Progress of proteolysis-targeting chimeras (PROTACs) delivery system in tumor treatment.

Proteolysis targeting chimeras (PROTACs) can use the intrinsic protein degradation system in cells to degrade pathogenic target proteins, and are currently a revolutionary frontier of development strategy for tumor treatment with small molecules. However, the poor water solubility, low cellular permeability, and off-target side effects of most PROTACs have prevented them from passing the preclinical research stage of drug development. This requires the use of appropriate delivery systems to overcome these challenging hurdles and ensure precise delivery of PROTACs towards the tumor site. Therefore, the combination of PROTACs and multifunctional delivery systems will open up new research directions for targeted degradation of tumor proteins. In this review, we systematically reviewed the design principles and the most recent advances of various PROTACs delivery systems. Moreover, the constructive strategies for developing multifunctional PROTACs delivery systems were proposed comprehensively. This review aims to deepen the understanding of PROTACs drugs and promote the further development of PROTACs delivery system.

Pharmacokinetics and Safety of Estradiol Valerate Tablet and Its Generic: A Phase 1 Bioequivalence Study in Healthy Chinese Postmenopausal Female Subjects.

Purpose: Estradiol valerate (Progynova®) is used as hormone therapy to supplement estrogen deficiency. This study aimed to assess the bioequivalence of an estradiol valerate tablet and its generic form, under fasting and fed conditions. Methods: A randomized, open-label, single-dose, 2-period crossover study was conducted on healthy postmenopausal Chinese female volunteers under fasting and fed conditions. For each period, the subjects received either a 1 mg tablet of estradiol valerate or its generic. Blood samples were collected before dosing and up to 72 hours after administration. Plasma levels of total estrone, estradiol, and unconjugated estrone were quantified using a validated liquid chromatography-tandem mass spectrometry method. Results: A total of 54 volunteers were enrolled in this study. The primary pharmacokinetic parameters, including Cmax, AUC0-t, and AUC0-∞, were similar for the two drugs under both fasting and fed conditions, with 90% confidence intervals for the geometric mean ratios of these parameters, all meeting the bioequivalence criterion of 80-125%. A total of 48 adverse events (AEs) were reported in the fed study compared with 24 AEs in the fasting study. Conclusion: Estradiol valerate and its generic form were bioequivalent and well tolerated under both fasting and fed conditions.

Bioequivalence Study of Two Formulations of Mifepristone Tablets in Healthy Chinese Subjects Under Fasting Conditions.

A single-dose, open-label, randomized, two-period crossover-design study was conducted to evaluate the bioequivalence of the reference and test formulations of mifepristone tablets. Each subject was randomized at the beginning to receive a 25-mg tablet of the test or the reference mifepristone under fasting conditions during the first period, then received the alternate formulation during the second period following a 2-week washout period. A validated high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was used to determine the plasma concentrations of mifepristone and its two metabolites (RU42633 and RU42698). Fifty-two healthy subjects were enrolled in this trial, 50 of whom completed the study. The 90% confidence intervals for the log-transformed Cmax , AUC0-t , and AUC0-∞ fell within the accepted 80%-125% range. Throughout the study period, a total of 58 treatment-emergent adverse events were reported. No serious adverse event was observed. In conclusion, the test and reference mifepristone were bioequivalent and well tolerated under fasting conditions.

Current progress of mesenchymal stem cell membrane-camouflaged nanoparticles for targeted therapy.

Nanodrug delivery systems have been widely used in disease treatment. However, weak drug targeting, easy to be cleared by the immune system, and low biocompatibility are great obstacles for drug delivery. As an important part of cell information transmission and behavior regulation, cell membrane can be used as drug coating material which represents a promising strategy and can overcome these limitations. Mesenchymal stem cell (MSC) membrane, as a new carrier, has the characteristics of active targeting and immune escape of MSC, and has broad application potential in tumor treatment, inflammatory disease, tissue regeneration and other fields. Here, we review recent progress on the use of MSC membrane-coated nanoparticles for therapy and drug delivery, aiming to provide guidance for the design and clinical application of membrane carrier in the future.

