Intracerebral delivery of drugs for the treatment of central nervous system disorders is usually limited by the blood-brain barrier (BBB). Transdermal drug delivery systems (TDDS) have the advantage of improving patient compliance and avoiding first-pass effects compared to intravenous, oral and intranasal drug delivery, and are an emerging non-invasive drug delivery route that facilitates long-term drug delivery to patients. The discovery of direct subcutaneous targeting of lymphatic pathways to brain tissue has made TDDS a new brain-targeted drug delivery strategy. At the same time, the development of nano-delivery technology has further facilitated the application of TDDS for targeted drug delivery to the brain. This review summarizes the mechanism of transdermal drug delivery into the brain and the application of TDDS in the treatment of brain diseases, providing new ideas and methods for the treatment of central nervous system diseases.

The purpose of the study is to construct R8 peptide (RRRRRRRR) and pH sensitive polyethylene glycols (PEG) co-modified liposomes (Cl-Lip) and utilize them in breast cancer treatment. The co-modified liposomes were prepared with soybean phospholipid, cholesterol, DSPE-PEG2K-R8 and PEG5K-Hz-PE (pH sensitive PEG). The size and zeta potential of Cl-Lip were also characterized. The in vitro experiment demonstrated that the Cl-Lip had high serum stability in 50% fetal bovine serum. The cellular uptake of Cl-Lip under different pre-incubated conditions was evaluated on 4T1 cells. And the endocytosis pathway, lysosome escape ability and tumor spheroid penetration ability were also evaluated. The results showed the particle size of the Cl-Lip was (110.4 ± 5.2) nm, PDI of the Cl-Lip was 0.207 ± 0.039 and zeta potential of the Cl-Lip was (-3.46 ± 0.05) mV. The cellular uptake of Cl-Lip on 4T1 cells was pH sensitive, as the cellular uptake of Cl-Lip pre-incubated in pH 6.0 was higher than that of pH 7.4 under each time point. The main endocytosis pathways of Cl-Lip under pH 6.0 were micropinocytosis and energy-dependent pathway. At the same time, the Cl-Lip with pre-incubation in pH 6.0 had high lysosome escape ability and high tumor spheroid penetration ability. All the above results demonstrated that the Cl-Lip we constructed had high pH sensitivity and is a promising drug delivery system.
Animals ; Cell Line, Tumor ; Cell-Penetrating Peptides ; chemical synthesis ; chemistry ; Cholesterol ; chemistry ; Drug Delivery Systems ; Liposomes ; Mice ; Oligopeptides ; chemical synthesis ; chemistry ; Particle Size ; Phospholipids ; chemistry ; Polyethylene Glycols

The purpose of this study is to prepare T7 and TAT dual modified liposomes (T7-TAT-LIP) to penetrate through blood brain barrier and target to brain tumor cells. The liposomes were prepared with CFPE, T7 modified PEG-DSPE, TAT modified PEG-DSPE, soybean phospholipid, PEG-DSPE and cholesterol. The CFPE was used to track the cellular uptake efficiency. The density of T7 and TAT and the length of PEG were optimized, and then the liposomes were characterized by particle size, zeta potential, morphology and stability. Afterwards, the cellular uptake by bEnd.3 and C6 cells were evaluated. The results showed that the optimized parameters were 6% of T7, 0.5% of TAT, the molecular weight of PEG for T7 was 2000 and the molecular weight of PEG for TAT was 1000. After optimization, the particle size of T7-TAT-LIP was 118 nm, the zeta potential was -6.32 mV and the particles were spherical. The turbidity and particle size of liposomes were not obviously changed after 24 h incubation in PBS at 37 °C. The particle size and polydispersity index were also stable during 1 month incubation at 4-8 °C. The cellular uptake by both bEnd.3 and C6 cells of T7-TAT-LIP was higher than that of T7 or TAT modified liposomes, suggesting dual modified liposomes possessed better blood brain barrier targeting ability and brain tumor targeting ability than the single ligand modified liposomes.
Biological Transport ; Blood-Brain Barrier ; Brain Neoplasms ; drug therapy ; Cell-Penetrating Peptides ; pharmacology ; Cholesterol ; Liposomes ; Particle Size ; Phosphatidylethanolamines ; Polyethylene Glycols

