Salvianolic acid B and tanshinone IIA synergistically improve early diabetic nephropathy through regulating PI3K/Akt/NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic nephropathy (DN) is one of the most common and serious complications of diabetes, which lacks effective treatment. Salviae Miltiorrhizae Radix Et Rhizoma is one of the key compatible traditional Chinese medicine in the prescription for the treatment of DN. Salvianolic acid B and tanshinone IIA are two monomer active components with high content and clear structure in Salvia miltiorrhiza, which can effectively improve early (DN), respectively. AIM OF THE STUDY: To evaluate the compatible effect of salvianolic acid B and tanshinone IIA on early DN rats and elucidate the mechanism. METHODS: Early DN rats were induced by streptozotocin combined with high glucose and high fat diet, and intervened by salvianolic acid B, tanshinone IIA and their combinations. The pathological sections of kidney, liver and biochemical indexes were analyzed. Network pharmacology method was used to predict the possible mechanism. The mechanisms were elucidated by metabolomics, Elisa, and Western blot. RESULTS: Given our analysis, salvianolic acid B and tanshinone IIA can synergistically regulate 24 h UTP, Urea and Scr and improve kidney damage in early DN rats. The metabolic abnormalities of early DN rats were improved by regulating the biosynthesis of saturated fatty acids, glycerol phospholipid metabolism, steroid biosynthesis, alanine, and arachidonic acid. Salvianolic acid B combined with tanshinone IIA at a mass ratio of 13.4:1 can significantly reduce kidney inflammation, up-regulate p-PI3K/PI3K and p-Akt/Akt and down-regulate p-NF-κB/NF-κB, which better than the single-used group and can be reversed by PI3K inhibitor LY294002. CONCLUSION: Salvianolic acid B and tanshinone IIA can synergistically improve glucose and lipid disorders, liver and kidney damage, and resist kidney inflammation in early DN rats, and the mechanism may be related to regulating PI3K/Akt/NF-κB signaling pathway.

[Effect and mechanism of Bovis Calculus on ulcerative colitis by inhibiting IL-17/IL-17RA/Act1 signaling pathway].

This study aimed to elucidate the effect and underlying mechanism of Bovis Calculus in the treatment of ulcerative colitis(UC) through network pharmacological prediction and animal experimental verification. Databases such as BATMAN-TCM were used to mine the potential targets of Bovis Calculus against UC, and the pathway enrichment analysis was conducted. Seventy healthy C57BL/6J mice were randomly divided into a blank group, a model group, a solvent model(2% polysorbate 80) group, a salazosulfapyridine(SASP, 0.40 g·kg~(-1)) group, and high-, medium-, and low-dose Bovis Calculus Sativus(BCS, 0.20, 0.10, and 0.05 g·kg~(-1)) groups according to the body weight. The UC model was established in mice by drinking 3% dextran sulfate sodium(DSS) solution for 7 days. The mice in the groups with drug intervention received corresponding drugs for 3 days before modeling by gavage, and continued to take drugs for 7 days while modeling(continuous administration for 10 days). During the experiment, the body weight of mice was observed, and the disease activity index(DAI) score was recorded. After 7 days of modeling, the colon length was mea-sured, and the pathological changes in colon tissues were observed by hematoxylin-eosin(HE) staining. The levels of tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1ß), interleukin-6(IL-6), and interleukin-17(IL-17) in colon tissues of mice were detected by enzyme-linked immunosorbent assay(ELISA). The mRNA expression of IL-17, IL-17RA, Act1, TRAF2, TRAF5, TNF-α, IL-6, IL-1ß, CXCL1, CXCL2, and CXCL10 was evaluated by real-time polymerase chain reaction(RT-PCR). The protein expression of IL-17, IL-17RA, Act1, p-p38 MAPK, and p-ERK1/2 was investigated by Western blot. The results of network pharmacological prediction showed that Bovis Calculus might play a therapeutic role through the IL-17 signaling pathway and the TNF signaling pathway. As revealed by the results of animal experiments, on the 10th day of drug administration, compared with the solvent model group, all the BCS groups showed significantly increased body weight, decreased DAI score, increased colon length, improved pathological damage of colon mucosa, and significantly inhibited expression of TNF-α,IL-6,IL-1ß, and IL-17 in colon tissues. The high-dose BCS(0.20 g·kg~(-1)) could significantly reduce the mRNA expression levels of IL-17, Act1, TRAF2, TRAF5, TNF-α, IL-6, IL-1ß, CXCL1, and CXCL2 in colon tissues of UC model mice, tend to down-regulate mRNA expression levels of IL-17RA and CXCL10, significantly inhibit the protein expression of IL-17RA,Act1,and p-ERK1/2, and tend to decrease the protein expression of IL-17 and p-p38 MAPK. This study, for the first time from the whole-organ-tissue-molecular level, reveals that BCS may reduce the expression of pro-inflammatory cytokines and chemokines by inhibiting the IL-17/IL-17RA/Act1 signaling pathway, thereby improving the inflammatory injury of colon tissues in DSS-induced UC mice and exerting the effect of clearing heat and removing toxins.

