Neuroprotective Effects of a Multi-Herbal Extract on Axonal and Synaptic Disruption in Vitro and Cognitive Impairment in Vivo.

Background: Alzheimer's disease (AD) is a multifactorial disorder characterized by cognitive decline. Current available therapeutics for AD have limited clinical benefit. Therefore, preventive therapies for interrupting the development of AD are critically needed. Molecules targeting multifunction to interact with various pathlogical components have been considered to improve the therapeutic efficiency of AD. In particular, herbal medicines with multiplicity of actions produce cognitive benefits on AD. Bugu-M is a multi-herbal extract composed of Ganoderma lucidum (Antler form), Nelumbo nucifera Gaertn., Ziziphus jujuba Mill., and Dimocarpus longan, with the ability of its various components to confer resilience to cognitive deficits. Objective: To evaluate the potential of Bugu-M on amyloid-ß (Aß) toxicity and its in vitro mechanisms and on in vivo cognitive function. Methods: We illustrated the effect of Bugu-M on Aß25-35-evoked toxicity as well as its possible mechanisms to diminish the pathogenesis of AD in rat cortical neurons. For cognitive function studies, 2-month-old female 3×Tg-AD mice were administered 400 mg/kg Bugu-M for 30 days. Behavioral tests were performed to assess the efficacy of Bugu-M on cognitive impairment. Results: In primary cortical neuronal cultures, Bugu-M mitigated Aß-evoked toxicity by reducing cytoskeletal aberrations and axonal disruption, restoring presynaptic and postsynaptic protein expression, suppressing mitochondrial damage and apoptotic signaling, and reserving neurogenic and neurotrophic factors. Importantly, 30-day administration of Bugu-M effectively prevented development of cognitive impairment in 3-month-old female 3×Tg-AD mice. Conclusion: Bugu-M might be beneficial in delaying the progression of AD, and thus warrants consideration for its preventive potential for AD.

A new lignan from Euscaphis konishii / 中国中药杂志

The chemical constituents from the extract of the twigs of Euscaphis konishii with anti-hepatoma activity were investigated, twelve compounds by repeated chromatography with silica gel, Sephadex LH-20 and preparative-HPLC. The structures of the chemical components were elucidated by spectroscopy methods, as konilignan(1),(7R, 8S)-dihydrodehydrodico-niferylalcohol-9-O-β-D-glucopyranoside(2),illiciumlignan B(3),threo-1-(4-hydroxy-3-methoxyphenyl)-2-[4-(3-hydroxypropyl)-2-methoxyphenoxy]-1,3-panediol(4),erythro-1-(4-hydroxy-3-methoxyphenyl)-2-[4-(3-hydroxypropyl)-2-methoxyphenoxy]-1,3-panediol(5), matairesinol(6), wikstromol(7), isolariciresinol(8),(+)-lyoniresinol(9), 4-ketopinoresinol(10), syringaresin(11), and vladinol D(12). Among them, compound 1 is a new lignan. Compounds 10 and 12 had moderate inhibitory activity on HepG2 cells, with IC_(50) values of 107.12 μmol·L~(-1) and 183.56 μmol·L~(-1), respectively.

Repeated dose multi-drug testing using a microfluidic chip-based coculture of human liver and kidney proximal tubules equivalents.

A microfluidic multi-organ chip emulates the tissue culture microenvironment, enables interconnection of organ equivalents and overcomes interspecies differences, making this technology a promising and powerful tool for preclinical drug screening. In this study, we established a microfluidic chip-based model that enabled non-contact cocultivation of liver spheroids and renal proximal tubule barriers in a connecting media circuit over 16 days. Meanwhile, a 14-day repeated-dose systemic administration of cyclosporine A (CsA) alone or in combination with rifampicin was performed. Toxicity profiles of the two different doses of CsA on different target organs could be discriminated and that concomitant treatment with rifampicin from day6 onwards decreased the CsA concentration and attenuated the toxicity compared with that after treatment with CsA for 14 consecutive days. The latter is manifested with the changes in cytotoxicity, cell viability and apoptosis, gene expression of metabolic enzymes and transporters, and noninvasive toxicity biomarkers. The on chip coculture of the liver and the proximal tubulus equivalents showed its potential as an effective and translational tool for repeated dose multi-drug toxicity screening in the preclinical stage of drug development.

