Safety, immunogenicity, and protective effective of inhaled COVID-19 vaccines: A systematic review and meta-analysis.

This study aimed to examine the safety, immunogenicity and protective effective of inhaled COVID-19 vaccines (ICVs). Literature research was done through EMBASE, Cochrane, PubMed, and Web of Science up to 10 March 2024. Pooled estimates with corresponding 95% confidence intervals (CI) were computed and compared using the random effects and common effects model. Of the 15 studies, 11 analyzed safety, 13 analyzed immunogenicity, and 3 analyzed protective effective. The results showed a favorable safety profile of ICVs for primary vaccination series, however it does not always seem to produce the expected immune response and protective effective. Meta-analysis of ICVs booster vaccinations (BVs) showed that the levels of neutralizing antibody Geometric mean titer (nAb-GMT) with aerosolised Ad5-nCoV (AAd5-nCoV) were all higher than those with inactivated vaccine (INA-nCoV) (standard mean difference (SMD) = 2.32; 95% CI: 1.96-2.69) and intramuscular Ad5-nCoV (IMAd5-nCoV) (SMD = 0.31; 95% CI: 0.14-0.48) against the original strain of SARS-CoV-2. Importantly, we also observed similar results in the omicron variant. In addition, ICV in BVs has high mucosal immunity to IgA antibodies. The risk of adverse events was comparable or lower for AAd5-nCoV compared to INA-nCoV or IMAd5-nCoV. Current evidence shows that the safety profile of ICVs were well. The booster dose of AAd5-nCoV had a high immune response (including mucosal immunity) and provided protection against COVID-19 caused by the SARS-CoV-2 omicron variant. Further studies are needed to investigate the long-term safety of intranasal vaccine booster protection and various types of ICVs.

Efficacy of adjuvant-associated COVID-19 vaccines against SARS-CoV-2 variants of concern in randomized controlled trials: A systematic review and meta-analysis.

BACKGROUND: Adjuvants may enhance the efficacy of vaccines. however, the efficacy of adjuvant-associated COVID-19 vaccines (ACVs) remains unclear since the emergence of the COVID-19 pandemic. This study aimed to address this gap by conducting a systematic review and meta-analysis of the efficacy of ACVs against Severe Acute Respiratory Syndrome Coronavirus 2 CoV (SARS-CoV-2) variants of concern (VOC). METHODS: A systematic search was conducted of randomized controlled trials (RCTs) evaluating the vaccine efficacy (VE) of ACVs against VOC (alpha, beta, gamma, delta, or Omicron), up to May 27, 2023. The DerSimonian-Laird random-effects model was used to assess VE with 95% confidence intervals (CI) through meta-analysis. Cochrane Risk of Bias tools were used to assess the risk of bias in RCTs. RESULTS: Eight RCTs with 113,202 participants were included in the analysis, which incorporated 4 ACVs [Matrix-M (NVX-CoV2373), Alum (BBV152), CpG-1018/Alum (SCB-2019), and AS03 (CoVLP]). The pooled efficacy of full vaccination with ACVs against VOC was 88.0% (95% CI: 83.0-91.5). Full vaccination was effective against Alpha, Beta, Delta, and Gamma variants, with VE values of 93.66% (95% CI: 86.5-100.74), 64.70% (95% CI: 41.87-87.54), 75.95% (95% CI: 67.9-83.99), and 91.26% (95% CI: 84.35-98.17), respectively. Currently, there is a lack of RCT evidence regarding the efficacy of ACVs against the Omicron variant. CONCLUSION: In this meta-analysis, it should be that full vaccination with ACVs has high efficacy against Alpha or Gamma variants and moderate efficacy against Beta and Delta variants. Notably, with the exception of the aluminum-adjuvanted vaccine, the other ACVs had moderate to high efficacy against the SARS-CoV-2 variant. This raises concerns about the effectiveness of ACVs booster vaccinations against Omicron.

Insights into serum metabolic biomarkers for early detection of incident diabetic kidney disease in Chinese patients with type 2 diabetes by random forest.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD) worldwide. Early detection is critical for the risk stratification and early intervention of progressive DKD. Serum creatinine (sCr) and urine output are used to assess kidney function, but these markers are limited by their delayed changes following kidney pathology, and lacking of both sensitivity and accuracy. Hence, it is essential to illustrate potential diagnostic indicators to enhance the precise prediction of early DKD. A total of 194 Chinese individuals include 30 healthy participants (Stage 0) and 164 incidents with type 2 diabetes (T2D) spanning from DKD's Stage 1a to 4 were recruited and their serums were subjected for untargeted metabolomic analysis. Random forest (RF), a machine learning approach, together with univariate linear regression (ULR) and multivariate linear regression (MvLR) analysis were applied to characterize the features of untargeted metabolites of DKD patients and to identify candidate DKD biomarkers. Our results indicate that 2-(α-D-mannopyranosyl)-L-tryptophan (ADT), succinyladenosine (SAdo), pseudouridine and N,N,N-trimethyl-L-alanyl-L-proline betaine (L-L-TMAP) were associated with the development of DKD, in particular, the latter three that were significantly elevated in Stage 2-4 T2D incidents. Each of the four metabolites in combination with sCr achieves better performance than sCr alone with area under the receiver operating characteristic curve (AUC) of 0.81-0.91 in predicting DKD stages. An average of 3.9 years follow-up study of another cohort including 106 Stage 2-3 patients suggested that "urinary albumin-to-creatinine ratio (UACR) + ADT + SAdo" can be utilized for better prognosis evaluation of early DKD (average AUC = 0.9502) than UACR without sexual difference.

