Polydopamine-coated mesoporous silica nanoparticles co-loaded with Ziyuglycoside I and Oseltamivir for synergistic treatment of viral pneumonia.

Viral pneumonia (VP) is a serious health risk to humans, however, there is still a lack of specific treatments for VP. The spread of the virus in the body induces an excessive inflammatory response that can cause chronic or irreversible damage to lungs. Hence, VP treatment requires rapid clearance of the virus and sustained inflammation control. In this study, an innovative mesoporous silica medication delivery system co-loaded with Ziyuglycoside I(ZgI) and Oseltamivirv(OST) in fast and slow monomeric forms ZgI@MSNs-OST@ Polydopamine (PDA) was prepared for targeted treatment of VP. The prepared ZgI@MSNs-OST@PDA nanoparticles had a homogeneous and membrane-encapsulated spherical structure, with an average particle size of approximately 760 nm. in vitro release and in vivo pharmacokinetic studies demonstrated that ZgI@MSNs-OST@PDA achieved immediate release of OST and sustained release of ZgI, which was readily taken up by the cells. In vitro anti-H1N1 virus experiments showed that nanoparticles rapidly killed the virus in host cells, and the anti-inflammatory effect was sustained and long-lasting, providing excellent protection to host cells. In vivo antiviral pneumonia experiments confirmed the rapid clearance of influenza viruses from mouse lungs and the effective control of overactivated immune responses by ZgI@MSNs-OST@PDA nanoparticles. Through a mechanistic study, we found that the treatment of viral pneumonia with nanoparticles was associated with inhibition of the NLRP3 inflammasome pathway. In conclusion, the constructed nanoparticles achieved synergistic therapeutic effects of ZgI and OST on VP, that is, rapid killing of influenza viruses by OST and effective control of the virus-induced hyperinflammatory response by ZgI.

Recent Advances in the Study of the Immune Escape Mechanism of SFTSV and Its Therapeutic Agents.

Sever fever with thrombocytopenia syndrome (SFTS) is a new infectious disease that has emerged in recent years and is widely distributed, highly contagious, and lethal, with a mortality rate of up to 30%, especially in people with immune system deficiencies and elderly patients. SFTS is an insidious, negative-stranded RNA virus that has a major public health impact worldwide. The development of a vaccine and the hunt for potent therapeutic drugs are crucial to the prevention and treatment of Bunyavirus infection because there is no particular treatment for SFTS. In this respect, investigating the mechanics of SFTS-host cell interactions is crucial for creating antiviral medications. In the present paper, we summarized the mechanism of interaction between SFTS and pattern recognition receptors, endogenous antiviral factors, inflammatory factors, and immune cells. Furthermore, we summarized the current therapeutic drugs used for SFTS treatment, aiming to provide a theoretical basis for the development of targets and drugs against SFTS.

Synthesis and bioactivity evaluation of pachymic acid derivatives as potential cytotoxic agents.

Pachymic acid, a well-known natural lanostane-type triterpenoid, exhibits various pharmacological properties. In this study, 18 derivatives of pachymic acid were synthesized by modifying their molecular structures and evaluated for their anticancer activity against two human cancer cell lines using the CCK-8 assay. Structure-activity relationship studies according to the in vitro cytotoxicity unexpectedly found one promising derivative A17 (namely tumulosic acid, also found in Poria cocos), which had stronger anti-proliferative activity than the positive drug cisplatin against HepG2 and HSC-2 cell lines with IC50 values of 7.36 ± 0.98 and 2.50 ± 0.15 µM, respectively. Further pharmacological analysis demonstrated that A17 induced HSC-2 cell cycle arrest at the S phase, cell apoptosis, and autophagy. Western blotting confirmed the regulatory effects of A17 on cell cycle arrest-, apoptosis-, and autophagy-related proteins expression. In addition, A17 regulated the AKT and AMPK pathways in HSC-2 cells. These results demonstrated that A17 possesses great potential as an anticancer agent.

Lithocarpus polystachyus (Sweet Tea) water extract promotes human hepatocytes HL7702 proliferation through activation of HGF/AKT/ERK signaling pathway.

