Vitamin B12 is associated negatively with anemia in older Chinese adults with a low dietary diversity level: evidence from the Healthy Ageing and Biomarkers Cohort Study (HABCS).

OBJECTIVE: The associations between plasma vitamin B12 level and anemia under different dietary patterns in elderly Chinese people are poorly understood. We aimed to examine the associations between plasma vitamin B12 levels and anemia under different dietary patterns in adults aged 65 years and older in nine longevity areas in China. METHODS: A total of 2405 older adults completed a food frequency questionnaire at the same time as a face-to-face interview. The dietary diversity score (DDS) was assessed based on the food frequency questionnaire, with the low DDS group referring to participants with a DDS score ≤ 4 points. Vitamin B12 levels were divided into two groups of high (>295 pg/mL) and low (≤ 295 pg/mL) with the median used as the cut-off point. Sub-analyses were also performed on older adults divided into tertiles of vitamin B12 levels: low (< 277 pg/mL), medium (277-375 pg/mL) and high (> 375 pg/mL) to study the association of these levels with anemia. RESULTS: Six hundred ninety-five (28.89%) of these people were diagnosed with anemia and had a mean age of 89.3 years. Higher vitamin B12 levels were associated with a decreased risk of anemia (multi-adjusted OR, 0.59, [95% CI, 0.45 ~ 0.77] P < 0.001) in older adults with a low DDS, whereas no significant association between vitamin B12 levels and anemia was found in older adults with a high DDS in a full-model after adjustment for various confounding factors (multi-adjusted OR, 0.88, [95% CI, 0.65 ~ 1.19], P = 0.41). CONCLUSION: The relationship between vitamin B12 levels and the prevalence of anemia was significant only when the level of dietary diversity in the older adults was relatively low. The dietary structure of the population should be taken into consideration in combination in order to effectively improve anemia status by supplementing vitamin B12.

Implications of biological clocks in pharmacology and pharmacokinetics of antitumor drugs.

Mammalians' circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN). SCN control biological rhythms such as the sleep-wake rhythm and homeostatic functions of steroid hormones and their receptors. Alterations in these biological rhythms are implicated in the outcomes of pathogenic conditions such as depression, diabetes, and cancer. Chronotherapy is about optimizing treatment to combat risks and intensity of the disease symptoms that vary depending on the time of day. Thus, conditions/diseases such as allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease, prone to manifest severe symptoms depending on the time of day, would be benefited from chronotherapy. Monitoring rhythm, overcoming rhythm disruption, and manipulating the rhythms from the viewpoints of underlying molecular clocks are essential to enhanced chronopharmacotherapy. New drugs focused on molecular clocks are being developed to improve therapeutics. In this review, we provide a critical summary of literature reports concerning (a) the rationale/mechanisms for time-dependent dosing differences in therapeutic outcomes and safety of antitumor drugs, (b) the molecular pathways underlying biological rhythms, and (c) the possibility of pharmacotherapy based on the intra- and inter-individual variabilities from the viewpoints of the clock genes.

Cyclodextrins as eminent constituents in nanoarchitectonics for drug delivery systems.

Cyclodextrins have been widely employed for drug delivery systems (DDSs) in which drugs are selectively delivered to a target site in the body. Recent interest has been focused on the construction of cyclodextrin-based nanoarchitectures that show sophisticated DDS functions. These nanoarchitectures are precisely fabricated based on three important features of cyclodextrins, namely (1) the preorganized three-dimensional molecular structure of nanometer size, (2) the easy chemical modification to introduce functional groups, and (3) the formation of dynamic inclusion complexes with various guests in water. With the use of photoirradiation, drugs are released from cyclodextrin-based nanoarchitectures at designated timing. Alternatively, therapeutic nucleic acids are stably protected in the nanoarchitectures and delivered to the target site. The efficient delivery of the CRISPR-Cas9 system for gene editing was also successful. Even more complicated nanoarchitectures can be designed for sophisticated DDSs. Cyclodextrin-based nanoarchitectures are highly promising for future applications in medicine, pharmaceutics, and other relevant fields.

