Role of Nanomedicine-Based Therapeutics in the Treatment of CNS Disorders.

Central nervous system disorders, especially neurodegenerative diseases, are a public health priority and demand a strong scientific response. Various therapy procedures have been used in the past, but their therapeutic value has been insufficient. The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier is two of the barriers that protect the central nervous system (CNS), but are the main barriers to medicine delivery into the CNS for treating CNS disorders, such as brain tumors, Parkinson's disease, Alzheimer's disease, and Huntington's disease. Nanotechnology-based medicinal approaches deliver valuable cargos targeting molecular and cellular processes with greater safety, efficacy, and specificity than traditional approaches. CNS diseases include a wide range of brain ailments connected to short- and long-term disability. They affect millions of people worldwide and are anticipated to become more common in the coming years. Nanotechnology-based brain therapy could solve the BBB problem. This review analyzes nanomedicine's role in medication delivery; immunotherapy, chemotherapy, and gene therapy are combined with nanomedicines to treat CNS disorders. We also evaluated nanotechnology-based approaches for CNS disease amelioration, with the intention of stimulating the immune system by delivering medications across the BBB.

SHR-A1403, a novel c-Met antibody-drug conjugate, exerts encouraging anti-tumor activity in c-Met-overexpressing models.

Emerging evidence demonstrates that a c-Met antibody-drug conjugate (ADC) has superior efficacy and safety profiles compared with those of currently available small molecules or antibody inhibitors for the treatment of c-Met-overexpressing cancers. Here we described both the in vitro and in vivo efficacies of SHR-A1403, a novel c-Met ADC composed of a humanized IgG2 monoclonal antibody against c-Met conjugated to a novel cytotoxic microtubule inhibitor. SHR-A1403 showed high affinity to c-Met proteins derived from human or monkey and potent inhibitory effects in cancer cell lines with high c-Met protein expression. In mice bearing tumors derived from cancer cell lines or patient HCC tissues with confirmed c-Met overexpression, SHR-A1403 showed excellent anti-tumor efficacy. Antibody binding with c-Met contributed to SHR-A1403 endocytosis; the subsequent translocation to lysosomes and cytotoxicity of the released toxin are speculated to be predominant mechanisms underlying the anti-tumor activity of SHR-A1403. In conclusion, SHR-A1403 showed significant anti-tumor activity in cancer cell lines, xenograft mouse models and an HCC PDX model, which all have high c-Met levels. These data provide references for SHR-A1403 as a potential therapy for the treatment of cancers with c-Met overexpression.

Recent advances in the role of endogenous hydrogen sulphide in cancer cells.

Hydrogen sulphide (H2 S) is a gaseous neurotransmitter that can be self-synthesized by living organisms. With the deepening of research, the pathophysiological mechanisms of endogenous H2 S in cancer have been increasingly elucidated: (1) promote angiogenesis, (2) stimulate cell bioenergetics, (3) promote migration and proliferation thereby invasion, (4) inhibit apoptosis and (5) activate abnormal cell cycle. However, the increasing H2 S levels via exogenous sources show the opposite trend. This phenomenon can be explained by the bell-shaped pharmacological model of H2 S, that is, the production of endogenous (low concentration) H2 S promotes tumour growth while the exogenous (high concentration) H2 S inhibits tumour growth. Here, we review the impact of endogenous H2 S synthesis and metabolism on tumour progression, summarize the mechanism of action of H2 S in tumour growth, and discuss the possibility of H2 S as a potential target for tumour treatment.

Assessment of Attitudes and Intentions towards COVID-19 Vaccines and Associated Factors among General Populations of Pakistan: A Cross-Sectional Study.