Immunogenicity and safety of adjuvant-associated COVID-19 vaccines: A systematic review and meta-analysis of randomized controlled trials.

Background: The benefits and risks of adjuvant-associated COVID-19 vaccines (ACVs) are unclear. The study aimed to assess the immunogenicity and safety of ACVs compared with controls (placebo or the same vaccine without adjuvants [NACVs]). Methods: Randomized controlled trials sourced from PubMed, EMBASE, Web of Science, and Cochrane Library were systematically reviewed. Evaluators extracted information independently. The evidence quality was assessed using random-effects models. The risk of bias was assessed using the Cochrane Risk of Bias tool. Results: Of the 33 studies, 27 analyzed immunogenicity (n = 9069, ACVs group; n = 3757, control), and 26 analyzed safety (n = 58669, ACVs groups; n = 30733 control). Compared with controls, full vaccination with ACVs produced significant immune responses (relative risk [RR] of seroneutralization reaction, 12.3; 95 % confidence interval [95 % CI], 6.92-21.89; standardized mean deviation of geometric mean titer 3.96, 95 % CI, 3.35-4.58). Additionally, ACVs produced significant immunoreactivity compared with NACVs only (P < 0.05). Furthermore, full vaccination with ACVs significantly increased the risk of local and systemic adverse reactions (AEs) compared with controls. However, vaccination with ACVs did not significantly increase the risk of systemic and localized AEs compared with vaccination with NACVs only (P > 0.05). It was observed that ACVs had a lower risk of all-cause mortality than controls (RR, 0.51; 95 % CI 0.30-0.87). It was further found that ACVs produced nAb response against all sublines of the Omicron variant, but the antibody titers were lower than those for the SARS-CoV-2 original strain. Conclusions: The findings of this meta-analysis demonstrate that ACVs may have a superior effect and an acceptable safety in preventing COVID-19. Although these results suggest the potential of ACVs, further studies are required.

Immunogenicity and effectiveness of COVID-19 booster vaccination among people living with HIV: a systematic review and meta-analysis.

Background: The effect of booster vaccinations with the coronavirus virus disease (COVID-19) vaccine on people living with HIV (PLWH) remains unknown. In this study, we aimed to investigate the immunogenicity and effectiveness of booster doses of the COVID-19 vaccine in PLWH. Methods: Literature research was done through the PubMed, Embase, Cochrane Review, and Web of Science databases up to 4 July 2023. Pooled estimates were calculated and compared using the DerSimonian and Laird method for a random effects model. Randomized control trials and observational studies were both considered for inclusion. Results: We included 35 eligible studies covering 30,154 PLWH. The pooled immune response rate (IRR) of PLWH after the COVID-19 booster vaccination was 97.25% (95% confidence interval [CI], 93.81-99.49), and similar to healthy control (HC) (risk ratio [RR] = 0.98, 95% CI, 0.96-1.00). The pooled IRR for PLWH with CD4+ T-cell counts ≤ 200 was 86.27 (95% CI, 65.35-99.07). For Omicron variants, the pooled IRR for PLWH after booster dose was 74.07% (95% CI, 58.83-89.30), and the risk of IRR was reduced by 10% in PLWH compared with HC (RR = 0.90, 95% CI, 0.80-1.00). The T-cell immune response of PLWH was found to be comparable to HC (p ≥ 0.05). Subgroup analyses revealed that mRNA vaccines produced a relatively high IRR in PLWH compared to other vaccines. In addition, the results showed that booster vaccination appeared to further reduce the risk of COVID-19-related infections, hospitalizations, and deaths compared with the primary vaccination. Conclusion: It was shown that booster vaccination with the COVID-19 vaccine provided a high IRR in PLWH and still produced a desirable moderate IRR in PLWH with a CD4+ T-cell count of ≤ 200. Importantly, the humoral and T-cell responses to booster vaccination in PLWH were comparable to HC, and similar results were observed with the SARS-CoV-2 Omicron variant. Our review strongly emphasizes the effect of mRNA vaccine booster vaccination in PLWH on eliciting desirable protective IRR. Furthermore, booster vaccination appears to further reduce the risk of COVID-19 infection, hospitalization, and death in PLWH compared to primary vaccination. However, more evidence is needed to confirm its effectiveness.

Derivative of cinnamic acid inhibits T3SS of Xanthomonas oryzae pv. oryzae through the HrpG-HrpX regulatory cascade.