Hypericin: A natural anthraquinone as promising therapeutic agent.

BACKGROUND: Hypericin is a prominent secondary metabolite mainly existing in genus Hypericum. It has become a research focus for a quiet long time owing to its extensively pharmacological activities especially the anti-cancer, anti-bacterial, anti-viral and neuroprotective effects. This review concentrated on summarizing and analyzing the existing studies of hypericin in a comprehensive perspective. METHODS: The literature with desired information about hypericin published after 2010 was gained from electronic databases including PubMed, SciFinder, Science Direct, Web of Science, China National Knowledge Infrastructure databases and Wan Fang DATA. RESULTS: According to extensive preclinical and clinical studies conducted on the hypericin, an organized and comprehensive summary of the natural and artificial sources, strategies for improving the bioactivities, pharmacological activities, drug combination of hypericin was presented to explore the future therapeutic potential of this active compound. CONCLUSIONS: Overall, this review offered a theoretical guidance for the follow-up research of hypericin. However, the pharmacological mechanisms, pharmacokinetics and structure activity relationship of hypericin should be further studied in future research.

Child undernutrition and associated factors among children 6-23 months old in largely food insecure areas of rural Ethiopia.

Child malnutrition is the leading public health problem in Sub-Saharan Africa, resulting in poor health and economic losses. Ethiopia has one of the highest child undernutrition rates in the world that occurs to multifaceted factors, including food insecurity. Thus, we performed a cross-sectional study to assess the prevalence and risk factors for child undernutrition in largely food insecure areas of Ethiopia. Data were collected from 354 mother-child pairs from the Siraro district. Both bivariate and multivariate logistic regression was used for statistical analysis. Variables with a P-value of <0⋅05 in multivariate analysis were used to detect statistical significance at a 95 % confidence level. About 67 % of households are food insecure. The prevalence of stunting wasting and underweight were 42⋅7, 9⋅9 and 27⋅7 %, respectively. Female gender, higher age of the child (12-23 months v. 6-11 months), living in a household with five or more siblings, not getting therapeutic zinc supplement at least once, inadequate diet diversity, lack of growth monitoring service, and maternal own income increases the likelihood of child undernutrition. It can be concluded that child undernutrition is a severe public health problem in the study area. Improving primary healthcare services related to zinc supplementation, growth monitoring and promotion, and improving infant and child feeding practices can be considered as a strategy to address the problem.

Sorafenib-loaded silica-containing redox nanoparticles for oral anti-liver fibrosis therapy.

Liver fibrosis is a chronic disease resulting from repetitive or prolonged liver injury with limited treatment options. Sorafenib has been reported to be a potential antifibrotic agent; however, its therapeutic effect is restricted because of its low bioavailability and severe adverse effects in the gastrointestinal (GI) tract. In this study, we developed sorafenib-loaded silica-containing redox nanoparticles (sora@siRNP) as an oral nanomedicine to treat liver fibrosis. The designed siRNP were prepared by self-assembly of amphiphilic block copolymers, which possess antioxidant nitroxide radicals as a side chain of the hydrophobic segment and porous silica particles in the nanoparticle core. The silica moieties in the core formed a crosslink between the self-assembling block copolymers to afford stable drug absorption, which could be useful in harsh GI conditions after oral drug administration. Based on in vitro evaluation, sora@siRNP exerted antiproliferative and antifibrotic effects against hepatic stellate cells (HSCs) and low toxicity against normal endothelial cells. A pharmacokinetic study showed that siRNP significantly improved the bioavailability and distribution of sorafenib in the liver. In an in vivo study using a mouse model of CCl4-induced liver fibrosis, oral administration of sora@siRNP significantly suppressed the fibrotic area in comparison to free sorafenib administration. In mice with CCl4-induced fibrosis, free sorafenib administration did not suppress the expression of α-smooth muscle actin; however, mice treated with sora@siRNP showed significantly suppressed expression of α-smooth muscle actin, indicating the inhibition of HSC activation, which was confirmed by in vitro experiments. Moreover, oral administration of free sorafenib induced severe intestinal damage and increased leakage into the gut, which can be attributed to the generation of reactive oxygen species (ROS). Our antioxidant nanocarriers, siRNP, reduced the adverse effects of local ROS scavenging in the GI tract. Our results suggest that sora@siRNP could serve as a promising oral nanomedicine for liver fibrosis.