Chlorella sorokiniana Extract Prevents Cisplatin-Induced Myelotoxicity In Vitro and In Vivo.

Cisplatin chemotherapy causes myelosuppression and often limits treatment duration and dose escalation in patients. Novel approaches to circumvent or lessen myelotoxicity may improve clinical outcome and quality of life in these patients. Chlorella sorokiniana (CS) is a freshwater unicellular green alga and exhibits encouraging efficacy in immunomodulation and anticancer in preclinical studies. However, the efficacy of CS on chemoprotection remains unclear. We report here, for the first time, that CS extract (CSE) could protect normal myeloid cells and PBMCs from cisplatin toxicity. Also, cisplatin-induced apoptosis in HL-60 cells was rescued through reservation of mitochondrial function, inhibition of cytochrome c release to cytosol, and suppression of caspase and PARP activation. Intriguingly, cotreatment of CSE attenuated cisplatin-evoked hypocellularity of bone marrow in mice. Furthermore, we observed the enhancement of CSF-GM activity in bone marrow and spleen in mice administered CSE and cisplatin, along with increased CD11b levels in spleen. In conclusion, we uncovered a novel mechanism of CSE on myeloprotection, whereby potentially supports the use of CSE as a chemoprotector against cisplatin-induced bone marrow toxicity. Further clinical investigation of CSE in combination with cisplatin is warranted.

Comparison of in vivo immunomodulatory effects of 5-hydroxymethylfurfural and 5, 5'-oxydimethylenebis (2-furfural).

The standard of 5-Hydroxymethylfurfural (5-HMF) existed in dextrose injection as an inevitable by-product during high-temperature setrilization has been included in pharmacopoeias considering its hazardous effects on human health. We found that the concentrations of 5-HMF in some traditional Chinese medicine injections (TCMIs) far exceeded its limit in dextrose injection. Besides, we detected 5, 5'-Oxydimethylenebis (2-furfural) (OMBF) in those TCMIs containing high concentrations of 5-HMF. We investigated the in vivo immunomodulatory effects of 5-HMF and OMBF at three dose levels using the reporter antigen popliteal lymph node assay (RA-PLNA), which allows the straightforward examination and mechanistic study of immunotoxicity of low molecular weight compounds. We found that 5-HMF increased the production of IgG2a and IFN-γ when co-injected with TNP-OVA, indicating its capability of providing a co-stimulatory signal to evoke a typical type-1 immune response. Compared with the 5-HMF, OMBF elevated the production of IgG1, IgG2, IL-4 and IFN-γ in response to both reporter antigens, suggesting that OMBF can act as a neo-antigen or neo-epitope to elicit a mixed type-1 and type-2 immune response. It indicates that both 5-HMF and OMBF have immunosensitizing potential with different mechanisms, and exposure to 5-HMF and OMBF may represent a safety concern for humans.

[Effects of Litchi chinensis Seed Saponins on Inhibiting Hyperplasia of Mammary Glands and Influence on Signaling Pathway of Estrogen in Rats].

OBJECTIVE: To discuss the role of Litchi chinensis seed saponins on hyperplasia of mammary glands(HMG) and the influence of estrogen signaling pathways in rats. METHODS: In addition to eight non-pregnant female SD rats in normal control group, the other 32 pathologic models of HMG rat model were randomly divided into other four groups: model control group, low and high dose groups, which were given experimental drug of Litchi chinensis seed saponins (LSE) 0. 1 g/kg and 0. 2 g/kg, and the positive control group with experimental drug of tamoxifen 4 mg/kg. Then all model rats were orally administrated for four weeks. The diameter and height of nipple were measured, and the content changes of estradiol(E2) and progestrogen(P) in serum were detected with ELISA method. The HMG were detected by the morphology examination. The expression of estrogen receptor(ER) and progesterone receptor(PR) in the mammary glands were investigated by immunohistochemical staining. RESULTS: According to LSE in the low and high dose groups, it was discovered that the nipple diameter and height of HMG rats, the expression of ER and PR in HMG and the content of serum E2 were reduced, the content of serum P were improved, and the hyperplasia of mammary glands was inhibited. CONCLUSION: LSE can obviously inhibit the rat hyperplasia of mammary gland, and its possible mechanism is related to adjusting the transduction pathway of estrogen signal to lower estrogen levels.