[Protective effects of three kinds of borneol on different brain regions in acute cerebral ischemia/reperfusion model rats].

This study compared the ameliorating effects of L-borneol, natural borneol, and synthetic borneol on the injury of different brain regions in the rat model of acute phase of cerebral ischemia/reperfusion(I/R) for the first time, which provides a reference for guiding the rational application of borneol in the early treatment of ischemic stroke and has important academic and application values. Healthy specific pathogen-free(SPF)-grade SD male rats were randomly assigned into 13 groups: a sham-operation group, a model group, a Tween model group, a positive drug(nimodipine) group, and high-, medium-, and low-dose(0.2, 0.1, and 0.05 g·kg~(-1), respectively) groups of L-borneol, natural borneol, and synthetic borneol according to body weight. After 3 days of pre-administration, the rat model of I/R was established by suture-occluded method and confirmed by laser speckle imaging. The corresponding agents in different groups were then administered for 1 day. The body temperature was monitored regularly before pre-administration, days 1, 2, and 3 of pre-administration, 2 h after model awakening, and 1 d after model establishment. Neurological function was evaluated based on Zea-Longa score and modified neurological severity score(mNSS) 2 h and next day after awakening. The rats were anesthetized 30 min after the last administration, and blood was collected from the abdominal aorta. Enzyme-linked immunoassay assay(ELISA) was employed to determine the serum levels of tumor necrosis factor-alpha(TNF-α), interleukin-6(IL-6), IL-4, and transforming growth factor-beta1(TGF-ß1). The brain tissues were stained with triphenyltetrazolium chloride(TTC) for the calculation of cerebral infarction rate, and hematoxylin-eosin(HE) staining was used for observing and semi-quantitatively evaluating the pathological damage in different brain regions. Immunohistochemistry was employed to detect the expression of ionized calcium binding adapter molecule 1(IBA1) in microglia. q-PCR was carried out to determine the mRNA levels of iNOS and arginase 1(Arg1), markers of polarization phenotype M1 and M2 in microglia. Compared with the sham-operation group, the model group and the Tween model group showed significantly elevated body temperature, Zea-Longa score, mNSS, and cerebral infarction rate, severely damaged cortex, hippocampus, and striatum, increased serum levels of IL-6 and TNF-α, and decreased serum levels of IL-4 and TGF-ß1. The three borneol products had a tendency to reduce the body temperature of rats 1 day after modeling. Synthetic borneol at the doses of 0.2 and 0.05 g·kg~(-1), as well as L-borneol of 0.1 g·kg~(-1), significantly reduced Zea-Longa score and mNSS. The three borneol products at the dose of 0.2 g·kg~(-1) significantly reduced the cerebral infarction rate. L-borneol at the doses of 0.2 and 0.1 g·kg~(-1) and natural borneol at the dose of 0.1 g·kg~(-1) significantly reduced the pathological damage of the cortex. L-borneol and natural borneol at the dose of 0.1 g·kg~(-1) attenuated the pathological damage of hippocampus, and 0.2 g·kg~(-1) L-borneol attenuated the damage of striatum. The 0.2 g·kg~(-1) L-borneol and the three doses of natural borneol and synthetic borneol significantly reduced the serum level of TNF-α, and the 0.1 g·kg~(-1) synthetic borneol reduced the level of IL-6. L-borneol and synthetic borneol at the dose of 0.2 g·kg~(-1) significantly inhibited the activation of cortical microglia, and 0.2 g·kg~(-1) L-borneol up-regulated the expression of Arg1 and down-regulated the expression level of iNOS. In conclusion, the three borneol products may alleviate inflammation to ameliorate the pathological damage of brain regions of rats in the acute phase of I/R by inhibiting the activation of microglia and promoting the polarization of microglia from M1 type to M2 type. The protective effect on brain followed a trend of L-borneol > synthetic borneol > natural borneol. We suggest L-borneol the first choice for the treatment of I/R in the acute phase.

l-Borneol and d-Borneol promote transdifferentiation of astrocytes into neurons in rats by regulating Wnt/Notch pathway to exert neuroprotective effect during recovery from cerebral ischaemia.

