Opportunities and perspectives of small molecular phosphodiesterase inhibitors in neurodegenerative diseases.

Phosphodiesterase (PDE) is a superfamily of enzymes that are responsible for the hydrolysis of two second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). PDE inhibition promotes the gene transcription by activating cAMP-response element binding protein (CREB), initiating gene transcription of brain-derived neurotrophic factor (BDNF). The procedure exerts neuroprotective profile, and motor and cognitive improving efficacy. From this point of view, PDE inhibition will provide a promising therapeutic strategy for treating neurodegenerative disorders. Herein, we summarized the PDE inhibitors that have entered the clinical trials or been discovered in recent five years. Well-designed clinical or preclinical investigations have confirmed the effectiveness of PDE inhibitors, such as decreasing Aß oligomerization and tau phosphorylation, alleviating neuro-inflammation and oxidative stress, modulating neuronal plasticity and improving long-term cognitive impairment.

The angelica Polysaccharide: a review of phytochemistry, pharmacology and beneficial effects on systemic diseases.

Angelica sinensis is a perennial herb widely distributed around the world, and angelica polysaccharide (APS) is a polysaccharide extracted from Angelica sinensis. APS is one of the main active components of Angelica sinensis. A large number of studies have shown that APS has hematopoietic, promoting blood circulation, radiation resistance, lowering blood glucose, enhancing the body immunity and other pharmacological effects in a variety of diseases. However, different extraction methods and extraction sites greatly affect the efficacy of APS. In recent years, with the emerging of new technologies, there are more and more studies on the combined application and structural modification of APS. In order to promote the comprehensive development and in-depth application of APS, this narrative review systematically summarizes the effects of different drying methods and extraction sites on the biological activity of APS, and the application of APS in the treatment of diseases, hoping to provide a scientific basis for the experimental study and clinical application of APS.

Therapeutic potential of natural products and underlying targets for the treatment of aortic aneurysm.

Aortic aneurysm is a vascular disease characterized by irreversible vasodilatation that can lead to dissection and rupture of the aortic aneurysm, a life-threatening condition. Thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) are two main types. The typical treatments for aortic aneurysms are open surgery and endovascular aortic repair, which are only indicated for more severe patients. Most patients with aneurysms have an insidious onset and slow progression, and there are no effective drugs to treat this stage. The inability of current animal models to perfectly simulate all the pathophysiological states of human aneurysms may be the key to this issue. Therefore, elucidating the molecular mechanisms of this disease, finding new therapeutic targets, and developing effective drugs to inhibit the development of aneurysms are the main issues of current research. Natural products have been applied for thousands of years to treat cardiovascular disease (CVD) in China and other Asian countries. In recent years, natural products have combined multi-omics, computational biology, and integrated pharmacology to accurately analyze drug components and targets. Therefore, the multi-component and multi-target complexity of natural products have made them a potentially ideal treatment for multifactorial diseases such as aortic aneurysms. Natural products have regained popularity worldwide. This review provides an overview of the known natural products for the treatment of TAA and AAA and searches for potential cardiovascular-targeted natural products that may treat TAA and AAA based on various cellular molecular mechanisms associated with aneurysm development.

The repeated administration of rhIL-12 for 14 weeks in rhesus monkeys: A toxicity assessment.

Interleukin-12 (IL-12) is known to exert antitumor immune effects by promoting the activation and proliferation of T cells and NK cells within the immune system. However, clinical trials have observed systemic toxicity associated with the administration of IL-12. This has shelved development plans for its use as a cancer therapeutic drug. Therefore, it is critical that we perform a systematic evaluation of the toxicity and safety of repeated IL-12 administration. In this study, we conducted a comprehensive evaluation of the toxicity and safety of repeated rhIL-12 (recombinant human interleukin-12) administration in rhesus monkeys by assessing its effects on the immune system, organ function, and vital signs. Rhesus monkeys were subcutaneously injected with 0.5, 2.5, and 12.5 µg/kg of rhIL-12 for up to for 14 consecutive weeks. The low dose exhibited no signs of toxicity, whereas animals receiving higher doses displayed symptoms such as loose stools, reduced activity, anemia, and elevated liver function indicators (AST and TBIL). Following three administrations of 12.5 µg/kg, high dosing was adjusted to 7.5 µg/kg due to manifestations of symptoms like loose stools, decreased activity, and huddling in the cage. Furthermore, rhesus monkeys exhibited marked immunogenic responses to recombinant human interleukin-12 (rhIL-12). However, based on overall study findings, the No Observed Adverse Effect Level (NOAEL) for the subcutaneous injection of rhIL-12, when repeatedly administered for 3 months in rhesus monkeys, was considered to be 0.5 µg/kg. The Highest Non-Severely Toxic Dose (HNSTD) was considered to be 7.5 µg/kg.