Pharmacokinetics and bioequivalence of two methylprednisolone tablet formulations in healthy Chinese subjects under fasting and fed conditions.

AIMS: The aims of this study were to evaluate and compare the pharmacokinetic profiles and bioequivalence of two tablet formulations of methylprednisolone (test formulation: Zhejiang Xianju Pharmaceutical Co., Ltd., China; reference formulation: Medrol, Pfizer Italia SRL) in healthy Chinese subjects under fasting and fed conditions. MATERIALS AND METHODS: Subjects were randomly allocated to either the fasting group or the fed group and also to one of two sequences (test-reference or reference-test), according to which they received a single 16-mg dose of the test or reference methylprednisolone tablet in the study periods. Blood samples were collected pre dose and at intervals up to 16 hours after administration. Plasma methylprednisolone concentrations were determined using a validated liquid chromatography tandem mass spectrometry method. The safety of the medications was monitored throughout the study. The primary pharmacokinetic parameters measured were Cmax, AUC0-t, and AUC0-∞. RESULTS: A total of 56 subjects were enrolled, and all completed the study. The 90% confidence intervals for Cmax, AUC0-t, and AUC0-∞, measured under both fasting and fed conditions, fell within the acceptable range for bioequivalence of 80 - 125%. Analysis of variance showed that there were no significant differences in the primary pharmacokinetic parameters (Cmax, AUC0-t, and AUC0-∞) between the test and reference formulation measured under both fasted and fed conditions. No serious or unexpected adverse drug reactions occurred during the study period. CONCLUSION: The test methylprednisolone 16 mg tablet produced in China is bioequivalent to the reference formulation (Medrol) in healthy Chinese subjects measured under both fasting and fed conditions. Both formulations were well tolerated by all study participants.

Nutrient addition alters plant community productivity but not the species diversity of a mountain meadow in Tajikistan.

Introduction: Tajikistan is a typical mountainous country covered by different mountain grasslands that are important pasture resources. Recently, grassland degradation has become widespread due to climate change and human activities and fertilization has been used to improve grassland production. However, fertilizer inputs can substantially alter species diversity, but it is uncl\ear how productivity and species diversity respond to nutrient enrichment in the mountain meadows of Tajikistan. Methods: Therefore, a 5-year (2018-2022) continuous in-situ mineral fertilizer experiment was conducted to examine the effects of three nitrogen (N) levels (0, 30, and 90 kg N ha-1 year-1), two phosphorus (P) levels (0 and 30 kg P ha-1 year-1), and their combinations on above-ground biomass (AGB) and species diversity in a mountain meadow grassland in Ziddi, Varzob region, Tajikistan. Five species diversity metrics-Margalef's species richness (Dma), the Shannon-Wiener index (H), the Simpson index (C), Pielou's equitability index (Epi), and the Evar Species Evenness index (Evar)-were used to measure species diversity. Results and discussions: The results indicated that the addition of different N and P amounts and their various combinations considerably increased both total and dominant species AGB, with the highest increase occurring in the N90P30 (90 kg N ha-1 year-1 combined with 30 kg P ha-1 year-1) treatment in 2022; during the experiment, the importance value of Prangos pabularia (dominant species) first decreased and then increased, but its dominant status did not change or fluctuate among the years. Furthermore, N, P, and their different combinations had no significant effect on species diversity (Dma, H, C, Epi, and Evar). All the species diversity indexes fluctuated among years, but there was no interaction with mineral fertilizer addition. Total AGB had a negative relationship with species diversity and low concentration N fertilizer addition (N30; P30) strengthened this negative trend. However, this trend decreased under the high N fertilizer condition (N90P30). Overall, nutrient addition to the natural mountain grassland of the Varzob region improved AGB, which meant that there was more forage for local animals. Mineral fertilizers had no significant effect on species diversity, but may enhance P. pabularia dominance in the future, which will help maintain the stability of the plant community and improve the quality of the forage because P. pabularia is an excellent and important winter fodder. Our study suggests that scientific nutrient management could effectively promote grassland production, conserve plant variety, and regenerate degraded grassland, which will counteract the desertification process in northwest Tajikistan mountain meadows.