Objective: Sweet Tea (ST), derived from the leaves of Lithocarpus polystachyus, is a Chinese folk medicine with wide pharmacological activities. However, the promotive effects of ST water extract on hepatocytes proliferation and its underlying mechanism remains still unknown. In the present study, the beneficial effects of ST water extract on human hepatocytes and its possible mechanism were investigated. Methods: MTT assay was used to detect the safety range of ST; HL7702 cells were divided into four groups: control group, ST low- (50 µg/mL), medium- (200 µg/mL) and high-concentration (800 µg/mL) groups; BrdU ELISA and EDU staining were used to observe DNA content and cell proliferation; Moreover, flow cytometry was applied to analyze the distribution of cell cycle. Furthermore, the expression of cyclin D1, CDK4, HGF/c-Met, Akt, Erk1/2 were detected by Western blot. Results: It was found that ST water extract concentration-dependent promoted human hepatocytes HL7702 cell proliferation within 72 h through accumulating the cells in S phase and G2/M phase. Furthermore, ST water extract up-regulated expression of Cyclin D1 and CDK4 proteins. Moreover, ST water extract not only increased HGF expression and phosphorylation of c-Met level, but also activated the phosphorylation levels of AKT, ERK1/2. Interestingly, both of AKT inhibitor A6730 and ERK1/2 inhibitor U0126 reversed the promotive effects of ST water extract, which further confirmed that activation of AKT and ERK1/2 were involved. Conclusion: The findings reveal that ST water extract promoted HL7702 cells proliferation through the stimulation of cell cycle mediated by activating the AKT- and ERK1/2-related pathway.

Pharmacological profiles and therapeutic applications of pachymic acid (Review).

Poria cocos is a saprophytic fungus that grows in diverse species of Pinus. Its sclerotium, called fu-ling or hoelen, has been used in various traditional Chinese medicines and health foods for thousands of years, and in several modern proprietary traditional Chinese medicinal products. It has extensive clinical indications, including sedative, diuretic, and tonic effects. Pachymic acid (PA) is the main lanostane-type triterpenoid in Poria cocos. Evidence suggests that PA has various biological properties such as cytotoxic, anti-inflammatory, antihyperglycemic, antiviral, antibacterial, sedative-hypnotic, and anti-ischemia/reperfusion activities. Although considerable advancements have been made, some fundamental and intricate issues remain unclear, such as the underlying mechanisms of PA. The present study aimed to summarize the biological properties and therapeutic potential of PA. The biosynthetic, pharmacokinetic, and metabolic pathways of PA, and its underlying mechanisms were also comprehensively summarized.

Trilobatin, a Naturally Occurring Food Additive, Ameliorates Exhaustive Exercise-Induced Fatigue in Mice: Involvement of Nrf2/ARE/Ferroptosis Signaling Pathway.

Nrf2-mediated oxidative stress is a promising target of exhaustive exercise-induced fatigue (EEIF). Trilobatin (TLB) is a naturally occurring food additive with antioxidant effect and Nrf2 activation potency. The present study aimed to investigate the effect of TLB on EEIF and elucidate its underlying mechanism. Our results showed that TLB exerted potent anti-EEIF effect, as reflected by the rope climbing test and exhaustive swimming test. Moreover, TLB also effectively reduced the levels of lactate, creatine kinase, and blood urea nitrogen, and increased liver glycogen and skeletal muscle glycogen in mice after EEIF insult. Additionally, TLB also balanced the redox status as evidenced by decreasing the generation of reactive oxygen species and improving the antioxidant enzyme activities including superoxide dismutase, catalase, and glutathione peroxidase, as well as the level of glutathione both in the tissue of muscle and myocardium. Furthermore, TLB promoted nuclear factor erythroid 2-related factor 2 (Nrf2) from the cytoplasm to the nucleus, and upregulated its downstream antioxidant response element (ARE) including quinone oxidoreductase-1 and heme oxygenase-1. Intriguingly, TLB also upregulated the GPx4 protein expression and reduced iron overload in mice after EEIF insult. Encouragingly, the beneficial effect of TLB on EEIF-induced oxidative stress and ferroptosis were substantially abolished in Nrf2-deficient mice. In conclusion, our findings demonstrate, for the first time, that TLB alleviates EEIF-induced oxidative stress through mediating Nrf2/ARE/ferroptosis axis.