OBJECTIVE: The goal of public health in combatting COVID-19 is to increase herd immunity. However, vaccine reluctance makes attaining herd immunity a worldwide challenge. This investigation aimed to identify negative and positive attitudes and intentions about COVID-19 vaccinations. METHODS: A cross-sectional online survey was conducted once free COVID-19 vaccines became available in Pakistan in 2021. 4392 Pakistanis aged 18 and older were surveyed from seven administrative units between 1 July and 30 August 2021. Online structured questionnaires were utilized to collect data using a simple sampling procedure. The questionnaires were divided into three major sections: sociodemographic, health factors, and attitudes toward COVID-19. RESULTS: The survey link was shared with approximately 4500 participants. 97.6%(4392) completed the survey once begun. Frequency, percentage and Chi-square tests were used to analyze statistical data. Most of the participants in the research were men (2703 (61.54%)), 3277 (74.61%) were aged 18-29 years, and 1824 (41.53%) were residents of the Khyber Pakhtunkhwa province. (18.69%) Respondents expressed COVID-19 vaccine hesitancy, whereas 36.66% of participants liked getting the Sinopharm and Sinovac vaccines and (35.84%) of participants preferred the Pfizer vaccine. A significant number of participants (38.05%) were concerned about the vaccine's unexpected side effects Thus, it is essential to realize that many participants were concerned about the vaccine's unexpected side effects. CONCLUSIONS: The overall high level of concern about the unforeseen side effects of COVID-19 vaccines, as well as widespread vaccine hesitancy among Pakistani populations and its predictors, should be taken into account if public health intervention campaigns in Pakistan are changing negative attitudes and improving compliance with regard to COVID-19 vaccines.

[Experimental studies of therapeutic effect of Rheum officinale on acute pancreatitis].

OBJECTIVE: To investigate the therapeutic effect of Rheum officinale on acute pancreatitis. METHODS: Buffered sodium taurocholate (3% m/V) was injected into the pancreatico-biliary duct to induce acute pancreatitis. Death rate,coefficient of pancreas, serum amylyse (AMY), hemocuprein (SOD), TNF-alpha and IL-1beta level were examined at 6, 12 and 24 hours after operations. Pathology analysis were also obtained. RESULTS: Compared with corresponding pancreatitis groups,death rate, coefficient of pancreas, serum TNF-alpha and IL-1beta level of drug groups decreased remarkably (P < 0.05), while serum SOD level significantly increased (P < 0.01). Serum AMY level of drug groups increased at 6 h (P < 0.01), decreased at 12 h (P < 0.01) and had no statistics disparity at 24 h (P > 0.05) compared with respective pancreatitis group. Although score points of all drug groups were lower than corresponding pancreatitis groups, the growth tendency of both were similar. CONCLUSION: Rheum officinale Baill has the effect of prevention to pancreas pathological changes in the animal pattern, but not able to reverse the tendency.

[In vitro study on two kind of recombinant adeno-associated virus-mediated transfection efficiency with enhanced green fluorescent protein into rats osteoblasts].

OBJECTIVE: To compare the transfection efficiency of two kind of recombinant adeno-associated virus-mediated transfection to rats osteoblasts with enhanced green fluorescent protein and assess the feasibility of it as a vector for gene therapy of osteoblast lesions. METHODS: The osteoblasts of rats were isolated, cultured and identified with type I collagen staged digestion method. According to different multiplicity of infection (MOI) (MOI = 1 x 10(3), 1 x 10(4), 1 X 10(4), 5 x 10(5)), rAAV-EGFP was transfected into osteoblasts with rAAV only and rAAV-ADV co-transfection respectively. The expression of EGFP along with the transfection time was observed under inverted fluorescence microscope. The transfection efficiency and fluorescence intensity was evaluated by flow cytometry. The best MOI value was analysed and the cell growth curves were obtained according to the best MOI value to evaluate the toxic effects of rAAV-EGFP. RESULTS: The cultured cells possessed the biological behaviors of osteoblasts. The transfection efficiency of the rAAV was increased with the increasing of MOI. The EGFP expression reached the maximum on day 5 in ADV(-) group, the transfection efficiency of rAAV2/6-EGFP and rAAV2/9-EGFP was 90.2% and 66.1% respectively when MOI was 1 x 10(5) and no significant increase was observed when MOI was 5 x 10(5). In ADV(+) group, EGFP expression reached its maximum on day 3, the transfection efficiency of rAAV2/6-EGFP and rAAV2/9-EGFP was 47.6% and 30.5% respectively when MOI was 5 x 10(5). And no significant biologic effects on the cyto-activity was observed. CONCLUSION: The transfection efficiency of two kind of virus vectors was both very high and rAAV2/6's is higher than that of rAAV2/9. This suggested the potential of rAAV-EGFP as a safe and efficient vector for gene therapy.

