumour necrosis factor-α, interleukin-6 and lipopolysaccharides. In the gut microbiota, DM corrected the increase in the abundance of Firmicutes, the increase in the ratio of Firmicutes/Bacteroidetes, and the decrease in the abundance of Bacteroidetes in diabetic rats. It also reversed the abundance of Lactobacillus, Ruminococcus and Allobaculum genera. Short chain fatty acids, isobutyric acid and ethylmethylacetic acid, were negatively and significantly correlated to Ruminococcus and Allobaculum. Isovaleric acid was positively and significantly correlated with Lactobacillus, which all contributing to the improvement in glucose level, systemic inflammation and cognitive function in diabetic rats.Our results demonstrated the potential of DM as a promising therapeutic agent in treating diabetic cognitive impairment and the underlying mechanism may be associated with regulating gut microbiota.

Context Pien-Tze-Huang (PTH) is traditionally applied to treat various inflammation-related diseases including stroke. However, literature regarding the anti-inflammatory effects and possible mechanisms of PTH in ischaemic stroke is unavailable. Objective This study investigates the anti-inflammatory effects and its underlying mechanism of PTH on ischaemic stroke. Materials and methods Cerebral ischaemia-reperfusion injury was induced through 2 h middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion in male Sprague-Dawley (SD) rats receiving oral pre-treatment with PTH (180 mg/kg) for 4 days. TLR4 antagonist TAK-242 (3 mg/kg) was injected intraperitoneally at 1.5 h after MCAO. MRI, HE staining, qRT-PCR, western blot, and immunofluorescence methods were employed. Results PTH treatment markedly reduced cerebral infarct volume (by 51%), improved neurological function (by 33%), and ameliorated brain histopathological damage in MCAO rats. It also reduced the levels of four inflammatory mediators including IL-1β (by 70%), IL-6 (by 78%), TNF-α (by 60%) and MCP-1 (by 58%); inhibited microglia and astrocyte activation; and decreased protein expression of iNOS and COX-2 in injured brains. Moreover, PTH down-regulated the protein expressions of TLR4, MyD88, and TRAF6; reduced the expression and nuclear translocation of NF-κB; and lowered the protein expressions of p-ERK1/2, p-JNK, and p-p38. Similar effects were observed in MCAO rats with TAK-242 treatment. However, combined administration of PTH and TAK-242 did not significantly reinforce the anti-inflammatory effects of PTH. Discussion and conclusion PTH improved cerebral ischaemia-reperfusion injury by inhibiting neuroinflammation partly via the TLR4/NF-κB/MAPK signalling pathway, which will help guide its clinical application.

Abstract Background Diabetic bladder disease is common complications of diabetes, its symptoms are diverse, can be due to different stages. In this study we investigate the mechanism of miR-128 targeting CB1 expression to mediate the occurrence of diabetic bladder disease. Methods Bioinformatics analysis predicts related regulatory factors of miR-128 in diabetic bladder disease. Models of diabetic bladder lesions were constructed in male SD rats by intraperitoneal injection of streptozotocin at 65 mg/kg body weight. The expression of miR-128 and CB1 mRNA in bladder tissues of each group was detected by RT-qPCR, and CB1, NF-KB, p-JNK and Bcl2 protein expression was detected by Western Blotting. We tested the function of the bladder by urodynamics, detected the pathological characteristics of the bladder tissue by HE staining, and verified the targeting relationship between miR-128 and CB1 through the prediction of the biological website, dual luciferase reporter gene assay and RIP. Results miR-128 was highly expressed in the bladder tissue of diabetic rats. Inhibition of miR-128 could improve the occurrence of diabetic bladder lesions in rats. miR-128 could target the inhibition of CB1 expression, and high expression of CB1 could antagonize miR-128 against diabetic bladder. In the diabetic bladder, miR-128 can regulate the expression of NF-KB and p-JNK through CB1 and affect the level of apoptosis. miR-128 regulates NF-KB/p-JNK through CB1, thus affecting the occurrence of diabetic bladder disease. Conclusion The high expression of miR-128 can down-regulate the expression of CB1, promote the activation of NF-KB and p-JNK, increase the level of apoptosis and promote the occurrence of diabetic bladder disease.