BACKGROUND: The Chinese medicines Borneolum and l-Borneolum have neuroprotective effects on acute cerebral ischaemia-reperfusion (IR) in rats. Research on their effects during recovery from cerebral IR is lacking. Cerebral ischaemia can activate astrocytes for conversion into neurons. Neurogenesis cannot be achieved without nutritional support from an improved brain microenvironment through the blood circulation. PURPOSE: The purpose of this study was to determine whether Borneolum and l-Borneolum can promote transdifferentiation of astrocytes into neurons by regulating the Wnt/Notch pathway to exert neuroprotective effects during recovery from cerebral ischaemia. STUDY DESIGN AND METHODS: A suture crossing the external carotid artery to occlude the middle cerebral artery was used to prepare a model of cerebral IR (Longa et al., 1989). The Longa neurological function score, modified neurological severity score, tape removal test and grid misstep experiment were used to evaluate motor nerve function. Triphenyltetrazolium chloride was used to determine the extent of cerebral infarction. Left/right hemisphere contrast was used to measure brain atrophy. Astrocytes labelled with adeno-associated virus were used to track their fate after transdifferentiation. Laser speckle contrast imaging was used to observe the effects of l-Borneolum and Borneolum on cerebral blood flow. Immunofluorescence and western blotting were used to investigate their mechanisms. RESULTS: l-Borneolum and Borneolum significantly improved neurological function and limb movement in rats with cerebral ischaemia during recovery and increased cerebral blood flow. l-Borneolum improved forelimb motor coordination more effectively than Borneolum and promoted transdifferentiation of astrocytes to GABAergic neurons in the striatal region. The expression of Wnt3a and Notch-1 was downregulated. The expression of vascular endothelial growth factor was not significantly changed. Borneolum improved forelimb sensitivity and alleviated cerebral infarction and brain atrophy more effectively than l-Borneolum, which promoted transdifferentiation of astrocytes into neurons and nestin expression and neurogenesis in the striatal zone. The expression of glycogen synthase kinase-3ß and ß-catenin was upregulated. l-Borneolum and Borneolum had no significant neuroprotective effect on the cortex and hippocampus. CONCLUSIONS: l-Borneolum and Borneolum exerted neuroprotective effects on cerebral ischaemia during recovery by promoting neurogenesis and blood circulation in the striatal and subventricular zones. Their mechanisms may be related to the Wnt3a and Notch-1 pathways.

Storax Attenuates Cardiac Fibrosis following Acute Myocardial Infarction in Rats via Suppression of AT1R-Ankrd1-P53 Signaling Pathway.

Myocardial fibrosis following acute myocardial infarction (AMI) seriously affects the prognosis and survival rate of patients. This study explores the role and regulation mechanism of storax, a commonly used traditional Chinese medicine for treatment of cardiovascular diseases, on myocardial fibrosis and cardiac function. The AMI rat model was established by subcutaneous injection of Isoproterenol hydrochloride (ISO). Storax (0.1, 0.2, 0.4 g/kg) was administered by gavage once/d for 7 days. Electrocardiogram, echocardiography, hemodynamic and cardiac enzyme in AMI rats were measured. HE, Masson, immunofluorescence and TUNEL staining were used to observe the degree of pathological damage, fibrosis and cardiomyocyte apoptosis in myocardial tissue, respectively. Expression of AT1R, CARP and their downstream related apoptotic proteins were detected by WB. The results demonstrated that storax could significantly improve cardiac electrophysiology and function, decrease serum cardiac enzyme activity, reduce type I and III collagen contents to improve fibrosis and alleviate myocardial pathological damage and cardiomyocyte apoptosis. It also found that storax can significantly down-regulate expression of AT1R, Ankrd1, P53, P-p53 (ser 15), Bax and cleaved Caspase-3 and up-regulate expression of Mdm2 and Bcl-2. Taken together, these findings indicated that storax effectively protected cardiomyocytes against myocardial fibrosis and cardiac dysfunction by inhibiting the AT1R-Ankrd1-P53 signaling pathway.

Multi-omics analysis reveals the pathogenesis of db/db mice diabetic kidney disease and the treatment mechanisms of multi-bioactive compounds combination from Salvia miltiorrhiza.