Phenotype assessment in neurologically impaired paediatric patients: Impact of a nutrition intervention protocol.

BACKGROUND: Deficits in nutritional status and functional feeding disorders are common in Neurologically Impaired Paediatric Patients (NIPP). Interventions addressing these problems could offer better overall health status and quality of life in this group of patients, but the extent of their effectiveness is yet to be determined. Recent guidelines concerning the nutritional care of NIPP have been published from ESPGHAN but compliance to them has not been assessed. AIM: The study aimed to assess the phenotypic profile of a group of NIPP attending the outpatient clinic of a pediatric department, and to implement, for the first time to our knowledge, an individualized nutritional intervention protocol following ESPGHAN guidelines 2017 as well as to assess the impact on phenotypic parameters and nutritional status. PATIENTS AND METHODS: 68NIPP and their caregivers aged 1m-17 years (83.8% suffering from cerebral palsy (CP) were invited to assess their phenotypic parameters and to implement in a nutrition intervention protocol in order to improve their dietary intake and nutritional status. Anthropometry (weight, height, triceps skinfold thickness, mid upper arm circumference) was expressed as z-scores for age and sex using WHO Anthro software and classified following the WHO criteria. Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS), Dysphagia Disorder Survey (DDS), Saliva Severity Scale (SSS), gastrointestinal complications, energy and nutrient intake were assessed at the beginning (zero point), after 6 (point 1) and 12 (point 2) months period. Intake to Requirement ratio (I/R) was derived. At zero point, following the baseline evaluation, caregivers were advised and educated on nutrition protocol and customized nutrition plans were handed out. The impact of the nutritional intervention on the phenotypic parameters was recorded on follow up visits (points 1, 2).The primary outcomes analyzed were anthropometric parameters (Waz), as indicators of nutritional status. GMFCS, MACS, DDS, SSS, FA were evaluated as possible predictors of this outcome. Secondary outcomes included the impact of the intervention protocol on the phenotypic parameters during the study period. RESULTS: Based on weight for age z-score (Waz ≤ -2) (WHO) 17 patients (32.1%) were undernourished, 5/68 (10, 4%) were with triceps skinfold thickness z-score (TSTz) <-2 and 3/68 (7%) with mid upper arm circumference z-score (MUACz) <-2. Z-scores (WHO) for weight (p1 = 0, 036) (p2 = 0, 003), body mass index (BMI) (p2 = 0,000), MUAC (p1 = 0, 029) and TST (p1 = 0, 021) (p3 = 0, 044) were significantly improved in follow-up evaluations compared to the baseline. Less NIPP were found to be underweight according to Waz from point 1 to point 2 (p3 = 0, 006), as well as stunding according to height for age z-score (Haz) from point 1 to point 2 (p ≤ 0,001). Patients with higher levels of GMFCS (p1 = 0,040), MACS (p1 = 0,028) DDS (p1 = 0,001) and SSS (p1 = 0,005) had significantly lower Haz. Patients with higher levels of SSS (p1 = 0,002) had significantly lower TSTz scores. There were no significant changes in the classification of NIPP according to DDS or the patients' feeding ability. The energy (kcals) intake/kg of body weight (bw) was significantly higher at point 2 compared to point zero (p3 = 0,028), protein intake/kg of body weight was significantly higher at points 1 and 2 compared to point zero (p1 = 0,026, p3 = 0,003), and fat intake/kg of body weight (bw) was significantly higher at point 2 compared to point zero (p3 = 0,012). Intake of energy (kcals)/bw (p1 = 0,026), (p2 = 0,046), (p3 = 0,048) carbs/bw (p1 = 0,014) (p2 = 0,042), I/R of pro (p1 = 0,032), (p3 = 0,013), and fat/kg (p2 = 0, 033) (p3 = 0,037) were found to be significantly lower in higher GMFCS levels. DQI did not improve during the study period nor correlated to any of the anthropometric parameters. Gastrointestinal complications correlated with Waz (r = -, 285 p1 = 0, 011). Feeding Ability (FA) was found to be the only strong predictor for Waz at baseline evaluation (p = 0,012) when a multiple regression was run along with DDS. CONCLUSION: Underweight was detected in one third of the patients, some degree of dysphagia in 69% and gastrointestinal complications in 58.8% of the sample. Height for age z-score (Haz) was the anthropometric parameter most sensitive to the changes in ranking on motor and functional feeding scores. The implementation of a customized nutrition intervention protocol in line with ESPGHAN's guidelines had a beneficial effect on improving dietary intake and nutritional status of NIPP after a 12 months period. Better results could be expected if dysphagia and feeding ability were also addressed by appropriate intervention protocols. Patients' feeding ability is of importance for predicting Waz.