NLRP3 inflammasome is a key mediator in ischemic stroke-induced neuroinflammation and subsequent brain injury. Our previous study demonstrated the potent activity of Pien-Tze-Huang (PTH), a well-known Chinese patent formula, in reducing mitochondria-mediated neuronal apoptosis in cerebral ischemia/reperfusion impaired rats. This study aims to elucidate the mechanistic action of PTH related to neuroinflammation in LPS-induced BV2 microglial cells and cerebral ischemia/reperfusion impaired rats. BV2 cells were stimulated with LPS for 12 h and treated with PTH with various concentrations. Modulation by PTH of relevant genes (IL-6, IL-1β, IL-18, TNF-α, COX-2 and iNOS mRNA) and proteins (NLRP3 inflammasome, autophagy and AMPK/mTOR/ULK signaling) was analyzed by real-time PCR and western blot, respectively. Similar analyses were conducted in middle cerebral artery occlusion rat model including neurological deficit, infarct volume, microglial activation, and key genes and proteins in modulating autophagy and NLRP3. Our results showed that PTH significantly inhibited the production of key proinflammatory mediators and protein expressions of NLRP3 and caspase-1 p20 in LPS induced BV2 cells. It also enhanced the autophagy response by modulating the key autophagy proteins via AMPK/mTOR/ULK related pathway. The reduced inflammatory responses and NLRP3 expressions by PTH were partially blocked by the autophagy inhibitor (3-MA) and AMPK blocker (compound C). In rats, PTH significantly reduced infarct size, suppressed microglial activation, and improved neuron deficit. It also promoted autophagy and reduced NLRP3 activity. Our study demonstrated that PTH inhibited NLRP3 inflammasome-mediated neuroinflammation, which was associated with enhanced autophagy via AMPK/mTOR/ULK1 pathway in vitro and in vivo.

Backfill of mined-out areas in Carlin-type gold mines always encounters the challenges of ultra-fine tailings, low backfill strength and difficult slurry transportation caused by fine tailings. To understand the influence of slurry mass concentration, waste rock content, and cement-sand ratio on the cemented backfill strength and fluidity, influential factors were determined by range analysis of orthogonal proportion experiments. Response surface methodology (RSM) was used to analyze the influence of each factor on response, and the backfill strength and slump were optimized using a robust optimization desirability function method. The results show that the cement-sand ratio has the highest effect on the backfill strength, and the slurry slump is dominated by the slurry mass concentration. The interaction between waste rock content and the cement-sand ratio significantly impacts the slump, while the interaction between the slurry mass concentration and the cement-sand ratio has a positive correlation with the backfill strength. The ultra-fine tailings cemented backfill proportion was optimized by using multi-response robust parameters as 68.36% slurry mass concentration, 36.72% waste rock content and 1:3 cement-sand ratio. The overall robust optimal desirability was 0.8165, and the validity of multi-response robust parameter optimization was verified by laboratory tests.

Alismatis rhizoma (AR) is the dried rhizome of Alisma orientale (Sam.) Juz. (Alismataceae). This traditional Chinese formula is diuretic, hypoglycemic, and hypolipidemic. Alisol C 23-acetate (AC23A) from AR is anti-inflammatory and ameliorates certain metabolic diseases. However, the mechanism by which AC23A mitigates osteoporosis is unknown. The present study investigated the anti-osteoporotic effects of AC23A in vivo and in vitro. In an ovariectomized (OVX) rat model, AC23A ameliorated OVX-induced organ coefficients and trabecular bone loss. In OVX rats, AC23A treatment lowered serum TRAP5b, CTK, β-CTX, TNF-α, IL-6, and IL-1β, raised serum E2, and did not significantly change serum OCN or BALP. AC23A inhibited osteoclast formation in a rat co-culture system without affecting osteoblast activity. RANK (receptor activator of nuclear factor kappaB) signaling channels are vital osteoclastogenesis transcription elements. AC23A inhibited RANK ligand (RANKL)-induced TRAP, c-Fos, MMP9, NFATc1, and CTK expression and JNK phosphorylation. Therefore, AC23A is anti-osteoclastogenic in vitro and in vivo by inhibiting RANKL-induced osteoclast differentiation and function. Moreover, AC23A could help prevent or limit osteoclast-mediated bone diseases by inhibiting osteoclastogenesis.