Diabetic kidney disease (DKD) is a common diabetic complication. Salvia miltiorrhiza has significant therapeutic effects on diabetes complications, although the mechanism remains unclear. Here, biochemical indicators and pathological changes were used to screen out the optimal Salvia miltiorrhiza multi-bioactive compounds combination. Metabolomics, transcriptomics and proteomics were used to explore the pathogenesis of DKD. RT-PCR and parallel reaction monitoring targeted quantitative proteome analysis were utilized to investigate treatment mechanisms of the optimal Salvia miltiorrhiza multi-bioactive compounds combination. The db/db mice showed biochemical abnormalities and renal lesions. The possible metabolic pathways were steroid hormone biosynthesis and sphingolipid metabolism. The 727 differential genes found in transcriptomics were associated with biochemical indicators via gene network to finally screen 11 differential genes, which were mainly key genes of TGF-ß/Smad and PI3K/Akt/FoxO signaling pathways. Salvia miltiorrhiza multi-bioactive compounds combination could significantly regulate the Egr1, Pik3r3 and Col1a1 genes. 11 differentially expressed proteins involved in the two pathways were selected, of which 9 were significantly altered in db/db mice compared to db/m mice. Salvia miltiorrhiza multi-bioactive compounds combination could callback Q9DBM2, S4R1W1, Q91Y97, P47738, A8DUK4, and A2ARV4. In summary, Salvia miltiorrhiza multi-bioactive compounds combination may ameliorate kidney injury in diabetes through regulation of TGF-ß/Smad and PI3K/Akt/FoxO signaling pathways.

d-Borneol enhances cisplatin sensitivity via autophagy dependent EMT signaling and NCOA4-mediated ferritinophagy.

BACKGROUND: d-Borneol has been widely used as a drug absorption enhancer, but there are few studies on the anti-resistance ability of d-borneol combined with cisplatin in cisplatin-resistant non-small cell lung cancer cells. Ferroptosis, autophagy and epithelial-mesenchymal transition (EMT) have been reported to be associated with drug resistance. PURPOSE: To investigate the molecular mechanisms and sensitizing effects of d-borneol combined with cisplatin to against drug cisplatin resistance from the perspective of ferroptosis, autophagy and EMT resistance. METHODS: H460/CDDP xenograft tumor model was established to verify the antitumor activity and safety in vivo. RNA sequencing was used to predict target molecules and signaling pathways. Reactive oxygen species (ROS) were used as marker of ferroptosis, and its level was determined by a dichlorodihydrofluorescein diacetate fluorescent probe and flow cytometry. Levels of glutathione (GSH), malondialdehyde (MDA), and antioxidants such as superoxide dismutase (SOD) and thioredoxin (Trx) involved in the balance of oxidative stress were measured by an assay kit or enzyme-linked immunosorbent assay. Western blotting and real-time polymerase chain reaction were used to assess the regulatory mechanism of EMT markers, autophagy, and ferroptosis signaling pathways. RESULTS: d-Borneol in combination with cisplatin reduced tumor volume and weight, enhanced tumor-inhibiting effects, and alleviated cisplatin-induced damage to the liver and kidney in vivo. RNA-sequencing showed that differentially expressed genes were enriched in ferroptosis. d-Borneol in combination with cisplatin promoted ROS accumulation, increased the content of MDA levels, and decreased GSH, SOD, Trx, and heme oxygenase-1 expression to induce oxidative damage. d-Borneol combination with cisplatin induced ferroptosis by promoting nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and regulating intracellular iron ion transport via upregulating PRNP and downregulating PCBP2. In addition, d-borneol combined with cisplatin promoted autophagy by upregulating expression of LC3II/ATG5/Beclin-1 and inhibited the EMT by increasing the expression of epithelial marker E-cadherin and decreasing mesenchymal markers (N-cadherin and vimentin) and transcription factors (Snail and ZEB1). CONCLUSION: For the first time, our study implies that d-borneol enhanced cisplatin sensitivity by inducing ferroptosis, promoting autophagy and inhibiting EMT progression, thereby enhancing antitumor activity. It suggests that d-borneol could be developed as a novel chemosensitizers.

Wound Healing Effects of Dracontomelon dao on Bacterial Infection Wounds in Rats and Its Potential Mechanisms under Simulated Space Environment.

Dracontomelon dao (D. dao) is the leaves of Dracontomelon duperreanum Pierre (D. dao auct. non (Blanco) Merr. and Rolfe; D. sinense Stopf.). As a valuable traditional Chinese medicine from Anacardiaceae, D. dao has a long history of treating bedsores, skin ulcers, and other infection diseases. In addition, the volatile oil from D. dao leaves exhibits antitumor effects. However, these reported studies only focused on evaluating the antimicrobial efficacy on model strains in vitro, without paying attention to the antimicrobial activity and anti-inflammatory effects in vivo. This study was aimed to provide evidence of antimicrobial activity and anti-inflammatory and proangiogenesis activities of Dracontomelon dao (D. dao) on the skin of rats under simulated space environment. The weightlessness model of rats in space environment was established. Then, rats were given D. dao for 15 days. Wound healing effects of D. dao on histopathology and inflammatory cytokines in E. coli-induced wound infection in weightless rats were analyzed. Furthermore, the molecular biology technology was performed to evaluate the wound healing effects of D. dao on the relative protein level of NF-κB as well as PI3K/Akt signaling pathways. Immunohistochemistry was used for the protein expression of VEGFA. The wound healing effects of D. dao on bacterially infected wounds in rats were manifested by lowering the size of the wound and significantly increasing the shrinkage rate of the wound. D. dao had effect on alleviating histological damage of skin tissue and downregulation inflammatory cytokines level. In addition, the results indicated that D. dao has a regulatory effect on inflammation and angiogenesis and could regulate the relative protein level of MAPK/NF-κB as well as PI3K/AKT signaling pathways. The current study highlighted the crucial role of D. dao in relieving skin tissue injury in E. coli-induced wound infection in weightless rats by regulating the MAPK/NF-κB as well as PI3K/AKT signaling pathways. This study could provide a new agent for the treatment of bacterial infected wounds in simulated space environment.