Association of depressive symptoms with marital status among the middle-aged and elderly in Rural China-Serial mediating effects of sleep time, pain and life satisfaction.

OBJECTIVE: This study aimed to explore the potential effect of sleep time, pain and life satisfaction on the association between marital status and depressive symptoms. METHODS: This study included 9780 individuals aged 45 years and older from the China Health and Retirement Longitudinal Study (CHARLS) in 2015. Regression analysis was used to explore the mediating effect of targeted mediators on the association between marital status and depressive symptoms. Bootstrap method was used to examine the statistical significance of the mediating effects. RESULTS: In the mediation model incorporating sleep time, pain and life satisfaction as mediators between marital status and depressive symptoms, the direct effect of marital status on depressive symptoms was statistically significant (p < 0.001, 95% CI = 0.699, 1.428). Approximately 39.28% (Indirect effect/Total effect) of the significant association between marital status and depressive symptoms was mediated by sleep time, pain, and life satisfaction. LIMITATIONS: Limitations include non-representativeness other than rural residents and unclear cause-and-effect relationship. CONCLUSIONS: Those separated/divorced/widowed/never-married middle-aged and elderly individuals might be high risk population of depressive symptoms. It could be possible to relieve the depressive symptoms of these people by guaranteeing sufficient sleep, relieving pain and improving life satisfaction.

Bioequivalence study of two formulations of terazosin hydrochloride capsule in healthy Chinese subjects under fasting and fed conditions.

OBJECTIVE: This study was conducted to assess the pharmacokinetic and safety profiles between a new oral formulation of terazosin hydrochloride capsule compared with the brand-name drug. MATERIALS AND METHODS: A randomized, open-label, single-dose, 2-period crossover study under fasting or fed conditions was conducted in healthy Chinese subjects. 24 individuals were selected, respectively. Each subject was randomized at the beginning to receive a 2-mg capsule of the test or the reference terazosin during the first period and then received the alternate formulation during the second period following a 1-week washout period. Blood samples were collected at pre-dose and up to 60 hours after administration. Plasma terazosin was quantified by a validated LC-MS/MS method. RESULTS: 48 healthy subjects were enrolled, and 47 completed the study. Cmax, AUC0-t, and AUC0-∞ were similar and the 90% CIs for the geometric mean ratios of these parameters between the two groups were all bounded within the predefined bioequivalence criterion of 80 - 125% under both fasting and fed conditions. Throughout the study period, a total of 30 treatment-emergent adverse events (TEAEs) were reported under fasting condition. 35 TEAEs were observed under fed conditions. No serious adverse event was observed. CONCLUSION: The test and reference formulations of terazosin were bioequivalent and well tolerated under both fasting and fed conditions.

Snow and rainfall independently affect the density, composition and productivity of ephemerals in a temperate desert.

Snow and rainfall are two main water resources required for vegetation growth in the Gurbantunggut Desert, China. Epehmerals, an important component of plant community in this temperate desert in early spring, tend to be more sensitive to water availability than other types of plants. While previous studies mainly focus on the separate effects of snowpack or rainfall on the growth parameters of ephemerals, it is unclear, whether there is any interaction between snowpack and rainfall. Here an in-situ field experiment was conducted with snowpack and rainfall manipulation in the southern part of this desert. During two consecutive years, we measured ephemeral density, composition, and biomass under three snowpack and three rainfall treatments. The results indicated that snow and rainfall independently affected the variation in the density, composition, and productivity of ephemerals in this temperate desert. Increased depth of snow increased the ephemeral density in dry year but did not affect the species richness and productivity in both dry and wet years. However, rainfall significantly affected these parameters in the dry year, but had no dramatic effects in the wet year. Snowpack and rainfall differentially affect seedling establishment and productivity, and their effects are independent no matter in a dry or wet year.