Anticancer potential of indirubins in medicinal chemistry: Biological activity, structural modification, and structure-activity relationship.

Indirubin is the crucial ingredient of Danggui Longhui Wan and Qing-Dai, traditional Chinese medicine herbal formulas used for the therapy of chronic myelocytic leukemia in China for hundreds of years. Although the monomeric indirubin has been used in China for the treatment human chronic myelocytic leukemia. However, due to low water solubility, poor pharmacokinetic properties and low therapeutic effects are the major obstacle, and had significantly limited its clinical application. Consequently, the attractive anticancer profile of indirubin has enthused numerous researchers to discover novel indirubin derivatives with improved pharmacodynamic activity as well as good pharmacokinetic property. In this paper, we comprehensively review the recent progress of anticancer potential of indirubins, structural modification and structure-activity relationship, which may provide useful direction for the further development of novel indirubins with improved pharmacological profiles for the treatment of various types of cancer.

Comparison of the curative effect of modified medial arc incision of achilles tendon and traditional straight incision in the treatment of old achilles tendon rupture.

Modified medial arc incision of Achilles tendon and traditional straight incision were applied to treat 50 cases of old rupture of Achilles tendon. Among them, there were 20 cases involved in the modified medial arc incision of Achilles tendon (group A).Furthermore, 30 cases accepted traditional straight incision treatment (group B). The same rehabilitation program was applied in both groups, combined with the evaluation using the clinical objective examination, subjective satisfaction of patients and the American Orthopaedic Foot and Ankle Society (AOFAS) scores. There was significant difference between group A and group B in the recovery time to normal motion ranges (P<0.05). The average AOFAS score of group A was higher more than (P<0.05). In addition, patients from the two groups did not suffer from cutaneous sensory disturbance of the dorsum of foot due to sural nerve injury, or no deep venous thrombosis. Except for 1 patient with deep infection, all patients recovered to normal motion ranges. The overall curative effect of modified medial arc incision of Achilles tendon is superior to traditional straight incision in the treatment of old Achilles tendon rupture, which is conducive to the early recovery to normal motion ranges before injury.

Trilobatin Protects Against Aß25-35-Induced Hippocampal HT22 Cells Apoptosis Through Mediating ROS/p38/Caspase 3-Dependent Pathway.

Emerging evidence reveals that an aberrant accumulation of ß-amyloid (Aß) is the main reason of Alzheimer's disease (AD) pathogenesis. Thus, inhibition of Aß-induced neurotoxicity may be promising therapeutic tactics to mitigate AD onset and advance. The development of agent candidates by cultured neurons against Aß-induced cytotoxicity is widely accepted to be an efficient strategy to explore the drug for AD patients. Previously, we have revealed that trilobatin (TLB), a small molecule monomer, derives from Lithocarpus polystachyus Rehd, possessed antioxidative activities on hydrogen peroxide-induced oxidative injury in PC12 cells. The present study was designed to investigate the effects and the underlying mechanism of TLB on Aß-induced injury in hippocampal HT22 cells. The results demonstrated that TLB attenuated Aß25-35-induced HT22 cell death, as evidenced by MTT assay and LDH release. Furthermore, TLB dramatically mitigated cell death after Aß25-35 insulted via decreasing the intracellular and mitochondrial ROS overproduction and restoring antioxidant enzyme activities, as well as suppressing apoptosis. Of note, Aß25-35 triggered increase in ratio of Bax/Bcl-2, activation of caspase-3, phosphorylation of tau, JNK, p38 MAPK, and decrease in Sirt3 expression, whereas TLB reversed these changes. Intriguingly, TLB could directly bind to p38, as evidenced by molecular docking and p38 inhibitor. Taken together, the results reveal that TLB effectively protects against Aß25-35-induced neuronal cell death via activating ROS/p38/caspase 3-dependent pathway. Our findings afford evidence for the potential development of TLB to hinder neuronal death during AD.

Novel hybrids of podophyllotoxin and formononetin inhibit the growth, migration and invasion of lung cancer cells.