[Effects of Panax notoginseng saponins on anti-hyperglycemic, anti-obese and prevention from kidney pathological changes in KK-Ay mice].

OBJECTIVE: To observe the effects of Panax notoginseng saponins (PNS) on anti-hyperglycemic, anti-obese and prevention from kidney pathological changes in a type 2 diabetic KK-Ay gene mice model. METHODS: All animals were divided into 4 groups: Normal control group (C57BL/6J mice) were treated by NS 10 mL/kg, KK-Ay mice were subdivided into 3 groups as DM administrated NS 10 mL/kg, PNS 50 mg/kg, PNS 200 mg/kg respectively. All the animals received daily intraperitoneal injections for 30 days consecutively. All of these following items were determined as the effect of PNS: fasting plasma glucose levels (FPG), intraperitoneal glucose tolerance, body weight, food intake, insulin resistance index (IRI), serum insulin, triglyceride (TG), cholesterol (CH) levels and contribution of glomerulus injury. RESULTS: On the 12th, 22nd and 30th day, PNS-treated group had significantly lower FPG and low body weight incremental percentage. After a 12-day treatment, glucose tolerance was significantly improved. On the 30th day the serum IRI and TG levels of PNS-treated group decreased significantly, and the development of the mice glomerular lesions was prevented significantly. All of these showed a dose-effect relationship. CONCLUSION: PNS has the effects of anti-diabetes, anti-obese and prevention from kidney pathological changes in type 2 diabetic KK-Ay mice.

Totally thoracoscopic closure of ventricular septal defect without a robotically assisted surgical system: a summary of 119 cases.

OBJECTIVES: To summarize the clinical outcomes of totally thoracoscopic closure of a ventricular septal defect (VSD). METHODS: Totally thoracoscopic VSD closure was performed in 119 patients (66 boys; mean age, 7.1 ± 3.6 years). An additional 35 patients undergoing open-chest VSD closure were selected as a control group. Using 3 port incisions in the right chest, pericardiotomy, bicaval occlusion, atriotomy, and VSD closure were performed by thoracoscopy without the aid of a robotically assisted surgical system. RESULTS: Cardiopulmonary bypass and aortic crossclamp times were 42.2 ± 9.8 and 32.5 ± 7.3 minutes, respectively. There were no deaths but 1 patient required insertion of a permanent pacemaker as a result of postoperative atrioventricular conduction block. The length of stay in the intensive care unit (11.0 ± 2.6 vs 22.9 ± 4.9 hours, P < .01) or postoperative hospital stay (4.2 ± 1.1 vs 6.6 ± 2.1 days, P < .03) in the thoracoscopic group were shorter than in the control group. The percentage of patients who required postoperative opioid analgesics in the thoracoscopic group was lower than in the control group (31.9% vs 74.2%, P < .001). Rate of blood transfusion during the operation (17.6% vs 65.7%, P = .001) and the postoperative use of opioid analgesics (31.9% vs 74.3%, P = .003) in the thoracoscopic group was lower than in the control group. Transesophageal echocardiographic analysis 4.6 ± 2.3 months after the operation showed complete closure of the defect. CONCLUSIONS: Totally thoracoscopic closure of VSD through a 3-port entry was safe and effective.

Effect of fluorescent silica nanoparticles in embryo and larva of Oryzias latipes: sonic effect in nanoparticle dispersion.

