Cuicui Liu

Natural products for treatment of osteoporosis: The effects and mechanisms on promoting osteoblast-mediated bone formation

Osteoporosis is a systemic metabolic bone disease characterized by a reduction in bone mass, bone quality, and microarchitectural deterioration. An imbalance in bone remodeling that is caused by more osteoclast-mediated bone resorption than osteoblast-mediated bone formation results in such pathologic bone disorder. Traditional Chinese medicines (TCM) have long been used to prevent and treat osteoporosis and have received extensive attentions and researches at home and abroad, because they have fewer adverse reactions and are more suitable for long-term use compared with chemically synthesized medicines. Here, we put the emphasis on osteoblasts, summarized the detailed research progress on the active compounds derived from TCM with potential anti-osteoporosis effects and their molecular mechanisms on promoting osteoblast-mediated bone formation. It could be concluded that TCM with kidney-tonifying, spleen-tonifying, and stasis-removing effects all have the potential effects on treating osteoporosis. The active ingredients derived from TCM that possess effects on promoting osteoblasts proliferation and differentiation include flavonoids, glycosides, coumarins, terpenoids (sesquiterpenoids, monoterpenoids, diterpenoids), phenolic acids, phenols and others (tetrameric stilbene, anthraquinones, diarylheptanoids). And it was confirmed that the bone formation effect induced by the above natural products was regulated by the expressions of bone specific matrix proteins (ALP, BSP, OCN, OPN, COL I), transcription factor (Runx2, Cbfa1, Osx), signal pathways (MAPK, BMP), local factors (ROS, NO), OPG/RANKL system of osteoblasts and estrogen-like biological activities. All the studies provided theoretical basis for clinical application, as well as new drug research and development on treating osteoporosis.

Repair of spinal cord injury by implantation of bFGF-incorporated HEMA-MOETACL hydrogel in rats.

There is no effective strategy for the treatment of spinal cord injury (SCI). An appropriate combination of hydrogel materials and neurotrophic factor therapy is currently thought to be a promising approach. In this study, we performed experiments to evaluate the synergic effect of implanting hydroxyl ethyl methacrylate [2-(methacryloyloxy)ethyl] trimethylammonium chloride (HEMA-MOETACL) hydrogel incorporated with basic fibroblast growth factor (bFGF) into the site of surgically induced SCI. Prior to implantation, the combined hydrogel was surrounded by an acellular vascular matrix. Sprague–Dawley rats underwent complete spinal cord transection at the T-9 level, followed by implantation of bFGF/HEMA-MOETACL 5 days after transection surgery. Our results showed that the bFGF/HEMA-MOETACL transplant provided a scaffold for the ingrowth of regenerating tissue eight weeks after implantation. Furthermore, this newly designed implant promoted both nerve tissue regeneration and functional recovery following SCI. These results indicate that HEMA-MOETACL hydrogel is a promising scaffold for intrathecal, localized and sustained delivery of bFGF to the injured spinal cord and provide evidence for the possibility that this approach may have clinical applications in the treatment of SCI.

Biotoxins for cancer therapy.

In recent times, a number of studies have provided evidence that biotoxins present great potential as antitumor agents, such as snake venom, bee venom, some bacteria toxins and plant toxins, and thus could be used as chemotherapeutic agents against tumors. The biodiversity of venoms and toxins make them a unique source from which novel anticancer agent may be developed. Biotoxins, also known as natural toxins, include toxic substances produced by plants, animals and microorganisms. Here, we systematically list representative biological toxins that have antitumor properties, involving animal toxins, plant toxins, mycotoxins as well as bacterial toxins. In this review, we summarize the current knowledge involving biotoxins and the active compounds that have anti-cancer activity to induce cytotoxic, antitumor, immunomodulatory, and apoptotic effects in different tumor cells in vivo or in vitro. We also show insights into the molecular and functional evolution of biotoxins.

Therapeutical Strategies for Spinal Cord Injury and a Promising Autologous Astrocyte-Based Therapy Using Efficient Reprogramming Techniques

Spinal cord injury (SCI) is a traumatic event resulting in disturbances to normal sensory, motor, or autonomic functions, which ultimately impacts a patient’s physical, psychological, and social well-being. Until now, no available therapy for SCI can effectively slow down or halt the disease progression. Compared to traditional treatments, e.g., medication, surgery, and functional electrical stimulation, stem cell replacement therapy shows high potential for repair and functional plasticity. Thus, stem cell therapy may provide a promising strategy in curative treatment of SCI, specifically when considering the requirement of neuron replenishment in the spinal cord after distinct acute injuries. However, the therapeutic application of neural stem cells (NSCs) still faces enormous challenges, such as ethical issues, possible inflammatory reactions, graft rejection, and tumor formation. Therefore, it is of vital interest to identify more suitable sources of cells with stem cell potential, which might potentially be harnessed for local neural repair. Due to abovementioned possible drawbacks, these cells should be autologous. Reprogramming of astrocytes to generate the desired neuronal cell types would open the door to autologous cell transplantation and treatment of SCI without possible severe side effects. In this paper, we review the relevant therapeutic strategies for SCI, and conversion of astrocyte into NSCs, suggesting this procedure as a possible treatment option.