In this study, three hybrids of podophyllotoxin and formononetin were synthesized and evaluated for anticancer efficacy. Some of the derivatives exhibited potent cytotoxicity against a panel of human and mouse cancer cell lines, with IC50 values in the low micromolar to submicromolar range. Evaluation against A549 lung tumor cell line identified that the IC50 value of compound 10a was 0.753 µM, indicating that 10a was 2.568-fold more efficacious than parent podophyllotoxin. Mechanistic studies revealed that 10a induced A549 cell apoptosis mainly via caspase pathway, as well as disrupted the microtubule organization by occupying the colchicine binding site of the tubulin. Moreover, wound healing assay and transwell invasion assay indicated that 10a displayed potent inhibitory effects on invasion and migration in A549 cancer cells. In additiona, a decrease in vimentin immunostaining was also observed in A549 cells after treatment with 10a. Overall, hybrid 10a might be a promising candidate for the potential treatment of human lung carcinoma.

Development and In Vivo Evaluation of Ziyuglycoside I-Loaded Self-Microemulsifying Formulation for Activity of Increasing Leukocyte.

Ziyuglycoside I (ZgI), a major effective ingredient of Sanguisorba officinalis L, has shown good activity in increasing leukocyte of myelosuppression mice. However, oral ZgI therapy has been deterred by poor bioavailability because of its low aqueous solubility and permeability. Our study was to develop ZgI-loaded self-microemulsifying drug delivery system (SMEDDS) and evaluate its intestinal absorption, and pharmacokinetic and pharmacodynamic activity for increasing leukocyte. The formulation was designed and optimized by measuring the equilibrium solubility of ZgI in different vehicles and the pseudoternary phase diagram. Further, morphology, particle size, stability, in vitro release, in situ single-pass intestinal perfusion (SPIP), in vivo activity, and in vivo pharmacokinetic (PK) of ZgI-SMEDDS were charactered or studied. Optimized formulations for in vitro dissolution were Obleique CC497, Tween-20, and Transcutol HP with a proportion of 0.25/0.45/0.30 via D-optimal mixture design. Results showed that the solubility of ZgI was enhanced up to 23.93 mg/g and its average particle size was 207.92 ± 2.13 nm. The release of ZgI had been greatly improved by the SMEDDS. In SPIP, the intestinal absorption of SMEDDS was much better than plain ZgI. In PK, we found the oral bioavailability of ZgI-SMEDDS was 6.94-fold higher absolute bioavailability (21.94 ± 4.67) % than ZgI (3.16 ± 0.89) %. The most important was that the mice WBC of ZgI-SMEDDS group was significantly higher than that of the ZgI group. Our study suggested that SMEDDS could increase the solubility of ZgI, which was beneficial to improve oral bioavailability and enhance biological activity.

Lithocarpus polystachyus Rehd. leaves aqueous extract protects against hydrogen peroxide­induced SH-SY5Y cells injury through activation of Sirt3 signaling pathway.

Lithocarpus polystachyus Rehd. (sweet tea; ST) leaves is a type of Chinese folkloric medicine from southern China. The purpose of the present study was to explore the neuroprotective effect of ST, and to explore its underlying mechanisms in hydrogen peroxide (H2O2)­induced neuronal cell injury in cultured human neuroblastoma. H2O2 was used as oxidant inducer and human SH­SY5Y neuroblastoma cells were treated with various concentrations of ST. Cell viability and cell death were detected using MTT and LDH assays, respectively. Additionally, the production of intracellular and mitochondrial reactive oxygen species (ROS) were determined by 2',7'­dichlorodihydrofluorescein diacetate (DCFH­DA) and MitoSOX Red, respectively. The production of malondialdehyde (MDA), reduced glutathione (GSH) level, glutathione peroxidase (GSH­Px), superoxide dismutase (SOD) activities, and NAD+/NADH ratio were confirmed using relevant kits. The expression of adenosine monophosphate­activated protein kinase (AMPK), peroxisome proliferator­activated receptor coactivator (PGC)­1α, Sirt3, isocitrate dehydrogenase (IDH)2, forkhead boxO3a (Foxo3a), and SOD2 were analyzed by western blot analysis. It was demonstrated that pre­treatment with ST enhanced cell viability and repressed cell death, and it also reduced intracellular and mitochondrial ROS accumulation. Additionally, ST attenuated MDA production and enhanced GSH level, GSH­Px and SOD activities. Furthermore, ST not only increased NAD+/NADH ratio, but also inhibited the decrease of AMPK, PGC­1α, Sirt3, IDH2, Foxo3a, and SOD2. The present study revealed that ST exerts protective effects against oxidative stress­induced SH­SY5Y cells injury, and the underlying mechanisms are, at least partly, associated with its antioxidant capacity and function through mitochondrial Sirt3 signaling pathway.