We characterized fluorescent silica nanoparticles (FNPs), which had been applied in many biological systems, in fish embryo rearing media (ERM) solution and evaluated the potential toxicity to the early development of Oryzias latipes embryos. Distribution of FNPs in embryos and larvae of O. latipes was studied by fluorescent and confocal laser scanning microscopic studies. Embryos exposed to three different concentrations of FNPs in stirred or sonicated ERM solutions were observed up to 2d after hatching. FNPs had a negligible effect on the hatchability of O. latipes embryos; however, compared to controls, more than 30% of eggs were abnormal in 10 and 50 mg FN P L(-1) solutions. We found that the toxic effect was increased in sonicated FNP solution, which seems to be related with the dissolution of FNPs in ERM solutions that could be accelerated by sonication. Further study found that the CaCl2 included in ERM solution might enhance the dissolution of the FNPs and the silicate ion released from FNPs partially contributed to larval toxicity. This study showed that some nanoparticles may not be stable in biological fluids even if they are stable in water. Dissolution factors such as sonication and cellular components should be considered in biological application of nanoparticles.

Anti-diabetic effects of Panax notoginseng saponins and its major anti-hyperglycemic components.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng (Burk) F.H. Chen (Araliaceae) is a well-known and commonly used traditional Chinese herb for treatment of various diseases, such as hemostasis, edema and odynolysis. AIM OF STUDY: Our aim was to investigate the mechanisms of anti-hyperglycemic and anti-obese effects of Panax notoginseng saponins (PNS) in KK-Ay mice, and explore the components in PNS for such effects. MATERIALS AND METHODS: KK-Ay mice received daily intraperitoneal injections of PNS 200mg/kg or vehicle for 30 days while ginsenoside Re 14 mg/kg, Rd 15 mg/kg, Rg1 40 mg/kg, Rb1 60 mg/kg and notoginsenoside R1 6 mg/kg for 12 days. Fasting blood glucose levels (FBGL), glucose tolerance (GT), serum insulin, leptin levels, body weight changes, food intake, adipose tissues and blood fat levels were measured at different time points. RESULTS: The PNS group had significantly lower FBGL, improved GT and smaller body weight incremental percentage after the 30-day treatment. Additionally, Rb1 exhibited significant reduction of FBGL on day 12, and Re also exhibited a decreasing trend after the 12-day treatment. CONCLUSIONS: PNS possess anti-hyperglycemic and anti-obese activities by improving insulin- and leptin sensitivity, and Rb1 is responsible for the anti-hyperglycemic effect among the five saponins in KK-Ay mice.

Fridericia peregrinabunda (Enchytraeidae) as a new test species for soil toxicity assessment.

The present study proposes Fridericia peregrinabunda (Michaelsen, 1913) as a new test species for assessment of soil ecotoxicity. Fridericia is the richest genus in the Enchytraeidae family (Oligochaeta: Annelida: Clitellata: Enchytraeidae), and widely distributed. The acute toxicity of cadmium (Cd) and antimony (Sb) on the survival of F. peregrinabunda were investigated in laboratory experiments. Adult survival of F. peregrinabunda in metal spiked soil was reduced. Cadmium was more toxic to F. peregrinabunda than Sb. In the artificial soil toxicity tests, the LC50 values for F. peregrinabunda exposed to Cd and Sb for 48 h were 37, and 446 mg kg(-1), respectively. The NOEC values for Cd and Sb were 20 and 100 mg kg(-1) up to 48 h exposure, respectively. This is the first report on the ecotoxicological assay of contaminated soils using the enchytraeids F. peregrinabunda as a test species. It can be concluded that F. peregrinabunda is a suitable test species to measure the acute toxicity of heavy metals, and this species is more sensitive to Cd and Sb than earthworm. The filter paper contact test and 2 day-artificial soil toxicity test appear to be rapid and cost-effective protocols for the potworm assay.

Effects of antimony on aquatic organisms (Larva and embryo of Oryzias latipes, Moina macrocopa, Simocephalus mixtus, and Pseudokirchneriella subcapitata).