A Novel Bromophenol Compound from Leathesia nana Inhibits Breast Cancer in a Direct Tumor Killing and Immunotherapy Manner.

Considering the resistance and toxicity of traditional chemotherapeutic drugs, seeking potential candidate for treating breast cancer effectively is a clinical problem that should be solved urgently. Natural products have attracted extensive attention, owing to their multi-target advantages and low toxicity. In the current study, the effects of XK-81, a novel bromophenol compound extracted from Leathesia nana, on breast cancer, and its underlying mechanisms, were explored. Firstly, data from in vitro experiments indicated that 4T-1, one of common mouse breast cancer cell lines, was a XK-81-susceptible cell line, and ferroptosis was the major death manner in response to XK-81 treatment, which was evidenced by increasing intracellular Fe2+ and ROS level with condensed mitochondrial membrane densities, as well as decreasing the protein expressions of SLC7A11 and GPX4. In vivo, XK-81 suppressed the growth of 4T-1 breast-tumor in both BALB/C mice and zebrafish. Obviously, XK-81 decreased the protein expression of SLC7A11 and GPX4 in tumor tissues, hinting at the occurrence of ferroptosis. Moreover, XK-81 increased CD8+ T cells and NK cells numbers and regulated M1/M2 macrophage ratio in tumor tissues, indicating XK-81's immunotherapeutic effect. Additionally, the secretions of immune-related cytokines, including TNF-α, IL-1ß, and IL-12, were elevated with XK-81 stimulation in RAW 264.7 cells. Intriguingly, compared with doxorubicin-induced heart damage, XK-81 demonstrated the therapeutic advantage of little cardiotoxicity on the heart. XK-81 demonstrated potential antitumor advantage by both directly inducing ferroptosis-mediated death of tumor cells and immunization.

Codelivery of Que and BCL-2 siRNA with Lipid-Copolymer Hybrid Nanocomplexes for Efficient Tumor Regression.

The efficacy of chemotherapy is often reduced due to the chemotherapy resistance of tumor cells, which is usually caused by abnormal gene overexpression. Herein, multifunctional nanocomplexes (Que/siBCL2@BioMICs) were developed to deliver quercetin (Que) and BCL-2 siRNA (siBCL2) to synergistically inhibit tumor growth. The nanocomplexes were composed of an amphiphilic triblock copolymer of poly(ethylene glycol) methyl ether methacrylate-poly[2-(dimethylamino) ethyl acrylate]-polycaprolactone (PEGMA-PDMAEA-PCL) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)-biotin (DSPE-PEG-biotin). Que was encapsulated into the cores through hydrophobic interactions, while negatively charged siBCL2 was loaded through electrostatic interactions. The nanocomplexes could effectively facilitate cellular uptake via biotin-mediated active targeting and cytosolic release of cargos by the "proton sponge effect" of PDMAEA. Que/siBCL2@BioMICs achieved enhanced cytotoxicity and anti-metastasis activity due to a synergistic effect of Que and siBCL2 in vitro. More importantly, superior anti-tumor efficacy was observed in orthotopic 4T1 tumor-bearing mice with reduced primary tumor burden and lung metastatic nodules, while no obvious side effects to major organs were observed. In conclusion, the biotin-targeted nanocomplexes with chemotherapeutic and nucleotide agent entrapment provide a promising strategy for efficient triple-negative breast cancer (TNBC) therapy.