BushenHuoxue Recipe for the Treatment of Prethrombotic State of ACA-Positive Recurrent Miscarriage via the Regulation of the PI3K-AKT Signaling Pathway.

BACKGROUND: Although the Bushen Huoxue (BSHX) recipe is commonly used for the effective treatment of the prethrombotic state of recurrent abortions, its mechanism of action is unclear. In this article, we investigated the therapeutic effects of BSHX on anti-cardiolipin antibody (ACA) positive recurrent miscarriage mice and the molecular mechanism involved in the treatment of the prethrombotic state of ACA-positive recurrent miscarriages based on the PI3K-Akt signaling pathway, to provide a scientific basis for clinical practice. METHODS: An ACA-positive recurrent miscarriage mouse model and normal pregnancy mouse model were adopted in this experiment. Seventy CBA/J female mice were induced to establish the ACA-positive recurrent model; the mice were mated with DBA/2 male mice. Of these mice, 50 became pregnant, which were randomly divided into a BSHX high-dose group (BH, 2.52 g/kg), BSHX medium-dose group (BM, 1.26 g/kg), BSHX low-dose group (BL, 0.63 g/kg), model group (M, distilled water), and an aspirin enteric-coated tablet group; each group had 10 mice. In addition, 16 CBA/J female mice were induced to establish the normal pregnant mouse model; the mice were mated with BALB/C male mice. Of these mice, 10 became pregnant, which were used as the blank control group (C) and received distilled water by gavage. Stillbirth and abortion rates were recorded for each group, and the uterine tissue, urine, and serum were collected. The serum expression levels of ACA, interleukin-6 (IL-6), progesterone ,estradiol, and endometrial histological changes were compared between the groups. Metabolomics was performed on the urine and uterine tissues of both groups using UHPLC-QTOF/MS, and the expression levels of PI3K, p-PI3K, AKT, and p-AKT proteins in the uterine tissues were detected using Western blot. RESULTS: Compared with the model pregnancy group, the BSHX high-dose group, BSHX medium-dose group, and BSHX low-dose group all had a lower absorption rate of mouse embryos, improved uterine histopathological morphology, significantly reduced serum levels of ACA and IL-6, increased serum levels of progesterone and estradiol, and significantly upregulated uterine levels of p-AKT, PI3K, and p-PI3K proteins. The metabolomic results showed that the metabolic levels in the urine and uterine tissues were significantly altered in the mouse model of ACA-positive recurrent abortion. The results also suggested that the pathogenesis of ACA-positive recurrent abortion may be associated with metabolic pathways, such as pentose, glucuronide, lysine degradation, and steroid hormone biosynthesis. CONCLUSION: The BSHX recipe improved the uterine histopathological morphology of pregnant mice and promoted vascular formation in uterine tissues. The mechanisms involved the reduction in serum ACA and IL-6 levels, the increment in serumprogesterone and estradiol levels, the upregulation of the levels of p-AKT, PI3K, and p-PI3K proteins, and the activation of the PI3K-Akt signaling pathway. These data will be useful for effective drug research and development.