Effect of Nutrient Addition on the Productivity and Species Richness of Grassland Along With an Elevational Gradient in Tajikistan.

Grasslands provide key resource for the millions of people who are dependent on livestock in Tajikistan. Productivity and species richness (SR) are important characteristics of grassland ecosystems and are greatly affected by nutrient inputs. The effect that climate change might have on these characteristics remains unclear. Here, an in situ nitrogen (N) and phosphorus (P) fertilization experiment was conducted at four sites along with an elevational gradient (650, 1,100, 1,250, and 2,000 m) in western Tajikistan over 2 years (2018 and 2019) to examine the influences of nutrient availability and climate change on aboveground biomass (AGB) and SR; precipitation and temperature were also considered to analyze the responses. It demonstrated that enrichment with N, P, and their combinations significantly increased AGB along with an elevational gradient (p < 0.05). AGB increased as the concentrations of nutrients added increased. The maximum AGB, which was 2-fold higher compared with control, was observed when 90 kg N ha-1year-1 and 30 kg P ha-1year-1 were added. In addition, nitrogen addition alone stimulated greater AGB than P addition, although no significant difference was observed between these two treatments. Enrichment with N, P, and their combination had no significant effect on SR; however, SR significantly changed at different elevation. Elevation had direct effect on precipitation and temperature, which, in turn, resulted in variation in AGB and SR. Moreover, both nutrient and elevation had significant effect on AGB and SR, but there was no interaction effect of them. AGB and SR interacted with significant negative correlation. In the high-elevation area, plants grew better in the warmer year (2018); this indicates that grasslands in high mountain areas in Tajikistan might have higher productivity as the climate warms, which will positively affect the economic development of the country.

SNHG16 aggravates chronic constriction injury-induced neuropathic pain in rats via binding with miR-124-3p and miR-141-3p to upregulate JAG1.

Neuropathic pain is caused by damage to the nervous system. Increasing studies have confirmed that jagged 1 (JAG1) plays a significant role in nervous system diseases. However, the regulatory mechanisms of JAG1 in neuropathic pain remain vague. In this study, a chronic constriction injury (CCI) rat model was performed. JAG1 was found to be upregulated in CCI rats. The recombinant lentiviruses containing sh-JAG1 were injected to the CCI rats for knockdown of JAG1 in rats. JAG1 knockdown improved the mechanical allodynia and thermal hyperalgesia in CCI rats, and decreased the concentrations and mRNA expression of inflammatory cytokines (IL-6, TNF-α and IL-1ß) in spinal cord dorsal horn of CCI rats, suggesting that JAG1 knockdown attenuated neuropathic pain. In addition, we explored for the upstream mechanism of JAG1. Through RNA pull down assay and luciferase reporter assay, we confirmed that miR-124-3p and miR-141-3p bound with JAG1. Long non-coding RNA (lncRNA) small nucleolar RNA host gene 6 (SNHG16) was verified to be the upstream molecule of miR-124-3p and miR-141-3p to negatively regulate miR-124-3p and miR-141-3p. SNHG16 positively regulated JAG1 expression through competitively binding with miR-124-3p and miR-141-3p. Moreover, SNHG16 was found to be upregulated in CCI rats. SNHG16 knockdown improved the mechanical allodynia and thermal hyperalgesia as well as reduced the concentrations and mRNA expression of inflammatory cytokines in CCI rats. Finally, SNHG16 was confirmed to aggravate neuropathic pain in CCI rats via upregulating JAG1. In conclusion, this study verified that SNHG16 aggravated neuropathic pain in CCI rats via binding with miR-124-3p and miR-141-3p to upregulate JAG1, which may provide new insights into the development of gene therapy for neuropathic pain.

Temporal-spatial variability of modern climate in the Altai Mountains during 1970-2015.