Endometriosis Susceptibility to Dapsone-Hydroxylamine-Induced Alterations Can Be Prevented by Licorice Intake: In Vivo and In Vitro Study.

Endometriosis, an estrogen-dependent chronic gynecological disease, is characterized by a systemic inflammation that affects circulating red blood cells (RBC), by reducing anti-oxidant defenses. The aim of this study was to investigate the potential beneficial effects of licorice intake to protect RBCs from dapsone hydroxylamine (DDS-NHOH), a harmful metabolite of dapsone, commonly used in the treatment of many diseases. A control group (CG, n = 12) and a patient group (PG, n = 18) were treated with licorice extract (25 mg/day), for a week. Blood samples before (T0) and after (T1) treatment were analyzed for: i) band 3 tyrosine phosphorylation and high molecular weight aggregates; and ii) glutathionylation and carbonic anhydrase activity, in the presence or absence of adjunctive oxidative stress induced by DDS-NHOH. Results were correlated with plasma glycyrrhetinic acid (GA) concentrations, measured by HPLC-MS. Results showed that licorice intake decreased the level of DDS-NHOH-related oxidative alterations in RBCs, and the reduction was directly correlated with plasma GA concentration. In conclusion, in PG, the inability to counteract oxidative stress is a serious concern in the evaluation of therapeutic approaches. GA, by protecting RBC from oxidative assault, as in dapsone therapy, might be considered as a new potential tool for preventing further switching into severe endometriosis.

Curcumin encapsulation in nanostructures for cancer therapy: A 10-year overview.

Curcumin (CUR) is a phenolic compound present in some herbs, including Curcuma longa Linn. (turmeric rhizome), with a high bioactive capacity and characteristic yellow color. It is mainly used as a spice, although it has been found that CUR has interesting pharmaceutical properties, acting as a natural antioxidant, anti-inflammatory, antimicrobial, and antitumoral agent. Nonetheless, CUR is a hydrophobic compound with low water solubility, poor chemical stability, and fast metabolism, limiting its use as a pharmacological compound. Smart drug delivery systems (DDS) have been used to overcome its low bioavailability and improve its stability. The current work overviews the literature from the past 10 years on the encapsulation of CUR in nanostructured systems, such as micelles, liposomes, niosomes, nanoemulsions, hydrogels, and nanocomplexes, emphasizing its use and ability in cancer therapy. The studies highlighted in this review have shown that these nanoformulations achieved higher solubility, improved tumor cytotoxicity, prolonged CUR release, and reduced side effects, among other interesting advantages.

UVA-Triggered Drug Release and Photo-Protection of Skin.

Light has attracted special attention as a stimulus for triggered drug delivery systems (DDS) due to its intrinsic features of being spatially and temporally tunable. Ultraviolet A (UVA) radiation has recently been used as a source of external light stimuli to control the release of drugs using a "switch on- switch off" procedure. This review discusses the promising potential of UVA radiation as the light source of choice for photo-controlled drug release from a range of photo-responsive and photolabile nanostructures via photo-isomerization, photo-cleavage, photo-crosslinking, and photo-induced rearrangement. In addition to its clinical use, we will also provide here an overview of the recent UVA-responsive drug release approaches that are developed for phototherapy and skin photoprotection.