A safety study of a novel photosensitizer, sinoporphyrin sodium, for photodynamic therapy in Beagle dogs.

Sinoporphyrin sodium (DVDMS) is a novel hematoporphyrin-like photosensitizer developed for photodynamic therapy (PDT), an effective therapeutic modality for tumor treatment; however, the safety of photosensitizer-based PDT is always of great concern. The purpose of the current study was to investigate the potential repeated-dose toxicity and describe the toxicokinetic process of DVDMS-based PDT in Beagle dogs. The dogs were randomly allocated to six groups, and then were administrated a DVDMS preparation intravenously at dose levels of 0, 1, 3, 9, 1 and 9 mg per kg body weight, respectively; then, the latter two groups were illuminated 24 h later with a 630 nm laser for 10 min, once every seven days for 5 weeks. During the study period, clinical signs, mortality, body weight, food consumption, body temperature, ophthalmoscopy, hematology, serum biochemistry, urinalysis, electrocardiograms, toxicokinetics, organ weights, gross anatomy and histopathology were examined. After the administration, no deaths were observed; however, the dogs that received PDT showed skin swelling and ulceration, indicating that DVDMS-PDT induced a phototoxic effect. DVDMS led to an increase in blood coagulation in dogs in the 9 mg kg(-1) group and in the two PDT groups on Day 35, whereas it induced a decrease in dogs in the 3 mg kg(-1) group and in the two PDT groups on Day 49. The toxicokinetic study showed that the systematic exposure of DVDMS in dogs occurred in a dose-dependent manner, and DVDMS did not accumulate in blood plasma. The DVDMS-based PDT group showed no obvious treatment-related pathological changes; however, slight or mild brown-and-yellow pigmentation of DVDMS (or its metabolite) was observed to deposit in the liver, spleen, local lymph nodes and marrow of dogs in the mid- and high-dose groups, as well as the high-dose PDT group. In females, the absolute and relative spleen weights increased in dogs in the 9 mg kg(-1) DVDMS groups with and without PDT during the treatment and recovery period, respectively. The target organs are presumed to be the liver and immune organs (spleen, bone marrow and lymph nodes), while all of the responses were slight. Based on the results above, the no-observed-adverse-effect level (NOAEL) was considered to be 1 mg kg(-1), and DVDMS-PDT appeared to be a safe and promising anti-tumor therapy in the clinic.

Clinical observation on the long-term effect of warming-promotion acupuncture on lumbar spinal stenosis / 中国针灸

<p><b>OBJECTIVE</b>To observe the difference effects between warming-promotion acupuncture and normal acupuncture on lumbar spinal stenosis (LSS).</p><p><b>METHODS</b>Sixty cases of LSS were randomly divided into a normal acupuncture group (30 cases) and a warming-promotion acupuncture group (30 cases). The two groups both chose Dazhui (GV 14), Mingmen (GV 4), Jiaji (EX-B 2),etc. Normal method without special manipulation was used in normal acupuncture group, while the warming-promotion manipulation was used in warming-promotion acupuncture group, all once daily, 10 treatments made one session. Compare the symptoms and spinal cord function of LSS, quality of life (QOL)and clinical effect in the two groups.</p><p><b>RESULTS</b>The comprehensive score of symptoms of LSS in warming-promotion group 3 months after treatment was 6.30 +/- 1.92, while that in normal acupuncture group was 4.67 +/- 13.70. The score of spinal cord function in warming-promotion group after treatment was 7.03 +/- 1.03, while that in normal acupuncture group was 6.33 +/- 1.12. The score of QOL in warming-promotion group after treatment was 53.67 +/- 8.91, while that in normal acupuncture group was 64.50 +/- 16.69. All the differences between these scores in two groups were statistically significant (all P < 0.05). The total effective rate was 90.0% (27/30)in warming-promotion group, and 80.0% (24/30) in normal acupuncture group. The effect of warming-promotion group was better than that in normal acupuncture group (P < 0.05).</p><p><b>CONCLUSION</b>In the field of treating LSS, the effect of warming-promotion acupuncture is better than normal acupuncture.</p>