Fucoxanthin (FX) is a marine carotenoid that has proven to be a promising marine drug due to the multiple bioactivities it possesses. However, the instability and poor bioavailability of FX greatly limit its application in pharmaceuticals or functional foods. In this study, the creative construction of a solid lipid nanoparticle-microcapsule delivery system using mixed lipids of palm stearin and cholesterol wrapped with gelatin/Arabic gum to load lipophilic FX was fabricated, aiming to improve the stability and bioavailability of FX. The results showed that the encapsulated efficiency (EE) and drug loading capacity (LC) of optimized FX microcapsules (FX-MCs) obtained were as high as 96.24 ± 4.60% and 0.85 ± 0.04%, respectively, after single-factor experiments. The average particle size was 1154 ± 54 nm with negative Zeta potential (−20.71 ± 0.93 mV) as depicted with size-zeta potential spectrometer. The differential scanning calorimeter (DSC) and thermogravimetric analyzer (TG) results indicated that FX-MC has a higher Tg and slower weight loss than FX monomers (FX crystal) and blank MCs. Besides, The Fourier transform infrared spectrometer (FTIR) confirmed the good double encapsulation of FX into the solid lipid and composite coacervate. Moreover, the encapsulated FX showed higher storage stability, sustained release (55.02 ± 2.80% release in 8 h), and significantly improved bioavailability (712.33%) when compared to free FX. The research results can provide a principle theoretical basis for the development and application of FX in pharmaceuticals or functional foods.

Tailings produced in the beneficiation of Carlin-type gold deposits are characterized by fine particle size and high mud content. When neutralized with wasted acid generated by pressurized pre-oxidation, the tailings turn to neutralized slag and perform as a novel backfill material. To understand the influential behavior of variable factors on the strength and its optimization of cemented neutralization slag backfill, RMS-BBD design test was carried out with 56–60% slurry mass fraction, 12.5–25% cement/(neutralization slag + waste rock) (i.e., C/(S+R)) and 30–40% waste rock content. A modified three-dimensional quadratic regression model was proposed to predict the strength of cemented neutralization slag backfill. The results showed that backfill strength predicted by the modified ternary quadratic regression model was in high coincidence with the data of backfill mixture tests. C/(S+R) was predominant in backfill strength with regard to every single influential factor throughout the curing age, and the mass fraction of slurry had a significant effect on the later strength. From the perspective of economic and engineering operation, a multi-objective function method was further introduced to optimize the backfill strength. The optimal mixture proportion of cemented neutralized slag backfill slurry was: 58.4% slurry mass fraction, 32.2% waste rock content, and 20.1% C/(S+R). The backfill strength of this mixture proportion on days 7, 28 and 56 was verified as 0.42, 0.64 and 0.85 MPa, respectively. RSM-BBD design and multi-objective function optimization proposed a reliable way to evaluate and optimize the strength of neutralized slag backfill with high mud content.

Fucoxanthin has potential anti-diabetic activities, but its precise effects and underlying mechanisms remain unclear. In this study, C57BL/KsJ-db/db mice were fed diets containing fucoxanthin (0.2% and 0.4%, w/w) for 6 weeks. Results showed dietary fucoxanthin significantly improved glucose/lipid metabolism and insulin resistance, and prevented pancreatic histological changes in db/db mice. Moreover, fucoxanthin markedly lowered blood glucose by regulating glucokinase and phosphoenolpyruvate carboxykinase mRNA expressions in liver, promoted glycogen synthesis by regulating glucose transporter 4, glycogen synthase and glycogen synthase kinase-3 beta protein expressions in skeletal muscle, and lowered blood lipid levels by regulating peroxisome proliferator-activated receptor alpha, p-acetyl CoA carboxylase, carnitine palmitoyltransferase 1 and fatty acid synthetase protein expressions in liver. Mechanistic studies indicated that fucoxanthin effectively regulates the expression of IRS-1/PI3K/AKT and AMPK signaling proteins in liver and skeletal muscle. All results suggested that fucoxanthin is a potential functional food or effective drug for type 2 diabetes mellitus.

Overlapping clustering is a fundamental and widely studied subject that identifies all densely connected groups of vertices and separates them from other vertices in complex networks. However, most conventional algorithms extract modules directly from the whole large-scale graph using various heuristics, resulting in either high time consumption or low accuracy. To address this issue, we develop an overlapping community detection approach in Ego-Splitting networks using symmetric Nonnegative Matrix Factorization (ESNMF). It primarily divides the whole network into many sub-graphs under the premise of preserving the clustering property, then extracts the well-connected sub-sub-graph round each community seed as prior information to supplement symmetric adjacent matrix, and finally identifies precise communities via nonnegative matrix factorization in each sub-network. Experiments on both synthetic and real-world networks of publicly available datasets demonstrate that the proposed approach outperforms the state-of-the-art methods for community detection in large-scale networks.