Use of Near-Infrared-Mid-Infrared Dual-Wavelength Spectrometry to Obtain Two-Dimensional Difference Spectra of Sesame Oil as Inactive Drug Ingredient.

The present study has investigated the transformation of sesame oil kept at low temperature during a definite period of time for refinement (called winterization) as an inactive drug ingredient by using two-dimensional difference spectra (2D-DS) analysis of spectra collected using a near-infrared (NIR) and mid-infrared (MIR) dual-wavelength spectrometer (NIR-MIR-DWS). The NIR and MIR spectra were measured nearly simultaneously from samples of sesame oil before and after winterization. The difference spectrum analysis of the obtained NIR-MIR data elucidated that, after the winterization process, the absorbances at peaks attributed to C=O, C=C, and OH groups decrease while the absorbances arising from the main chain (CH2) increase. The result indicated the removal of lignan and the fatty acids with relatively short main chains. Moreover, sesame oil unwinterized was cooled from room temperature to near 1 ℃ and subsequently warmed to room temperature. And the cycle was repeated two times. Real-time monitoring during the cooling and warming processes were carried out using the NIR-MIR-DWS. The prediction results obtained from partial least square calibration model for the temperature suggests that there are subtle differences in the oil composition between the first cooling process and after the warming and cooling cycle. For the more detailed analysis, the 2D-DS method is proposed. The results of the analyses using 2D-DS revealed that the starting point of the transformation is around 15 ℃. It can be estimated that sesame oil is mainly transformed by the first cooling down. Moreover, it was implied that the structure of methylene (CH2) was significantly related to the modifications in sesame oil with temperature change. A series of experimental results elucidated that the winterization of sesame oil removed its impurities and stabilized its conditions. These results are probably the first report on the effect of the winterization process on sesame oil.

A Review of Mesoporous Silica Nanoparticle Delivery Systems in Chemo-Based Combination Cancer Therapies.

Chemotherapy is an important anti-tumor treatment in clinic to date, however, the effectiveness of traditional chemotherapy is limited by its poor selectivity, high systemic toxicity, and multidrug resistance. In recent years, mesoporous silica nanoparticles (MSNs) have become exciting drug delivery systems (DDS) due to their unique advantages, such as easy large-scale production, adjustable uniform pore size, large surface area and pore volumes. While mesoporous silica-based DDS can improve chemotherapy to a certain extent, when used in combination with other cancer therapies MSN based chemotherapy exhibits a synergistic effect, greatly improving therapeutic outcomes. In this review, we discuss the applications of MSN DDS for a diverse range of chemotherapeutic combination anti-tumor therapies, including phototherapy, gene therapy, immunotherapy and other less common modalities. Furthermore, we focus on the characteristics of each nanomaterial and the synergistic advantages of the combination therapies. Lastly, we examine the challenges and future prospects of MSN based chemotherapeutic combination therapies.

DNA-RNA Heteroduplex Oligonucleotide for Highly Efficient Gene Silencing.

Heteroduplex oligonucleotides (HDOs) were a novel type of nucleic acid drugs based on an antisense oligonucleotide (ASO) strand and its complementary RNA (cRNA ) strand. HDOs were originally designed to improve the properties of RNase H-dependent ASOs and we reported in our first paper that HDOs conjugated with an α-tocopherol ligand (Toc-HDO ) based on a gapmer ASO showed 20 times higher silencing effect to liver apolipoprotein B (apoB) mRNA in vivo than the parent ASO. Thereafter the HDO strategy was found to be also effective for improving the properties of ASOs modulating blood-brain barrier function and ASO antimiRs which are RNase H-independent ASOs. Therefore, the HDO strategy has been shown to be versatile technology platform to develop effective nucleic acid drugs.

Emerging Applications of Drug Delivery Systems in Oral Infectious Diseases Prevention and Treatment.