The effects of amiloride, a Na+-H+ exchange inhibitor, on iliac artery stenosis after balloon injury in rabbits.

This study was designed to explore the effects of amiloride, a Na+-H+ exchange (NHE) inhibitor, on vessel stenosis by observing the expression of NHE-1 protein in vascular smooth muscle (VSM) after balloon injury and the effects of amiloride on VSM cell proliferation, migration, and excretion of extracellular matrices (ECMs). A total of 32 adult male New Zealand white rabbits were randomly divided into a balloon injury group (BG), an amiloride-treated group (AG), and a sham-operated group (SG). The left iliac artery was injured by inflating a 2.5 mm x 20 mm Foley catheter in BG and AG rabbits; in SG rabbits, the Foley catheter was inserted but not inflated. Amiloride (5 mg x kg(-1) x d(-1)) was injected intraperitoneally in AG and the same volume of distilled water was used in BG 3 days before balloon injury and for 28 days after the injury. The left iliac artery was stained by hematoxylin-eosin, alpha-actin, and Masson's trichrome to observe the vessel cava, neointima, media layer, and ECMs. NHE-1 proteins of the VSM were detected by Western blotting. A narrowing of the arterial cava, neointima formation, and thickened VSM layer were observed 28 days after balloon injury in BG and AG. However, in AG, the vessel cava was not as narrowed as that of BG and the intimal areas were to a lesser extent than in BG. In AG, the alpha-actin-positive areas and the ECM areas in the neointima were increased compared with SG, but to a lesser extent than in BG. The expression of NHE-1 protein in VSM was increased in BG and AG after balloon injury; however, the levels in AG were significantly less than in BG. In conclusion, VSM cell proliferation, migration, and excretion of ECMs contributed to vessel stenosis in the BG and AG rabbits. The expression of NHE-1 protein in VSM increased after balloon injury. Amiloride, an inhibitor of NHE-1, can limit the development of vessel stenosis through inhibition of VSM cell proliferation, migration, and excretion of ECMs.

Effects of garlic oil and two of its major organosulfur compounds, diallyl disulfide and diallyl trisulfide, on intestinal damage in rats injected with endotoxin.

Garlic and its active components are known to possess antioxidant and antiinflammatory effects. The present study investigated the effects of garlic oil and its organosulfur compounds on endotoxin-induced intestinal mucosal damage. Wistar rats received by gavage 50 or 200 mg/kg body weight garlic oil (GO), 0.5 mmol/kg body weight diallyl disulfide or diallyl trisulfide, or the vehicle (corn oil; 2 ml/kg body weight) every other day for 2 weeks before being injected with endotoxin (i.p., 5 mg/kg body weight). Control rats were administered with corn oil and were injected with sterile saline. Samples for the measurement of proinflammatory cytokines were collected 3 h after injection, and all other samples were collected 18 h after injection. The low dose of GO suppressed endotoxin-induced inducible nitric oxide synthase (iNOS) activity, ulceration, and apoptosis in the intestinal mucosa (P < 0.05). The high dose of GO significantly lowered the peripheral level of nitrate/nitrite and endotoxin-induced iNOS activity in the intestinal mucosa (P < 0.05) but worsened intestinal mucosal damage accompanied by elevated peripheral proinflammatory cytokines. Diallyl trisulfide but not diallyl disulfide showed similar toxic effect as that of high-dose GO. These results suggest the preventive effect and possible toxicity of garlic oil and its organosulfur compounds in endotoxin-induced systemic inflammation and intestinal damage.