Rhizoma Alismatis (RA), widely known as “Ze-Xie” in China, is the tuber of Alisma orientale (Sam.) Juzep (Alismaceae), a Chinese herbal medicine that has been used to treat hyperlipidemia, diabetes, hypertension, dysuria, and inflammation. In this study, a sensitive and reliable method based on an ultra-performance liquid chromatography (UPLC) couple with two ionisation modes, including electrospray ionisation (ESI) and atmospheric pressure chemical ionisation (APCI) tandem mass spectrometry (MS), namely, UPLC-ESI/APCI-MS/MS was developed and validated to simultaneously determine 8 triterpenoids (ESI mode) and 2 sesquiterpenoids (APCI mode) in RA. Ten marker compounds were analysed with a Waters’ CORTECS UPLC C18 column (200 mm × 2.1 m, 1.6 μm) and gradient elution with water (contained 0.1% formic) and acetonitrile within 7 min. The established method was validated for linearity, intra- and interday precisions, accuracy, recovery, and stability. The calibration curve for 10 marker compounds showed good linear regression (r > 0.9971). The limits of detection and quantification for analytes were 0.14–1.67 ng/mL and 0.44–5.65 ng/mL, respectively. The relative standard deviations (RSD, %) and accuracy (RE, %) of intra- and interday precisions were less than 3.83% and 1.21% and 3.22% and 1.46%, repeatability and stability for real samples were less than 2.78% and 3.19%, respectively. All recoveries of the 10 marker compounds ranged from 97.24% to 102.49% with RSDs less than 4.05%. The developed method efficiently determined the 10 marker compounds in RA and was subsequently applied to optimise harvest time and crude processing temperature. The result indicated the 90% wilted phase and 70°C (or lower) may be the best harvest time and the processing temperature of RA.

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s12967-021-02719-3

Shexiang Tongxin dropping pill (STP) is a traditional Chinese medicine formula that consists of total saponins of ginseng, synthetic Calculus bovis, bear gall, Venenum bufonis, borneol and Salvia miltiorrhiza. STP has been widely used in China and Southeast Asia for the treatment of cardiovascular diseases. In this study, a qualitative analytical method using high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry was developed for identification of the major constituents in STP. Based on the retention time and MS spectra, 41 components were identified by comparison with reference compounds and literature data. Moreover, using ultra-performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry in multiple-reaction monitoring mode, we quantified 13 of the identified constituents (ginsenoside Rg1, ginsenoside Rk3, cinobufagin, arenobufagin, bufalin, resibufogenin, tanshinone IIA, taurine, tauroursodeoxycholic acid, taurocholic acid, cholic acid, deoxycholic acid, and chenodeoxycholic acid). These results suggest that this new approach is applicable for the routine analysis and quality control of STP products and provides fundamental data for further in vivo pharmacokinetical studies.

A simple, rapid and specific ultra-performance liquid chromatography-triple quadrupole mass spectrometry method was developed for the analysis of 29 bioactive components (10 phenolic acids, 16 flavonoids, and three iridoid glycosides) in Yinhua Kanggan tablet (YHKGT), a herbal prescription used for treating upper respiratory infections, fevers, coughs and pharyngalgia. The separation was successfully achieved using a Waters Cortecs UPLC C18 column (50 × 2.1 mm, 1.6 μm) and gradient elution with water-0.1% formic acid and acetonitrile. Polarity switching mode was used in the optimization of multiple reaction monitoring conditions. The analytical method was validated for linearity, precision and accuracy. Calibration curves for the 29 marker compounds showed good linear regression (r > 0.9982). The limits of detection (LOD) and limits of quantification (LOQ) for the 29 analytes were in the range of 0.03–4.99 ng/mL and 0.16–14.87 ng/mL, respectively. The relative standard deviation (RSD) values of intra-day precision, inter-day precision, repeatability, and stability were less than 2.79%, 4.87%, 4.18% and 4.71%, respectively. The recoveries of the 29 marker compounds were in the range of 94.67%–104.78% (RSD ≤ 4.72%). These results have shown that this developed method was efficient for the quality evaluation of YHKGT.