Recent strategies for efficient production of polyhydroxyalkanoates by micro-organisms.

Polyhydroxyalkanoates (PHAs) are polyesters accumulated by many bacteria under unbalanced growth conditions, and have been used to meet the various demands in areas of agriculture, medicine, and materials especially belong to a rapidly expanding area of biomedical research. Unfortunately, the high production cost than the traditional synthetic materials has greatly limited the wide application of PHA. Here, we systematically summarized recent progress in production of PHAs and a series of optimization strategies such as supplying renewable carbon substrates, developing better bacterial strains, optimization of fermentation processes, engineering new pathways and etc., were applied to reduce production cost, therefore providing many new ideas and methods for the production of PHAs in economically viable processes. This is believed to be a comprehensive report to show different strategies and methods for low‐cost production of PHAs. Further studies are still needed to make PHAs more and more economically viable to meet a wide range of applicability.

Application of bee venom and its main constituent melittin for cancer treatment

Bee venom and its main constituent melittin (MEL) have been extensively studied in the treatment of tumors. However, the non-specific cytotoxicity and hemolytic activity have hampered the clinical application. Currently, a number of research groups have reported a series of optimization strategies, including gene therapy, recombinant immunotoxin incorporating MEL or MEL nanoparticles, targeting tumor cells to attenuate the cytotoxicity and improve its antitumor efficiency and therapeutic capabilities, which have shown very promising in overcoming some of these obstacles. In this review, we summarize the current knowledge regarding anticancer effects of bee venom and its main compound MEL on different kinds of tumor cells as well as elucidate their possible anticancer mechanisms. It could be concluded that MEL exerts multiple effects on cellular functions of cancerous cells such as proliferation, apoptosis, metastasis, angiogenesis as well as cell cycle, and the anticancer processes involve diverse signal molecules and regulatory pathways. We also highlight the recent research progress for efficient delivery of MEL peptide, thus providing new ideas and hopeful strategies for the in vivo application of MEL.

MicroRNA-Mediated Reprogramming of Somatic Cells into Neural Stem Cells or Neurons

Cellular reprogramming is a promising strategy to generate neural stem cells (NSCs) or desired subtype-specific neurons for cell-based therapeutic intervention. By far, the intricate cell event like reprogramming of non-neural cells to desired cell types can be achieved by forced expression of lineage-related transcription factors (TFs), nuclear transfer, a defined set of factors, and via non-coding microRNAs (miRNAs), as well as other precisely defined conditions. In addition, scientists have been trying to develop better approaches for reprogramming, either by using distinct combinations of a set of small molecules and certain TFs or delivery of appropriate small molecules and miRNAs. The miRNA-mediated approach is fascinating because of its potential to rapidly generate a variety of therapeutically desired cell types from other cell lineages. Recent studies have made great progress in miRNA-mediated neural reprogramming of somatic cells to various specific neuronal subtypes with more efficiency even though the exact mechanisms remain to be further explored. Based on key roles of miRNAs in neural reprogramming across differentiated cell lineages, it is of vital interest to summarize the recent knowledge regarding the instructive role of miRNAs in direct conversion of somatic cells into neural lineages. This precise review mainly focuses on recent discoveries of miRNAs functions in initiating cell reprogramming and fate specification of the neuronal subtype. Moreover, we discuss most recent findings about some miRNAs’ activity in regulating various developmental stages of neurons, which is helpful for understanding the event network between miRNAs and their targets.

Lipopolysaccharide and Curcumin Co-Stimulation Potentiates Olfactory Ensheathing Cell Phagocytosis Via Enhancing Their Activation.