As a new type of carbon nanomaterials, fluorescent carbon dots (fluorescent CDs) have many advantages when compared with the traditional fluorescent probes. They are photoluminescence stable and resistance to photo bleaching. Moreover, they are excellent in biocompatibility, low-toxic and easy to modify. All these above make them a promising optical image material as a probe in optical image. This article reviews structure, the common carbon sources, the preparation methods, and the light-emitting principles of the carbon dots. We also introduce the research progress of fluorescent carbon dots in biomedicine, and the problems need to be resolved in the study of fluorescent CDs.
Carbon ; chemistry ; Fluorescent Dyes ; chemistry ; Nanostructures ; chemistry ; Quantum Dots ; chemistry

OBJECTIVETo investigate the facial aging analysis of 1200 Han adult people in Dalian with iris diameter, so as to provide reference for facial rejuvenation in Han people.

METHODS1200 facial digital photographs from the second-generation ID card of China were stratified randomly selected as the research sample, excluding facial deformity, tattooing eyebrow, tattooing lid margin, ptosis, lip grain and eyebrow deformity cases, as well as the cases whose join point of upper eyelid and lower eyelid not exposed at the nasal side. These photos were divided into six cohorts: female aged 18, 38, and 68 years old; and male aged 18, 38, and 68 years old, with 200 cases in each cohort. The individual iris diameter was divided into 20 equal parts in each photograph, with each part marked one unit as individual iris diameter ruler. Ten values were made from a horizontal plane between the medial canthus to ten points at one face ( the line between two medial canthus is used as the horizontal line, circumocular and facial soft tissue were measured with individual iris diameter ruler on the photographs), then the results were analyzed with Adobe Photoshop software.

RESULTSThere are statistically significant differences in eyebrow height (36.42 ± 4.22 unit in 18 years old male group, 40.22 ± 6.90 unit in 38 years old male group, 34.83 ± 9.39 unit in 68 years old male group; 37.59 ± 6.72 unit in 18 years old female group, 41.09 ± 5.15 unit in 38 years old female group, 36.84 ± 9.45 unit in 68 years old female group), palpebral fissure height, physiognomic external canthus height, palpebral fissure width, pupil height and other items (P < 0.05).

CONCLUSIONS(1) The brow position rises to the peak level at middle age (38 years old group), then drops down gradually with aging. (2) The physiognomic external canthus moves towards the nasal side and caudal side with aging. (3) Eyeball moves towards caudal side with aging. (4) The soft tissue around bilateral angle of mouth, nasal tip and submaxilla moves towards caudal side with aging. (5) The measurement of individual iris diameter ruler can apply to analyze the aging changes of facial soft tissue, and is more suitable for the case when facial photographs are taken at different distances.

Adolescent ; Adult ; Age Factors ; Aged ; Aging ; China ; ethnology ; Cohort Studies ; Eye ; anatomy & histology ; Eyebrows ; anatomy & histology ; Face ; anatomy & histology ; Female ; Humans ; Iris ; anatomy & histology ; Lip ; anatomy & histology ; Male ; Nose ; anatomy & histology ; Photography ; Rejuvenation ; Sex Factors