RIP1 Mediates Manzamine-A-Induced Secretory Autophagy in Breast Cancer.

Cancer-derived small extracellular vesicles (sEVs) serve as critical mediators of cell-to-cell communication. Manzamine A (MA), a unique marine-derived alkaloid with various bioactivities, exerts anticancer effects against several kinds of tumors, but it remains unclear whether it has the same activity against breast cancer. Here, we proved that MA inhibits MDA-MB-231 and MCF-7 cell proliferation, migration, and invasion in a time- and dose-dependent manner. In addition, MA promotes autophagosome formation but suppresses autophagosome degradation in breast cancer cells. Importantly, we also found that MA stimulates sEVs secretion and increases autophagy-related protein accumulation in secreted sEVs, further potentiated by autophagy inhibitor chloroquine (CQ). Mechanistically, MA decreases the expression level of RIP1, the key upstream regulator of the autophagic pathway, and reduces the acidity of lysosome. Overexpression of RIP1 activated AKT/mTOR signaling, thus attenuating MA-induced autophagy and the corresponding secretion of autophagy-associated sEVs. Collectively, these data suggested that MA is a potential inhibitor of autophagy by preventing autophagosome turnover, and RIP1 mediates MA-induced secretory autophagy, which may be efficacious for breast cancer treatment.

Targeting necroptosis as an alternative strategy in tumor treatment: From drugs to nanoparticles.

Over last decades, most antitumor therapeutic strategies have focused on apoptosis, however, apoptosis resistance and immunological silence usually led to treatment failure. In this sense, triggering other programmed cell death such as necroptosis may achieve a better therapeutic efficacy and has gained widespread attentions in tumor therapy. Studies in this field have identified several types of necroptosis modulators and highlighted the therapeutic potential of necroptotic cell death in cancer. Nanoparticles further provide possibilities to improve therapeutic outcomes as an efficient drug delivery system, facilitating tumor targeting and controlled cargo release. Furthermore, some nanoparticles themselves can trigger/promote programmed necrosis through hyperthermia, ultrasound and autophagy blockage. These investigations have entered necroptosis for consideration as a promising strategy for tumor therapy, though numerous challenges remain and clinical applications are still distant. In this review, we would briefly introduce molecular mechanism and characteristics of necroptosis, and then summarize recent progress of programmed necrosis and their inducers in tumor therapy. Furthermore, the antitumor strategies that take advantages of nanoparticles to induce necroptosis are also discussed.

Electrospun multifunctional nanofibrous mats loaded with bioactive anemoside B4 for accelerated wound healing in diabetic mice.

With the worldwide prevalence of diabetes and considering the complicated microenvironment of diabetic wounds, the design and development of innovative multifunctional wound dressing materials are much wanted for the treatment of hard-to-heal wounds in diabetic patients. In the present study, anti-inflammatory ingredients loaded with nanofibrous wound dressing materials were manufactured by a promising blend-electrospinning strategy, and their capability for treating the diabetic wound was also systematically explored. A polymer blend consisting of Chitosan (CS) and polyvinyl alcohol (PVA) was electrospun into CS-PVA nanofibrous mats as control groups. In the meanwhile, a bioactive ingredient of Chinese medicine Pulsatilla, anemoside B4(ANE), with different contents were loaded into the electrospinning solution to construct CS-PVA-ANE nanofibrous mats. The developed CS-PVA-ANE wound dressing materials exhibited multifunctional properties including prominent water absorption, biomimetic elastic mechanical properties, and sustained ANE releasing behavior, as well as outstanding hemostatic properties. The in vitro studies showed that the CS-PVA-ANE nanofiber mats could significantly suppress lipopolysaccharide (LPS)-stimulated differentiation of pro-inflammatory (M1) macrophage subsets, and notably reduce the reactive oxygen species (ROS) generation, as well as obviously decrease inflammatory cytokine release. The in vivo animal studies showed that the CS-PVA-ANE nanofiber mats promoted the healing of diabetic wounds by significantly enhancing wound closure rates, accelerating excellent angiogenesis, promoting re-epithelization and collagen matrix deposition throughout all stages of wound healing. The present study demonstrated that CS-PVA-ANE nanofiber mats could effectively shorten the wound-healing time by inhibiting inflammatory activity, which makes them promising candidates for the treatment of hard-to-heal wounds caused by diabetes.