The oral cavity is a unique complex ecosystem colonized with huge numbers of microorganism species. Oral cavities are closely associated with oral health and sequentially with systemic health. Many factors might cause the shift of composition of oral microbiota, thus leading to the dysbiosis of oral micro-environment and oral infectious diseases. Local therapies and dental hygiene procedures are the main kinds of treatment. Currently, oral drug delivery systems (DDS) have drawn great attention, and are considered as important adjuvant therapy for oral infectious diseases. DDS are devices that could transport and release the therapeutic drugs or bioactive agents to a certain site and a certain rate in vivo. They could significantly increase the therapeutic effect and reduce the side effect compared with traditional medicine. In the review, emerging recent applications of DDS in the treatment for oral infectious diseases have been summarized, including dental caries, periodontitis, peri-implantitis and oral candidiasis. Furthermore, oral stimuli-responsive DDS, also known as "smart" DDS, have been reported recently, which could react to oral environment and provide more accurate drug delivery or release. In this article, oral smart DDS have also been reviewed. The limits have been discussed, and the research potential demonstrates good prospects.

Probiotics, Anticipation Stress, and the Acute Immune Response to Night Shift.

Introduction: Sleep disturbance and sleep disruption are associated with chronic, low grade inflammation and may underpin a range of chronic diseases in night shift workers. Through modulation of the intestinal microbiota, probiotic supplements may moderate the effects of sleep disruption on the immune system. The aim of this study was to examine 14 days of daily probiotic supplementation on the acute response of acute phase proteins and immune markers to sleep disruption associated with night shift work (Australia and New Zealand Clinical Trials Registry: 12617001552370). Methods: Individuals (mean age 41 ± 11 yrs; 74% female) performing routine night shift were randomly assigned to a probiotic group (1 × 1010 colony forming units (CFU) Lactobacillus acidophilus DDS-1 or 1 × 1010 CFU Bifidobacterium animalis subsp. lactis UABla-12) or placebo (n= 29 per group). Participants undertook a 14-day supplementation period that coincided with a period of no night shifts followed by two consecutive night shifts. Blood samples were collected prior to the start of supplementation (V1), prior to commencing the first night shift (V2), after the first night shift (V3) and after the second night shift (V4). Serum was assessed for markers of stress (cortisol), acute phase response (C reactive protein (CRP), erythrocyte sedimentation rate, pentraxin), adhesion markers (serum E-selectin, mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), and serum cytokines (interleukin (IL)-1ra, IL-1ß, IL-6, tumor necrosis factor (TNF)-α, IL-10). Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and a Fitbit activity tracker. Results: The groups were well balanced on key markers and the probiotic strains were well tolerated. The 14-day supplementation period that coincided with typical night-day sleep-wake cycles leading up to night shift (V1 to V2) was associated with significant changes in the placebo group in the concentration of serum cortisol (p = 0.01), pentraxin (p = 0.001), MAdCAM-1 (p = 0.001), and IL-1ra (p=0.03). In contrast, probiotic supplementation moderated changes in these serum markers from V1 to V2. No significant interaction effects (time by group) were observed for the serum markers prior to and after night shift work following probiotic supplementation due to the substantial changes in the serum markers that occurred during the normal sleep period from V1 to V2. Conclusions: Probiotics may moderate the effects of anticipatory stress on the immune system in the lead up to night shift.

Anti-inflammatory activity of the sesquiterpene lactone diacethylpiptocarphol in dextransulfate sodium-induced colitis in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Sesquiterpene lactones are organic compounds derived mainly from plants that exhibit anti-inflammatory and antitumor activities being one of the key mechanism of action of NF-kB pathway and synthesis of cytokines such as IL-1 and TNF- α. AIM OF THE STUDY: The overall objective of the present study was to evaluate the anti-inflammatory action of a sesquiterpene lactone diacethylpiptocarphol (DPC) from Vernonia scorpioides (Lam.) Pers. and parthenolide (PTH) in Balb-c mice with DSS-induced colitis. MATERIALS AND METHODS: The anti-inflammatory effects of Intraperitonial administration of DPC (5 mg/kg/day) were evaluated in Balb/c mice with DSS-induced colitis, and further the body weight measurement, TNF-α and TGF-ß level was determined. RESULTS: After intraperitoneal treatment for one week, DSS-induced colitis was significantly reduced in mice treated with either of both sesquiterpenes lactones, as witnessed by reduced cellular infiltration, tissue damage, TNF-α production, and enhanced production of TGF-ß. CONCLUSIONS: Sesquiterpene lactone DPC, isolated from Vernonia scorpioides showed anti-inflammatory activity, in this experimental model of colitis the sesquiterpene lactones DPC and PTH exhibit equal anti-inflammatory activity.