Antimony is widespread in aquatic environment. Trivalent forms of antimony are known to be more toxic than other chemical species of antimony. In the present study, antimony potassium tartrate (APT), the trivalent inorganic forms of antimony, was selected as a test antimony compound due to its high water solubility. The effects of antimony on Japanese medaka (Oryzias latipes), planktonic crustacea (Moina macrocopa and Simocephalus mixtus), and green algae (Pseudokirchneriella subcapitata) were evaluated. Larval survival and the embryonic development were measured for fish assay. APT was less toxic to larval medaka (24-h LC50, 261; 48-h LC50, 238 mg L(-1)). Simocephalus mixtus was killed by very low concentrations of APT (24-h LC50, 4.92 mg L(-1)), and antimony was also toxic to Moina macrocopa (24-h LC50, 12.83 mg L(-1)). Toxicities of APT to S. mixtus and Moina macrocopa were about 50 and 20 times more toxic to Oryzias latipes larvae, respectively, in terms of 24-h LC50 value. Growth inhibition of Pseudokirchneriella subcapitata was observed in the presence of APT (72-h EC50, 206 mg L(-1)). This study demonstrated that APT is more toxic to planktonic crustacea than fish and green algae, and planktonic crustacea appears a better indicator of antimony pollution in aquatic environment.

[Relationship of apoptotic receptor expression in normal human peripheral blood lymphocytes to cell apoptosis].

The aim of this study was to detect the expression and cell cycle specificity of Fas, TNFRI and TNFRII in human peripheral blood lymphocytes (PBL), and to study the potential role of Fas, TNFRIand TNFRII in cell cycle specific apoptosis. The improved double-parameter flow cytometry was used to detect the expressions of Fas, TNFRI and TNFRII and cell cycle specificity in PBL which were incubated for 24 hours in the presence or absence of phytohaematoagglutinin (PHA) respectively. Apoptosis induced by IgM type anti-Fas and TNF-alpha was detected by API method. The results showed that compared with PBL treated in the absence of PHA in G(0) phase, the ratio of Fas, TNFRI and TNFRII expressions in PHA-stimulated PBL entering cell cycle increased (35.55 +/- 6.63)%, (30.63 +/- 2.66)%, (26.62 +/- 5.14)% respectively (P < 0.01), and mainly appeared at G(1)-phase; no apoptosis was induced by anti-Fas and TNF-alpha in G(0)-phase PBL cultured in the absence of PHA. On the contrary, the apoptosis was induced by anti-Fas and TNF-alpha in PBL which entered cell cycle after stimulation with PHA and mainly initiated at G(1)-Phase. It is concluded that there is evident dose-effect relationship between apoptotic receptor and receptor-mediated apoptosis. Moreover, the cell cycle specificity of receptor-mediated apoptosis is correlated with the cell cycle specific expressions of apoptotic receptor. The induction of apoptosis by apoptotic factors (anti-Fas and TNF-alpha) depends on whether cell entering cell cycle or not.

[Correlation of receptor-mediated apoptosis to cell cycle].

BACKGROUND & OBJECTIVE: Chondriosome-mediated apoptosis is closely related to cell cycle, however, the correlation of receptor-mediated apoptosis to cell cycle progression is unclear yet. This study was to observe the receptor-mediated apoptosis and cell cycle specificity in cultured normal and tumor lymphocytes, and investigate their correlation. METHODS: Exponentially growing human leukemia cell lines Molt-4 and Jurkat were treated with tumor necrosis factor-alpha (TNF-alpha) or Anti-Fas. Peripheral blood lymphocytes (PBLs) from healthy donors were stimulated by phytohemagglutinin (PHA), and further incubated with the presence of TNF-alpha or anti-Fas. Annexin V/PI was used to detect the apoptosis, and API method was used to illustrate the cell cycle specificity of apoptotic cells. RESULTS: Unstimulated PBLs kept blunt to stimulation with TNF-alpha or anti-Fas, and the apoptotic rate was 6%-8%. Molt-4 cells, Jurkat cells, and stimulated PBLs which were treated with TNF-alpha or anti-Fas went to apoptosis, and the apoptosis rates were 15%-28%. Most receptor-mediated apoptosis happened in early G1 phase. CONCLUSION: Receptor-mediated apoptosis is closely related to cell cycle and presents cell cycle specificity.