IL-12 inhibits postoperative residual tumor growth in murine models of sarcoma and renal carcinoma.

Surgical tumor removing is the most common procedure after a confirmed cancer diagnosis with no detected metastasis. Surgery can reduce tumor burden and address pathologic changes caused by local compression of tissues by the tumor. This lowers the chances of tumor cell spreading and creates more favorable conditions for further treatment. However, not all tumor cells can be eliminated through surgery. Even in the early stages of the disease, tumor cells often metastasize and cannot be identified by current detection methods. These tiny, disseminated tumors are often the cause of tumor recurrence. There is currently a lack of effective treatment options that can completely prevent tumor recurrence after surgery. To simulate the actual clinical situation, we selected murine-derived tumor cell lines S180 and Kcc853 to establish a post-transplantation residual tumor model in mice. Surgery was performed on mice inoculated with tumors. Tumor tissue was partially excised to set up the postsurgical residual tumor models. The model simulated the clinical situation where tumor cells were not completely eliminated or there were small tumors that had metastasized before surgery. IL-12 was injected to observe its effect on residual tumors or metastatic microtumors. The administration of IL-12 after surgery can significantly inhibit the growth of residual tumors and metastasis, improve the postoperative tumor-free rate and address the problem of tumor recurrence caused by the growth of residual tumors and micro-metastasis. Therefore, the use of IL-12 antitumor cytokine combined with surgery can effectively inhibit tumor recurrence. Low-dose IL-12 (1-10 ng/kg in humans) can inhibit residual tumor growth.

Dual-targeting tumor cells and tumor associated macrophages with lipid coated calcium zoledronate for enhanced lung cancer chemoimmunotherapy.

Lung cancer is the leading cause of cancer death among both men and women, and non-small cell lung cancer (NSCLC) accounts for almost 80% of such death. Tumor associated macrophage (TAMs) are abundant components in NSCLC. TAMs play critical roles in angiogenesis, immune escape and chemoresistance. Here we developed a dual-targeting drug delivery system (CaZOL@BMNPs) of zoledronate, which could bind to both tumor cells with overexpressed biotin receptors and macrophage mannose receptor (MMR) positive TAMs. The biotin- and mannose-modified lipid coated calcium zoledronate nanoparticles were preferentially internalized in both tumor cells and TAMs, and thereby inhibited their survivals. Our studies demonstrated that CaZOl@BMNPs treatment obviously reduced angiogenesis, reprogrammed immunosuppressive tumor microenvironment and eventually restrained tumor progression with negligible systemic toxicity. Collectively, CaZOL@BMNPs could be a promising approach by dual-targeting tumor cells and TAMs for NSCLS chemoimmunotherapy.

Erratum: Hispidulin prevents hypoxia-induced epithelial-mesenchymal transition in human colon carcinoma cells.

[This corrects the article on p. 1047 in vol. 5, PMID: 26045985.].

Cryptotanshinone protects dextran sulfate sodium-induced experimental ulcerative colitis in mice by inhibiting intestinal inflammation.

The incidence of ulcerative colitis (UC) is increasing in recent years. The protective effect of cryptotanshinone, a natural compound from Salvia miltiorrhiza Bunge, on UC was investigated both in vivo and in vitro models. UC model was established by dextran sulfate sodium administration in drinking water and cryptotanshinone was orally administrated. RAW264.7 cells were stimulated by lipopolysaccharide (LPS) with or without cryptotanshinone pretreatment. The body weights and disease activity index (DAI) were recorded. The pathological alterations were evaluated by H&E staining. The levels of pro-inflammatory cytokines in colon tissues and cell culture medium were determined with enzyme-linked immune sorbent assay (ELISA) kits. The protein expression was detected by Western blotting and immunohistochemistry. Results showed that cryptotanshinone significantly increased the body weight and colon length, reduced the score of DAI, and improved pathological changes. Furthermore, the expression of inducible nitric oxide synthase, cyclooxygenase-2, receptor-interacting protein kinase 3, NF-κB p65 and the secretion of tumor necrosis factor-α, IL-6 in colon tissues and LPS-stimulated cells were significantly inhibited by cryptotanshinone. Besides, cryptotanshinone significantly inhibited LPS-triggered toll-like receptor 4 luciferase reporter activity with an IC50 at 7.2 µM. In conclusion, cryptotanshinone ameliorated experimental UC possibly by inhibiting intestinal inflammation.