The gradual deterioration following central nervous system (CNS) injuries or neurodegenerative disorders is usually accompanied by infiltration of degenerated and apoptotic neural tissue debris. A rapid and efficient clearance of these deteriorated cell products is of pivotal importance in creating a permissive environment for regeneration of those damaged neurons. Our recent report revealed that the phagocytic activity of olfactory ensheathing cells (OECs) can make a substantial contribution to neuronal growth in such a hostile environment. However, little is known about how to further increase the ability of OECs in phagocytosing deleterious products. Here, we used an in vitro model of primary cells to investigate the effects of lipopolysaccharide (LPS) and curcumin (CCM) co-stimulation on phagocytic activity of OECs and the possible underlying mechanisms. Our results showed that co-stimulation using LPS and CCM can significantly enhance the activation of OECs, displaying a remarkable up-regulation in chemokine (C-X-C motif) ligand 1, chemokine (C-X-C motif) ligand 2, tumor necrosis factor-α, and Toll-like receptor 4, increased OEC proliferative activity, and improved phagocytic capacity compared with normal and LPS- or CCM-treated OECs. More importantly, this potentiated phagocytosis activity greatly facilitated neuronal growth under hostile culture conditions. Moreover, the up-regulation of transglutaminase-2 and phosphatidylserine receptor in OECs activated by LPS and CCM co-stimulation are likely responsible for mechanisms underlying the observed cellular events, because cystamine (a specific inhibitor of transglutaminase-2) and neutrophil elastase (a cleavage enzyme of phosphatidylserine receptor) can effectively abrogate all the positive effects of OECs, including phagocytic capacity and promotive effects on neuronal growth. This study provides an alternative strategy for the repair of traumatic nerve injury and neurologic diseases with the application of OECs in combination with LPS and CCM.

Huangqin flavonoid extraction for spinal cord injury in a rat model

Flavonoids from Huangqin (dried roots of Scutellaria baicalensis Georgi) have anti-inflammatory effects, and are considered useful for treatment of spinal cord injury. To verify this hypothesis, the T9–10 spinal cord segments of rats were damaged using Allens method to establish a rat spinal cord injury model. Before model establishment, Huangqin flavonoid extraction (12.5 g/kg) was administered intragastrically for 1 week until 28 days after model establishment. Methylprednisolone (30 mg/kg) was injected into the tail vein at 30 minutes after model establishment as a positive control. Basso, Beattie, and Bresnahan locomotor scale scores were used to assess hind limb motor function. Hematoxylin-eosin staining was used to detect pathological changes in the injured spinal cord. Immunofluorescence and western blot assays were performed to measure immunoreactivity and expression levels of brain-derived neurotrophic factor, neuronal marker neurofilament protein, microglial marker CD11b and astrocyte marker glial fibrillary acidic protein in the injured spinal cord. Huangqin flavonoid extraction markedly reduced spinal cord hematoma, inflammatory cell infiltration and cavities and scars, and increased the Basso, Beattie, and Bresnahan locomotor scale scores; these effects were identical to those of methylprednisolone. Huangqin flavonoid extraction also increased immunoreactivity and expression levels of brain-derived neurotrophic factor and neurofilament protein, and reduced immunoreactivity and expression levels of CD11b and glial fibrillary acidic protein, in the injured spinal cord. Overall, these data suggest that Huangqin flavonoid extraction can promote recovery of spinal cord injury by inducing brain-derived neurotrophic factor and neurofilament protein expression, reducing microglia activation and regulating reactive astrocytes.

Potential molecular mechanisms mediating the protective effects of tetrahydroxystilbene glucoside on MPP+-induced PC12 cell apoptosis

Our previous work demonstrated that tetrahydroxystilbene glucoside (TSG) was able to effectively attenuate 1-methyl-4-phenylpyridinium (MPP+)-induced apoptosis in PC12 cells partially via inhibiting reactive oxygen species (ROS) generation. However, the precise molecular mechanisms of TSG responsible for suppressing neuronal apoptosis have not been fully elucidated. To investigate the possible mechanism, we studied the neuroprotective effects of TSG on MPP+-induced PC12 cells apoptosis and explored the molecular mechanisms that mediated the effects of TSG. Our results showed that treatment with TSG prior to MPP+ exposure effectively attenuated the cell viability decrease in PC12 cells, reversed the cell apoptosis, and further restored the mitochondria membrane potential (MMP). In addition, TSG remarkably enhanced the anti-oxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and efficiently reduced the malondialdehyde (MDA) content in the PC12 cells. Meanwhile, TSG markedly upregulated the Bcl-2/Bax ratio, reversed release of Cytochrome c, and inhibited the activation of caspase-3 induced by MPP+. Furthermore, TSG significantly inhibited the activation of p38 mitogen-activated protein kinase (p38MAPK) signaling pathway, while extracellular signal-regulated protein kinases (ERK) phosphorylation was not affected. Together, these findings provide the basis for TSG clinical application as a new therapeutic strategy in the treatment of neurodegenerative diseases.