Located in the intermediate zone between the taiga forests in Siberian Plain and the deserts in Central Asia, the Altai Mountains are of scientific concern about Holocene climate change in the past decades. However, researches about modern climate changes are relatively scarce in the Altai Mountains. In this study, temporal- spatial changes of air temperature and precipitation were investigated systematically in the Altai Mountains based on fifteen meteorological records over the period of 1970-2015. The Altai Mountains experienced a rapid warming trend with a rate of 0.41°C/decade and an insignificantly wetting trend at a rate of 4.82 mm/decade during 1970-2015. The magnitude of temperature trend was negatively correlated with elevation in cold season (spring and winter), whereas that was positively correlated with elevation in warm season (summer and autumn). The cyclonic anomalies to the northwest and an anticyclonic anomalies to the southeast blocked the southward cold air and then provided the favorable condition for an increasing precipitation via the southwesternly wind in the Altai Mountains.

A Randomized Phase 1 Pharmacokinetic Study Comparing the Potential Biosimilar LRG201902 With Liraglutide (Victoza®) in Healthy Male Subjects.

Objective: Pharmacokinetic (PK) similarity between biosimilar candidate LRG201902 and European Union-sourced liraglutide reference product (Victoza®) was evaluated. Safety and immunogenicity were also assessed. Methods: This single-dose, randomized, open-label, 2-period crossover study (CTR20192342) was conducted in thirty-eight healthy adult male subjects. Volunteers were randomized 1:1 at the beginning to receive a single 0.6 mg dose of Victoza® or LRG201902 by subcutaneous injection during the first period. Following 8 days washout period, all subjects received the alternate formulation during the second period. Blood samples were collected up to 72 h after administration. The primary pharmacokinetic endpoints were AUC0-t, AUC0-∞, and Cmax. Pharmacokinetic similarity was achieved if 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of AUC0-t, AUC0-∞, and Cmax were within the range of 80-125%. Other pharmacokinetic parameters including Tmax, t½, and λz were also measured. Safety profile and immunogenicity data were collected from each subject. Results: Cmax, AUC0-t, and AUC0-∞ were similar between the two groups. GMRs of Cmax, AUC0-t, and AUC0-∞ were 113.50%, 107.21%, and 106.97% between LRG201902 and Victoza® respectively. The 90% CIs for the GMRs of Cmax, AUC0-t, and AUC0-∞ were all within the PK equivalence criteria. Mean serum concentration-time profiles, secondary pharmacokinetic parameters (Tmax, t½, and λz) were comparable between groups. Treatment-related adverse events were reported by 27.8% and 23.7% subjects in the LRG201902 and Victoza® arms, respectively. All post-dose samples were detected negative for anti-drug antibodies. Conclusion: This study demonstrates pharmacokinetic similarity of LRG201902 to Victoza® in healthy subjects. The safety and immunogenicity profiles were similar for the two products.

Sitagliptin protects against hypoxia/reoxygenation (H/R)-induced cardiac microvascular endothelial cell injury.

Inhibition of hypoxia/reoxygenation (H/R)-induced insult in cardiac microvascular endothelial cells (CMECs) has been considered as a promising therapeutic strategy for the treatment of ischemic cardiovascular disease. In the present study, we found that H/R significantly increased the expression of dipeptidyl peptidase (DPP)-4 in CMECs. Treatment with the DPP-4 inhibitor sitagliptin, a licensed drug used for the treatment of type 2 diabetes mellitus (T2DM), ameliorated H/R-induced oxidative stress by decreasing the expression of NOX-4 and restoring the intracellular level of GSH in CMECs. Sitagliptin could also improve H/R-induced mitochondrial dysfunction by increasing intracellular MMP and ATP. Additionally, we found that the presence of sitagliptin prevented H/R-induced reduced cell viability and LDH release. Notably, our findings indicate that sitagliptin possesses an anti-inflammatory effect against H/R-induced expression of IL-6, IL-8, and TNF-α as well as secretion of HMGB1. Mechanistically, we found that sitagliptin suppresses activation of p38/NF-κB signaling. These findings suggest that sitagliptin may have potential as a therapeutic agent for the treatment of cardiovascular diseases.