Preventive effects of a natural anti-inflammatory agent Salvianolic acid A on acute kidney injury in mice.

Acute kidney injury (AKI) is an abrupt loss of kidney function with high mortality. Inflammatory is considered driving the progression of AKI. Salvianolic acid A (SA), one of the major ingredients of Salvia miltiorrhiza Bunge, displays plenty of biological effects. Herein, the effect of SA on lipopolysaccharide (LPS)-induced AKI in mice and further related mechanism in inflammatory cells were explored. In vivo experiments demonstrated that SA significantly ameliorated LPS-challenged AKI by preventing glomerulus atrophy and decreasing plasma creatinine and blood urea nitrogen (BUN) levels. Meanwhile, SA significantly decreased the release of serum inflammatory cytokines and blocked macrophage infiltration in damaged renal tissue. In in vitro studies, SA significantly decreased TNF-α and IL-6 release levels and altered the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in LPS-stimulated macrophages, which were consistent with the results from in vivo experiments. Furthermore, SA that bound to Toll-Like Receptor 4 (TLR4) was able to reduce endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation in response to LPS stimulation. All silence of TLR4 gene, ROS scavenger and Ca2+ chelator decreased inflammatory cytokines releases. Taken together, SA could be used as a potential therapeutic agent for preventing AKI by suppressing inflammatory responses.

Structural characterization and in vitro-in vivo evaluation of effect of a polysaccharide from Sanguisorba officinalis on acute kidney injury.

We report here an acidic polysaccharide, namely RSP-3, which ameliorates acute kidney injury and is obtained from Sanguisorba officinalis. We extracted and purified two polysaccharides from this herb based on the acidity and screened them for their effect in regulating the immunological activity of macrophages. Among them, RSP-3 exhibited significant anti-inflammatory activity against lipopolysaccharide (LPS)-stimulated macrophages by decreasing TNF-α and IL-6 levels. Subsequently, we found that RSP-3 suppressed ER stress, reduced ROS production and blocked NF-κBp65 translocation. After fully characterizing RSP-3 with a series of analytical technologies, we tested its anti-acute kidney injury (AKI) effect in vivo. In a murine AKI model induced by LPS, treatment with RSP-3 effectively ameliorated renal function. Besides, it decreased the levels of TNF-α and IL-6 in serum and reduced macrophage infiltration in injured kidney tissue. In sum, RSP-3, with a significant protective effect against AKI by showing anti-inflammatory activity, may become a meaningful drug candidate for treatment of AKI.

Design, synthesis and biological evaluation of 4-piperidin-4-yl-triazole derivatives as novel histone deacetylase inhibitors.

Histone deacetylase is an important member of epigenetics and a well validated target for anti-cancer drug discovery. In this study, we designed and synthesized a series of twenty-one novel hydroxamic acid-based histone deacetylase inhibitors with 4-piperidin-4-yl-triazole as the core skeleton. Most target compounds displayed excellent inhibition rates toward histone deacetylases at the concentration of 1 µM. Among them, the inhibition rates of two compounds MH1-18 and MH1-21 exceeded 90%. Furthermore, these two compounds selectively inhibited the activity of histone deacetylase 6 with low IC50 values. The high potency of them toward histone deacetylase 6 was rationalized by molecular docking studies. We found that MH1-18 and MH1-21 moderately inhibited the proliferation of four human cancer cell lines SGC-7901, NCI-H226, MCF-7, and HL-60. However, MH1-21 showed potent efficacy in suppressing the migration of MCF-7 cells. Results obtained in the current study shed light on designing potent HDAC6 inhibitors as anti-cancer agents.