Combination of mulberry leaf active components possessed synergetic effect on SD rats with diabetic nephropathy by mediating metabolism, Wnt/ß-catenin and TGF-ß/Smads signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Mulberry leaf has attracted much attention due to its excellent curative effect on diabetes and its complications, whether the combination of its effective components have protective and synergistic effect on diabetic nephropathy (DN) in vivo remain unclear. AIM OF THE STUDY: The aim of this study was to investigate the protective and synergistic effect of the combination (MAF1:1 and MAF1:5) of mulberry leaf alkaloids (MA) and flavonoids extract (MF) on DN. MATERIALS AND METHODS: A step by step method consisted of network pharmacological prediction, animal in vivo validation and metabolic mechanism research was used to construct the multi-component-target-pathway network of mulberry leaf against DN. Firstly, the potential components and mechanism of mulberry leaf against DN was explored by network pharmacology analysis. Secondly, DN animal model was established to validate the anti-DN activity of these potential compounds. Thirdly, the metabolomics of serum and urine samples from animal experiments was analyzed to explore the anti-DN mechanism of these potential compounds. RESULTS: The results of network pharmacology demonstrated that a total of 7 compounds detected in MA and MF exhibited anti-DN activity, their mechanism were strongly in connection with metabolic pathways, arachidonic acid metabolism, sphingolipid signaling pathway, etc. The results of animal experiment indicated that MAF1:1 and MAF1:5 significantly relieved metabolic disorders through regulating Wnt/ß-catenin and TGF-ß/Smads signaling pathway, just like MF or MA alone. Metabolomics suggested they could regulate 16 serum and 7 urine endogenous metabolites through arachidonic acid metabolism, phenylalanine metabolism and sphingolipid metabolism, thus alleviated DN. Significantly, MAF1:1 and MAF1:5 might possess synergistic effect considering their therapeutic effects on DN rats were superior to the single use of MA or MF. CONCLUSIONS: MAF1:1 and MAF1:5 possessed protective and synergistic effect on DN rats through multi-target and multi-pathways. These findings were of great scientific significance and application value to reveal the advantage of mulberry leaf in preventing and treating DN.

Recent Progress on the Synergistic Antitumor Effect of a Borneol-Modified Nanocarrier Drug Delivery System.

Borneol, a traditional Chinese medicine, can enhance therapeutic efficacy by guiding the active ingredients to the target site. Reportedly, borneol improves the penetration capacity of the nasal, cornea, transdermal, intestinal, and blood-brain barriers. Although nanotechnology dramatically changed the face of oncology by targeting tumor sites, the efficiency of nanoparticles delivered to tumor sites is very low, with only 0.7% of the total particles delivered. Thus, based on the penetration ability and the inhibition drug efflux of borneol, it was expected to increase the targeting and detention efficacy of drugs into tumor sites in nanocarriers with borneol modification. Borneol modified nanocarriers used to improve drug-targeting has become a research focus in recent years, but few studies in this area, especially in the antitumor application. Hence, this review summarizes the recent development of nanocarriers with borneol modification. We focus on the updated works of improving therapeutic efficacy, reducing toxicity, inhibiting tumor metastasis, reversing multidrug resistance, and enhancing brain targeting to expand their application and provide a reference for further exploration of targeting drug delivery systems for solid tumor treatment.

Storax, A Promising Botanical Medicine for Treating Cardio-Cerebrovascular Diseases: A Review.

In recent years, the incidence and mortality of cardio-cerebrovascular diseases have been increasing year by year, which has become global burden and challenge. Based on the holistic thinking of "brain disease affects the heart" and "heart disease affects the brain," as well as the characteristics of multi-target and multi-path effects of Chinese medicine, Chinese medicine is more advantageous in the treatment of cardio-cerebrovascular diseases. As a botanical medicine, storax is known for its resuscitation, filth avoidance and pain-relieving effects in the treatment of cardio-cerebrovascular diseases. By reviewing and collating the relevant domestic and international literature in the past 10 years, we have sorted out an overview of the medicinal parts, traditional uses and chemical composition of storax. For the first time, based on the idea of "cerebral and cardiac simultaneous treatment," the pharmacological activities and mechanisms of heart and brain protection of storax for treating cardio-cerebrovascular diseases were summarized and analyzed, showing that storax has the pharmacological effects of anti-cerebral ischemia, regulation of blood-brain barrier, bidirectional regulation of the central nervous system, anti-myocardial ischemia, anti-arrhythmia, anti-thrombosis and anti-platelet aggregation. It mainly exerts its protective effects on the brain and heart through mechanisms such as inhibition of inflammatory immune factors, anti-oxidative stress, anti-apoptosis, pro-neovascularization and regulation of NO release. On the basis of the current findings and limitations, the future research strategies and perspectives of storax are proposed, with a view to providing a reference for further application and development of this medicine, as well as contributing new thoughts and visions for the clinical application of "treating brain-heart synchronously".

Application and advantages of zebrafish model in the study of neurovascular unit.

The concept of "Neurovascular Unit" (NVU) was put forward, so that the research goal of Central Nervous System (CNS) diseases gradually transitioned from a single neuron to the structural and functional integrity of the NVU. Zebrafish has the advantages of high homology with human genes, strong reproductive capacity and visualization of neural circuits, so it has become an emerging model organism for NVU research and has been applied to a variety of CNS diseases. Based on CNKI (https://www.cnki.net/) and PubMed (https://pubmed.ncbi.nlm.nih.gov/about/) databases, the author of this article sorted out the relevant literature, analyzed the construction of a zebrafish model of various CNS diseases，and the use of diagrams showed the application of zebrafish in the NVU, revealed its relationship, which would provide new methods and references for the treatment and research of CNS diseases.