Design, synthesis and antineoplastic activity of novel hybrids of podophyllotoxin and indirubin against human leukaemia cancer cells as multifunctional anti-MDR agents.

To overcome cancer drug resistance, in present study, a series of podophyllotoxin-indirubin hybrids were designed, synthesized, and evaluated for anticancer efficacy against two human chronic myeloid leukemia cell cultures. Among them, compound Da-1 was the most potent in resistent K562/VCR cells with an IC50 value of 0.076 ±â€¯0.008 µM. Preliminary mechanism studies showed that Da-1 significantly induced apoptosis and cell cycle arrest at the G2 phase. Decrease in mitochondrial membrane potential, accompanied by activated PARP cleavage, was observed in K562/VCR cells after incubation with Da-1. Meanwhile, Da-1 caused the accumulation of intracellular ROS, regulated JNK and AKT signaling, and down-regulated the expression levels of P-gp and MRP1 proteins. Importantly, Western blotting revealed that Da-1 could induce K562/VCR cells autophagy, by increasing the levels of Beclin1 and LC3-II. Finally, Da-1 could disrupt microtubule organization, and binding mode to tubulin was investigated by using molecular modeling. Together, Da-1 was a novel hybrid with potent antiproliferative activity and might be a promising agent for the treatment of drug-resistant leukemia cancer.

Icariside II, a PDE5 inhibitor from Epimedium brevicornum, promotes neuron-like pheochromocytoma PC12 cell proliferation via activating NO/cGMP/PKG pathway.

Icariside II (ICS II), a phosphodiesterase 5 inhibitor (PDE 5-I), is a major ingredient of Epimedium brevicornum, with wide spectrum of neuroprotective properties. However, little is known about the potential beneficial effect of ICS II on neuronal cell proliferation, and its possible underlying mechanism remains still unclear. We hypothesized that the beneficial effect of ICS II on neuron-like highly differentiated rat pheochromocytoma (PC12) cell proliferation is correlated with the nitric oxide (NO) signaling pathway and its upstream of PI3K/AKT pathway. PC12 cells were treated with ICS II alone or together with L-NMMA, H89, KT-5823, and/or LY294002 (the inhibitor of NOS, PKA, PKG, PI3K, respectively). It was found that ICS II concentration-dependently promoted PC12 cells proliferation, and cell cycle analysis showed that the proportion of ICS II-treated PC12 cells in S phase was higher than that of control. Moreover, ICS II at the appropriate concentration (100 µM) not only increased nNOS expression, NO production, but also enhanced cGMP content and PKG activity. The addition of L-NMMA and KT-5 823 significantly inhibited the effects of ICS II on nNOS expression, NO production and PKG activity. Furthermore, LY294002 significantly decreased p-AKT level, NOS activity, NO production and nNOS expression, but it did not affect iNOS expression. These findings demonstrate that the beneficial effect of ICS II on neuronal cell proliferation, and its possible underlying mechanisms are, at least partly, through activating AKT/nNOS/NO/cGMP/PKG signaling pathway.

Synthesis and antiviral bioactivities of alpha-aminophosphonates containing alkoxyethyl moieties.

A simple, efficient, and general method has been developed for the synthesis of various alpha-aminophosphonate derivatives 4a-4l by treatment of substituted benzaldehydes and aniline with bis(2-methoxyethyl)- or bis(2-ethoxyethyl) phosphite under microwave irradiation without solvents and catalysts. The products were characterized by elemental analysis, IR, 1H-NMR, 13C- and 31P-NMR spectra. The X-ray crystallographic data of the representative compound 4l was determined. The new alpha-aminophosphonate derivatives were found to possess moderate to good antiviral activity.