Alismatis Rhizoma (AMR) is a well-known natural medicine with a long history in Chinese medicine and has been commonly used for treating a wide range of ailments related to dysuria, edema, nephropathy, hyperlipidaemia, diabetes, inflammation as well as tumors in clinical applications. Most beneficial effects of AMR are attributed to the presence of protostane terpenoids, the major active ingredients of Alismatis Rhizoma (AMR). In this study, a systematic high performance liquid chromatography/diode-array detector/quadrupole-time-of-flight mass spectrometry (HPLC-DAD-Q-TOF MS) and ultra-performance liquid chromatography/triple quadrupole mass spectrometry (UPLC-QqQ MS) method was developed for qualitative and quantitative analyses of the major AMR triterpenoids. First, a total of 25 triterpenoid components, including 24 known compounds and one new compound were identified by comparison with UV spectra, molecular ions and fragmentation behaviors of reference standards or the literature. Second, an efficient method was established for the rapid simultaneous determination of 14 representative triterpenoids by UPLC-QqQ MS. Forty-three batches of AMR were analyzed with linearity (r, 0.9980–0.9999), intra-day precision (RSD, 1.18%–3.79%), inter-day precision (RSD, 1.53%–3.96%), stability (RSD, 1.32%–3.97%), repeatability (RSD, 2.21%–4.25%), and recovery (98.11%–103.8%). These results indicated that new approaches combining HPLC-DAD-Q-TOF MS and UPLC-QqQ MS are applicable in the qualitative and quantitative analysis of AMR.

Background/Aims: Obesity contributes to the development of cardiometabolic disorders such as type 2 diabetes, fatty liver disease and cardiovascular disease. Salvianolic acid B (Sal B) is a molecule derived from the root of Salvia miltiorrhiza (Danshen), which is a traditional Chinese medicine that is widely used to treat cardiovascular diseases. However, the role of Sal B in obesity and obesity-related metabolic disorders is unknown. In this study, we aimed to investigate the effects of Sal B on high-fat diet-induced obesity and determine the possible mechanisms involved. Methods: Male C57BL/6J mice fed a high-fat diet for 12 weeks received a supplement of Sal B (100 mg/kg/day) by gavage for a further 8 weeks. These mice were compared to control mice fed an un-supplemented high-fat diet. 3T3-L1 preadipocytes were used in vitro studies. Results: Sal B administration significantly decreased body weight, white adipose tissue weight, adipocyte size and lipid (triglyceride and total cholesterol) levels in obese mice. Eight weeks of Sal B administration also improved the intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test (IPITT) scores in high-fat diet-induced obese mice. In 3T3-L1 preadipocytes that were cultured in vitro and induced to differentiate, Sal B reduced the accumulation of lipid droplets and lipid content in a dose-dependent manner. Immunoblotting indicated that Sal B decreased peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα) expression but increased the expression of GATA binding protein 2 and 3 (GATA 2, GATA 3) both in vivo and in vitro. Conclusion: Our data suggest that Sal B may reduce obesity and obesity-related metabolic disorders by suppressing adipogenesis. The effects of Sal B in adipose tissue may be related to its action on PPARγ, C/EBPα, GATA-2 and GATA-3.

Pien-Tze-Huang (PTH) is a famous and commonly used traditional Chinese medicine formula in China. It was first formulated by a royal physician of the Ming Dynasty (around 1555 AD). Recently, PTH has attracted attention worldwide due to its beneficial effects against various diseases, especially cancer. This paper systematically reviewed the up-to-date information on its chemical composition, pharmacology, and clinical application. A range of chemical compounds, mainly ginsenosides and bile acids, have been identified and quantified from PTH. Pharmacological studies indicated that PTH has beneficial effects against various cancers, hepatopathy, and ischemic stroke. Furthermore, PTH has been used clinically to treat various diseases in China, such as colorectal cancer, liver cancer, and hepatitis. In summary, PTH is a potential agent with extensive therapeutic effects for the treatment of various diseases. However, the lack of information on the side effects and toxicity of PTH is a non-negligible issue, which needs to be seriously studied in the future.

Introduction: Cavability issues often arise in hard rock mines employing the block caving mining method. Hydraulic fracturing stands out as a promising preconditioning technology for hard rock masses, with its pre-conditioning effects dependent on variable parameters. Methods: The impact of cluster number, injection rate, and liquid volume on fracture propagation was investigated through on-site hydraulic fracturing practices. Fracturability was initially verified via true triaxial fracturing tests, and preconditioning parameters were subsequently optimized using numerical simulations. The optimized on-site construction was monitored using electromagnetic methods. Results: The study revealed a negative correlation between fracture radius and the number of clusters, gradually decreasing with an increase in cluster number. However, the fracture weakening area increased with the rise in the number of clusters. The fracture weakening area also increased with the injection rate. Additionally, the fracture radius initially increased and then decreased. Both fracture weakening area and radius increased with an increase in liquid volume. The optimized parameters were identified as four clusters, an injection rate of 4 m3/min, and a liquid volume of 500 m3. Discussion: Building upon these findings, on-site experiments were conducted and monitored using electromagnetic methods. The monitored results demonstrated that the optimized parameters effectively achieved hydraulic fracturing expansion, accomplishing the goal of weakening hard rock. [ABSTRACT FROM AUTHOR]