Objective To observe the clinical curative effet and survival condition of sorafenib for patients with advanced hepatocellular carcinoma.Methods Sixty-six patients with hepatocellular carcinoma during January 2013 to January 2015 in Chang'an Hospital were included.All patients were randomly divided into transcatheter arterial chemoembolization (TACE) group (n =33) and sorafenib + TACE group (n =33) according to the random digital table method.Followed up for 2 years,we observed the clinical curative effect,including 6-months survival rate,1-year survival rate,the changes of serum alpha fetoprotein level before and after the treatment,survival time and related adverse reactions.Results The disease control rate of sora-fenib + TACE group was 84.85％ (28/33),which was significantly higher than that of TACE group (60.61％,20/33),and the difference was statistically significant (x2 =4.889,P =0.027).The median survival time of patients with sorafenib +TACE group was 20.30 months,which was longer than that of TACE group (12.50 months),and the difference was statistically significant (x2 =29.570,P =0.000).The 6-months and 1-year survival rates in patients with sorafenib + TACE group were 93.93％ and 75.76％,respectively,which were significantly higher than those of TACE group (84.85％,51.52％).The rate of 1-year recurrence and metastasis of sorafenib + TACE group was 21.21％,which was lower than that of TACE group (39.39％),and the difference was statistically significant (x2 =2.908,P =0.041).After 6 months treatment,the serum level of alpha fetoprotein in patients with sorafenib + TACE group was (1 911.53 ± 457.86)ng/ml,which was signi-ficantly lower than that of TACE group [(2 979.83± 842.71)ng/ml],and the difference was statistically significant (t =11.996,P =0.001).The median survival time of patients with Child-Pugh A was significantly longer than that of patients with Child-Pugh B (20.50 months vs.13.95 months),with a significant difference (x2 =3.973,P =0.046).Patients in sorafenib + TACE group and TACE group had adverse reactions including nausea,vomiting and abnormal liver function,and there was significant difference in the incidence of untoward effects (87.88％ vs.60.61％;x2 =6.418,P =0.011).Conclusion The application of sorafenib the-rapy in the treatment of advanced hepatocellular carcinoma based on TACE can effectively improve the disease control rate,prolong the survival time of patients and improve the survival rate of patients.

Objectives To clarify the basic data such as prevalent range,regiohal characteristics and the population at risk of drinking brick-tea type fluorosis in China.Methods Comprehensive survey for basic information was conducted in the provinces and autonomous regions where drinking brick-tea type fluorosis Wag prevalent,ineluding Inner Mongolia Autonomous Region,Tibet Autonomous Region, Sichuan Province,Xinjiang Autonomous Region, Qinghai Province,Gansu Province,Ningxia Autonomous Region and Yunan Province.The survey included the number ot counties(cifies)and townships(towns)where the people were accustomed to drinking brick-tea,pepulation,ethnic minority composition,the production and living style,sales and the kinds of brick-tea aIn so on.Results Two hundred and forty-one counties and 3246 townships were found to haye the habit 0f drinking brick-tea,among which 87.46%(2839/3246)had the habit for more than 30 years.There were 31 684 administrative vilages(residents' committees),15 047 elementary schools and 2873 temples surveyed,coveting a total population of 31 052 398 and 122 739 monks.Fifty-three ethnic minorities were involved.Han accounted for 44.86%(12 902 710/31 052 398), Uighur ethnic for 20.98%(7 416 474/31 052 398),Tibetan ethnic for 13.34%(4 323 272/31 052 398),Muslim ethnicfor 8.15%(2 767 603/31 052 398),Mongolian ethnic for 4.61%(1 400 206/31 052 398),Kazak ethnicfor 3.45% (1 218 272/31 052 398),of the population of drinking brick-tea,farmer population accounted for 64.13%(19 912 833/ 31 052 398),herdsman population for 8.79%(2 728 418/31 052 398),farmer-herdsman population for 12.53%(3 889 678/ 31 052 398)and town population for 14.56%(4 521 169/31 052 398).There Was 3926.74 tons of brick-tea sold per year in the investigated regions,mainly of Fu brick-tea,Green brick-tea and Black brick-tea.Areas with high brick- tea consumption distributed mainly in farmer region and farmer-herdsman region.Annual per capita consumption of brick-tea for farmers was 3.77 kg,and for farmer-herdsman population was 2.05 kg.Conclusions Begions with the habit of drinking brick-tea distributes extensively in western China and cover a huge population,and the herdsmen and farmer-herdsman are the main risk population.Drinking brick-tea type fluorosis is a seriolls public health issue in western China.