A natural product of acteoside ameliorate kidney injury in diabetes db/db mice and HK-2 cells via regulating NADPH/oxidase-TGF-ß/Smad signaling pathway.

This study was designed to investigate the protective effects and mechanisms of acteoside on DKD in diabetes male db/db mice and high glucose-induced HK-2 cells. The diabetes db/db mice were divided randomly into model group, metformin group, irbesartan group, and acteoside group. We observed the natural product of acteoside exhibiting a significant effect in renal protection through analyzing of biochemical indicators and endogenous metabolites, histopathological observations, and western blotting. HK-2 cells subjected to high glucose were used in invitro experiments. The molecular mechanisms of them were investigated by RT-PCR and western blot. Acteoside prevents high glucose-induced HK-2 cells and diabetes db/db mice by inhibiting NADPH/oxidase-TGF-ß/Smad signaling pathway. Acteoside regulated the disturbed metabolic pathway of lipid metabolism, glyoxylate and dicarboxylate metabolism, and arachidonic acid metabolism. We discovered the natural product of acteoside exhibiting a significant effect in renal protection. This study paved the way for further exploration of pathogenesis, early diagnosis, and development of a new therapeutic agent for DKD.

Neonatal surgical outcomes after prenatal diagnosis of complex congenital heart disease: experiences of a perinatal integrated diagnosis and treatment program.

BACKGROUND: This study aimed to evaluate neonatal surgical outcomes of patients diagnosed with complex congenital heart disease (CHD) during pregnancy and treated by the newly initiated "perinatal integrated diagnosis and treatment program (PIDTP)". METHODS: We reviewed clinical data of 207 neonates (surgical age ≤ 28 days) who underwent cardiac surgeries in a single center from January 2017 to December 2018, including 31 patients with referrals from the "PIDTP" (integration group) and 176 patients with routine referral treatment (non-integrated group). RESULTS: In the integration group, median admission age was 0 days and median age at surgery was 4 days. In the non-integrated group, median admission age was 8 days (P = 0.001) and median age at surgery was 13 days (P = 0.001). The emergency surgery rate in patients with duct-dependent defects was 36% in the integration group and 59% (P = 0.042) in the non-integrated group, respectively. The in-hospital mortality was 16% in the integration group and 14% (P = 0.78) in the non-integrated group. The 2-year cumulative survival rate after surgery was 83.9% ± 6.6% in the integration group and 80.3% ± 3.1% (P = 0.744) in the non-integrated group. According to multivariable regression analysis, independent risk factors for early mortality of overall neonatal cardiac surgery were low body weight, high serum lactate level, postoperative extracorporeal membrane oxygenation (ECMO) support and prolonged cardiopulmonary bypass (CPB) time. CONCLUSIONS: PIDTP shortens the postnatal transit interval, reduces the emergency operation rate of neonatal critical CHD, and provides better preoperative status for surgery. Patients treated by the PIDTP tend to have more complicated anatomical deformity and a greater requirement for the operation and postoperative management, but early outcome and follow-up prognosis are satisfactory.

Protective effects and mechanisms of Rehmannia glutinosa leaves total glycoside on early kidney injury in db/db mice.

The spontaneous db/db mice were used to elucidate the biological effects and mechanisms of Rehmannia glutinosa leaves total glycoside (DHY) on kidney injury through biochemical indicators, kidney pathological section analysis, metabolic profiling, intestinal flora analysis and in vitro Human renal tubular epithelial (HK-2) cell model induced by high glucose. It was found that DHY can decrease the blood sugar level (insulin, INS; fasting blood glucose, FBG), blood lipid level (Total Cholesterol, T-CHO; Triglyceride, TG) significantly and improve kidney injury level (blood urea nitrogen, BUN; urine microalbumin, mALB; serum creatinine, Scr). It can also alleviate kidney tubular epithelial cell oedema and reduce interstitial connective tissue hyperplasia of the injury kidney induced by high glucose. 13 endogenous metabolites were identified in serum, which involved of ether lipid metabolism, sphingolipid metabolism, glyoxylic acid and dicarboxylic acid metabolism and arachidonic acid metabolism. High glucose can also lead to the disorder of intestinal flora, especially Firmicutes and Bacteroides. Meanwhile, DHY also inhibited the expression of α-SMA, TGF- ß1, Smad3 and Smad4 in the kidney tissues of db/db mice and HK-2 cells. To sum up, DHY may restore the dysfunctional intestinal flora to normal and regulate glycolipid level of db/db mice as well as TGF-ß/Smad signalling pathway regulation to improve early kidney damage caused by diabetes.

Antibacterial evaluation of plants extracts against ampicillin-resistant Escherichia coli (E. coli) by microcalorimetry and principal component analysis.