Chronopharmacological strategies focused on chrono-drug discovery.

In mammals, the circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN) and influences a multitude of biological processes, including the sleep-wake rhythm. Circadian rhythms regulate diverse physiologic processes, including homeostatic functions of steroid hormones and their receptors. Perturbation of these rhythms is associated with pathogenic conditions such as cancer, metabolic syndrome, cardiovascular disease, sleep disorder and depression. Clock genes ultimately control a vast array of circadian rhythms involved in physiology and behavior. They regulate several diseases described above. Chronotherapy is especially relevant when the risk and/or intensity of symptoms of a disease vary predictably over time. The effectiveness and toxicity of several drugs vary depending on the dosing time. Such chronopharmacological phenomena are influenced by not only the pharmacodynamics but also the pharmacokinetics of a medication. The underlying mechanisms are associated with the 24-h rhythms of biochemical, physiological, and behavioral processes under the control of the circadian clock. Identifying a rhythmic marker based on the molecular clock for choosing dosing time can lead to the progress and diffusion of chronopharmacotherapy. To monitor the rhythmic markers such as clock genes, it might be useful to choose the most appropriate time of a day for the administration of a drug, to increase its therapeutic effects and/or reduce its side effects. On the contrary, several drugs affect the molecular clock and alter the 24-h rhythms of various processes. Alterations in rhythmicity are sometimes associated with therapeutic effects, or it might lead to illness and altered homeostatic regulation. Furthermore, to produce new rhythmicity by manipulating the molecular clock of organs by rhythmic administration of drugs at altered feeding schedules appears to lead to a new concept of chronopharmacotherapy. An approach to increase the efficiency of pharmacotherapy is administering drugs at times when they are best tolerated. From the perspective of pharmaceutics, the application of biological rhythm to pharmacotherapy can be accomplished by the appropriate timing of administration of conventionally formulated tablets and capsules, and also by the use of special drug-delivery system to synchronize drug concentrations to the rhythms in disease activity. New drugs targeting the molecular clock are being developed to manage diseases in human. For instance, novel molecular mechanisms that mediate renal dysfunction in mice with chronic kidney disease (CKD) have been identified by examining the relationship between the circadian clock and CKD aggravation. The inhibition of cell cycle regulatory factor ameliorated renal inflammation in a mouse model of CKD. A novel inhibitor of cell cycle regulatory factor has been identified, supporting the potential utility of cell cycle regulatory factor inhibition in the treatment of CKD. Although malignant phenotypes of triple-negative breast cancer are subject to circadian alterations, the role of cancer stem cells (CSCs) in defining this circadian change remains unclear. The effectiveness of anticancer drugs varies with the circadian dynamics of CSCs, which are regulated by the tumor microenvironmental factors. The finding reveals that the circadian dynamics of CSCs are regulated by the tumor microenvironment and provides a proof of principle of its implication for chronotherapy against triple-negative breast cancer. Therefore, we present an overview of the dosing-time-dependent alterations in therapeutic outcome and safety of a drug and the regulatory system of biological rhythm from the perspective of clock genes and the possibility of pharmacotherapy based on the molecular clock.

Development of analytical methods for evaluating the quality of dissociated and associated amphiphilic poly(γ-glutamic acid) nanoparticles.