Objective To assess the quantitative relationship between the distribution of Himalayan marmot and its ecological environment,the terrain,the temperature and the precipitation,using remote sensing and geographic information system in Qinghai province.Methods The distribution of Himalayan marmot was located by Google Earth and ArcGIS software and by using field survey data provided by Chinese Center for Disease Control and Prevention.The corresponding ecological environment of marmot including terrain,temperature and precipitation were derived from the spatial information datasets.All results were processed according to the overlay and statistics analysis using ArcGIS software.Results Seventy-seven point twenty-seven percent(153/198) of Himalayan marmot were distributed in the area of elevation between 3000 and 4000 meters.The number of marmot reached the highest when the slope was between 0 and 17 degrees,and aspect range was between 91 and 270 degrees,180 degree was as south direction.During the period with the maximum temperature of the warmest month of 14.3-17.5 ℃,17.6-20.8 ℃ and 20.9-24.0 ℃,the distribution of marmot reached 95％(186/198) of the total area.Meanwhile,most of the marmot were presented in the area with average precipitation of 46-108 mm.Conclusions A quantitative analysis of appropriate ecological environment of Himalayan marmot in a large scope is carried uul successfully using remote sensing and geographic information system.The study indicates that spatial information technology has important applications in plague prevention and control.

Biomacromolecules participate in various kinds of vital processes. Observing and analyzing their structural dynamic and the dynamic processes of intermolecular interaction at molecular level is important for understanding the action mechanism. Since its advent, single molecular fluorescence resonance energy transfer (SM-FRET) has demonstrated its great potential in studying the conformational change and interaction process of biomacromolecules, and a series of new mechanisms have been revealed. This review summarized recent progresses of SM-FRET in studying protein structural dynamic, nucleic acid structural dynamic, protein-protein and protein-nucleic acid interactions.

BACKGROUNDCortical spreading depression can cause migraine attack, and up-regulate matrix metalloproteinase-9 (MMP-9) expression in animal. This study aimed to determine the impact on the structure and function of the blood-brain barrier by measuring plasma MMP-9 levels in patients at the acute and late stages of migraine attacks in order to elucidate the pathological mechanisms involved.

METHODSWe recruited a case-control cohort of 38 adult migraine patients and 20 age- and gender-matched healthy control subjects. Five milliliter blood samples were collected at the acute and late stages of migraine (days 1 - 7), and also from the control subjects. Solid phase double antibody sandwich enzyme-linked immunosorbent assay was used to determine plasma MMP-9 levels. Statistical analysis was performed using the SAS version 9.1.

RESULTSInitial plasma MMP-9 levels of migraine patients were significantly higher than those of controls ((12.612 ± 0.016) µg/L vs. (6.069 ± 0.023) µg/L, respectively, P < 0.05). High MMP-9 expression was observed during days 1 - 6 of migraine attacks, with highest expression occurring on day 3 ((17.524 ± 0.035) µg/L). During attacks, MMP-9 levels were similar in migraine patients with and without aura (P > 0.05); in addition, levels were not correlated with degree of headache pain (P > 0.05).

CONCLUSIONSWe hypothesize that migraine could lead to increased plasma MMP-9 levels resulting in blood-brain barrier damage. MMP-9 levels increase during days 1 - 6 of migraine attacks, peaking on day 3. Therefore, MMP-9 could be used as a biological marker to guide treatment of migraine attacks.

Adult ; Blood-Brain Barrier ; metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Male ; Matrix Metalloproteinase 9 ; blood ; Middle Aged ; Migraine Disorders ; physiopathology ; Young Adult