Antibiotics abuse has caused increased bacterial resistance, which severely limits the application of antibiotics to the treatment of bacterial infections. Therefore, it is urgent to develop new antibacterial drugs through other sources. Dracontomelon dao (Blanco) Merr. & Rolfe (Ren Mianzi in Chinese) is a traditional medicinal material derived from Anacardiaceae with a long history of treating various infectious diseases, such as decubitus and skin ulcers. Recent research has indicated that different extracts from the leaves of D. dao, especially the ethyl acetate (EtOAc) fraction containing flavonoids and phenolic acids, exhibit potent antibacterial activities. In this research, the combined anti-drug-resistant bacterial activities of these active ingredients were investigated. Six samples (S1-S6) were obtained from the EtOAc fraction of D. dao leaves. Microcalorimetric measurements and principal component analysis were performed on the in vitro samples. The results showed that all six samples had notable antibacterial activities. Specifically, sample S6 exhibited a prominent antibacterial effect, with an IC50 value of 84.3 µg mL-1, which was significantly lower than that of other samples. The relative contents of main flavonoids and phenolic acids in S6 sample were confirmed by UPLC/Q-TOF-MS. In conclusion, sample S6 from the EtOAc fraction of D. dao leaves could be used as a potential antimicrobial resource in the treatment of infectious diseases. This work provides an insight into the effect of traditional Chinese medicine on drug-resistant bacteria. Moreover, the purification and characterization of the chemical compounds from the sample S6 deserve further analysis.

Investigation of dynamic accumulation and regularity of nine glycosides and saccharides in Rehmannia glutinosa by rapid quantitative analysis technology.

In the process of planting and harvesting of Rehmannia glutinosa, only the underground part is used, and a large number of stems and leaves that are considered non-medicinal parts are usually discarded. Recent studies have shown that the chemical components in the leaves are similar to those identified in the roots. In this study, we selected leaves and roots from Rehmannia glutinosa at different growth stages and leaves from different cultivation regions to investigate the dynamic accumulation of three kinds of glycosides (catalpol, acteoside, and ajugol), six kinds of carbohydrates (rhamnose, fructose, sucrose, melibiose, stachyose, and verbascose), and acidic and neutral polysaccharides via rapid quantitative analysis technology, including ultra high performance liquid chromatography triple quadrupole tandem mass spectrometry, high-performance liquid chromatography, and UV spectroscopy. The results showed that the Rehmannia glutinosa leaves also contained higher content of catalpol (3.81∼24.51 mg/g), ajugol (0.55∼10.23 mg/g), acteoside (1.34∼21.16 mg/g), monosaccharide/ oligosaccharides (7.71∼120.73 mg/g), and polysaccharides (5.63∼15.57%). In this study, we developed a new rapid and simple method for determination to clarify the distribution and dynamic accumulation of nine glycosides and saccharides in Rehmannia glutinosa leaves to provide a scientific basis for the discovery, development, and utilization of the resource value of Rehmannia glutinosa leaves.

[Efficacy and safety of Saw Palmetto Extract Capsules in the treatment of benign prostatic hyperplasia].

OBJECTIVE: To assess the efficacy and safety of Saw Palmetto Extract Capsules in the treatment of benign prostatic hyperplasia (BPH). METHODS: We conducted a multi-centered open clinical study on 165 BPH patients treated with Saw Palmetto Extract Capsules at a dose of 160 mg qd for 12 weeks. At the baseline and after 6 and 12 weeks of medication, we compared the International Prostate Symptom Scores (IPSS), prostate volume, postvoid residual urine volume, urinary flow rate, quality of life scores (QOL), and adverse events between the two groups of patients. RESULTS: Compared with the baseline, both IPSS and QOL were improved after 6 weeks of medication, and at 12 weeks, significant improvement was found in IPSS, QOL, urinary flow rate, and postvoid residual urine. Mild stomachache occurred in 1 case, which necessitated no treatment. CONCLUSION: Saw Palmetto Extract Capsules were safe and effective for the treatment of BPH.

[Quantification of metallothionein induced with selenium by using competitive ELISA].

Metallothionein induced by selenium was assayed with competitive ELISA. It was found that in control mice, the liver contained (2.47+/-0.90) microgram MT/g wet weight tissue, while the mice administered with ZnSO(4) contained (8.15+/-2.20) microgram MT/g wet weight liver tissue and the mice given with selenium malt contained (12.80+/-1.44) microgram MT/g wet weight liver. A significant difference was found between the control and the latter two groups (P<0.05, P<0.05). The MT content of selenium group was significantly higher than the zinc group. It is suggested that the selenium was more potent in induction of MT and was a stronger inducer than ZnSO(4) in its effective dose range, therefore selenium may be developed into a novel and safe MT inducer.