A quantitative method of analyzing nanoparticles (NPs) for drug delivery is urgently required by researchers and industry. Therefore, we developed new quantitative analytical methods for biodegradable and amphiphilic NPs consisting of polymeric γ-PGA-Phe [phenylalanine attached to poly(γ-glutamic acid)] molecules. These γ-PGA-Phe NPs were completely dissociated into separate γ-PGA-Phe molecules by adding sodium dodecyl sulfate (SDS). The dissociated NPs were chromatographically separated to analyze parameters such as the γ-PGA-Phe content in the NPs, the impurities present [using reverse-phase (RP) HPLC with an ultraviolet (UV) detector], and the absolute MW [using size-exclusion chromatography (SEC) with refractive index detection (RI) and multiangle light scattering (MALS) detection, i.e., SEC-RI/MALS]. The chromatographic patterns of the NPs were equivalent to those of the component polymer (γ-PGA-Phe), and excellent chromatographic separation for the quantitative evaluation of NPs was achieved. To the best of our knowledge, this is the first report of the quantitative evaluation of NPs in the field of NP-based delivery systems. Furthermore, these methods were applied to optimize and evaluate the NP manufacturing process. The results showed that impurities were effectively removed from the γ-PGA-Phe during the manufacturing process, so the purity of the final γ-PGA-Phe NPs was enhanced. In addition, the appearance, clarity of solution, particle size, zeta potential, particle matter, osmolarity, and pH of the product were evaluated to ensure that the NPs were of the required quality. Our approach should prove useful for product and process characterization and quality control in the manufacture of NPs. γ-PGA-Phe NPs are known to be a powerful vaccine adjuvant, so they are expected to undergo clinical development into a practical drug-delivery system. The analytical methods established in this paper should facilitate the reliable and practical quality testing of NP products, thus aiding the clinical development of γ-PGA-Phe-based drug-delivery systems. Moreover, since these analytical methods employ commonly used reagents and chromatographic systems, the methods are expected to be applicable to other NP-based drug-delivery products too. Graphical abstract NPs were completely dissociated into separate γ-PGA-Phe polymeric molecules, which yielded a similar chromatogram to that seen for the NPs.

Systematic review of antioxidant types and doses in male infertility: Benefits on semen parameters, advanced sperm function, assisted reproduction and live-birth rate.

OBJECTIVE: To explore the current evidence concerning the effect of oral antioxidant supplementation on various male fertility outcomes, as antioxidants are widely available compounds that are commonly used for the treatment of male infertility. MATERIALS AND METHODS: PubMed, Medline and Cochrane electronic databases were searched according to a modified Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines looking for studies investigating the effect of antioxidant therapy on infertile men. The studies were explored looking for antioxidants: (i) types and doses; (ii) mechanism of action and rationale for use; and (iii) effect on the different outcome measures reported. RESULTS: In all, 26 studies reported a significant positive effect of antioxidant therapy on basic semen parameters, advanced sperm function, outcomes of assisted reproductive therapy, and live-birth rate. Vitamin E, vitamin C, carnitines, N-acetyl cysteine, co-enzyme Q10, zinc, selenium, folic acid and lycopene were most commonly used. The vitamins' mechanism of action and reported doses is presented in Table 1, Table 2. CONCLUSION: Antioxidants generally have a favourable effect on male fertility. Further studies are needed to identify the optimal antioxidant regimen that can be used safely and efficiently in clinical practice.

Development of a nanogel-based nasal vaccine as a novel antigen delivery system.

INTRODUCTION: Nasal vaccination is one of the most effective immunization methods because it can induce effective antigen-specific immune responses not only at the mucosal site of administration but also at distant mucosal surfaces, as well as in the systemic compartment. Based on this advantage, many nasal vaccines are being developed and some have been licensed and marketed for clinical use. However, some have been withdrawn because of unacceptable adverse events such as inactivated influenza vaccine administrated with a heat-labile enterotoxin of Escherichia coli as an adjuvant. Thus, it is important to consider both the efficacy and safety of nasal vaccines. Areas covered: This review describes the benefits of cholesteryl group-bearing pullulan (CHP) nanogels for nasal vaccine delivery and vaccine development identified on Pubmed database with the term 'Nanogel-based nasal vaccine'. Expert commentary: CHP nanogels have been developed as novel drug delivery system, and a cationic CHP nanogels have been demonstrated to induce effective immunity as a nasal vaccine antigen carrier. Since vaccine antigens incorporated into CHP nanogels have exhibited no brain deposition after nasal administration in mice and nonhuman primates, the vaccine seems safe, and could be a promising new delivery system.