Bacterial leaf blight (BLB) caused by Xanthomonas oryzae pv. oryzae (Xoo) has a significant impact on rice yield and quality worldwide. Traditionally, bactericide application has been commonly used to control this devastating disease. However, the overuse of fungicides has led to a number of problems such as the development of resistance and environmental pollution. Therefore, the development of new methods and approaches for disease control are still urgent. In this paper, a series of cinnamic acid derivatives were designed and synthesized, and three novel T3SS inhibitors A10, A12 and A20 were discovered. Novel T3SS inhibitors A10, A12 and A20 significantly inhibited the hpa1 promoter activity without affecting Xoo growth. Further studies revealed that the title compounds A10, A12 and A20 significantly impaired hypersensitivity in non-host plant tobacco leaves, while applications on rice significantly reduced symptoms of bacterial leaf blight. RT-PCR showed that compound A20 inhibited the expression of T3SS-related genes. In summary, this work exemplifies the potential of the title compound as an inhibitor of T3SS and its efficacy in the control of bacterial leaf blight.

Elemene induces cell apoptosis via inhibiting glutathione synthesis in lung adenocarcinoma.

ETHNOPHARMACOLOGICAL RELEVANCE: The rhizome of Curcuma wenyujin Y.H. Chen & C. Ling, also known as Wen-E-Zhu, has been used for cancer treatment since ancient times, with roots dating back to the Song Dynasty. Elemene (EE), a sesquiterpene extract with potent anticancer properties, is extracted from Wen-E-Zhu, with ß-elemene (BE) being its main active compound, along with trace amounts of ß-caryophyllene (BC), γ-elemene and δ-elemene isomers. EE has demonstrated broad-spectrum anti-cancer effects and is commonly used in clinical treatments for various types of malignant cancers, including lung cancer. Studies have shown that EE can arrest the cell cycle, inhibit cancer cell proliferation, and induce apoptosis and autophagy. However, the exact mechanism of its anti-lung cancer activity remains unclear and requires further research and investigation. AIM OF THE STUDY: In this study, the possible mechanism of EE and its main active components, BE and BC, against lung adenocarcinoma was investigated by using A549 and PC9 cell lines. MATERIALS AND METHODS: The subcutaneous tumor model of nude mice was constructed to evaluate the efficacy of EE in vivo, then the in vitro half-inhibitory concentration (IC50) of EE and its main active components, BE and BC, on A549 and PC9 cells at different concentrations were determined by CCK-8. Flow cytometry was used to detect the apoptosis and cycle of A549 and PC9 cells treated with different concentrations of BE and BC for 24 h. Non-targeted metabolomics analysis was performed on A549 cells to explore potential target pathways, which were subsequently verified through kit detection and western blot analysis. RESULTS: Injection of EE in A549 tumor-bearing mice effectively suppressed cancer growth in vivo. The IC50 of EE and its main active components, BE and BC, was around 60 µg/mL. Flow cytometry analysis showed that BE and BC blocked the G2/M and S phases of lung adenocarcinoma cells and induced apoptosis, leading to a significant reduction in mitochondrial membrane potential (MMP). Results from non-targeted metabolomics analysis indicated that the glutathione metabolism pathway in A549 cells was altered after treatment with the active components. Kit detection revealed a decrease in glutathione (GSH) levels and an increase in the levels of oxidized glutathione (GSSG) and reactive oxygen (ROS). Supplementation of GSH reduced the inhibitory activity of the active components on lung cancer and also decreased the ROS content of cells. Analysis of glutathione synthesis-related proteins showed a decrease in the expression of glutaminase, cystine/glutamate reverse transporter (SLC7A11), and glutathione synthase (GS), while the expression of glutamate cysteine ligase modified subunit (GCLM) was increased. In the apoptosis-related pathway, Bax protein and cleaved caspase-9/caspase-9 ratio were up-regulated and Bcl-2 protein was down-regulated. CONCLUSIONS: EE, BE, and BC showed significant inhibitory effects on the growth of lung adenocarcinoma cells, and the mechanism of action was linked to the glutathione system. By down-regulating the expression of proteins related to GSH synthesis, EE and its main active components BE and BC disrupted the cellular redox system and thereby promoted cell apoptosis.

Anti-tumour and radiosensitising effects of PARP inhibitor on cervical cancer xenografts.

This study evaluated the radiosensitising effect of niraparib; a poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor on HeLa cervical cancer cells in nude mice and explored its possible mechanism. Twenty-four 3-5-week-old female BALB/c nude mice, inoculated with HeLa cells into the right hind leg, were randomly assigned into eight groups with three mice per group and treated. The tumour volume was significantly reduced under niraparib + radiotherapy combination as compared to monotherapy and untreated mice. The tumour growth was significantly delayed by 23.33-39 days when treated with combination therapy (p<.05). Further, univariate analysis revealed prolonged time for tumour growth when radiotherapy was followed by niraparib (I.G.) rather than niraparib (I.P.) (p=.003). Combination therapy reduced levels of PARP-1 precursor, PARP-1 splicer, PAR and RAD51 protein with high expression of γ-H2AX/CC3 and low expression of Ki-67. Niraparib in combination with radiotherapy can enhance the formation of DNA double strand breaks in HeLa cells and up regulate the expression of γ-H2AX/CC3.IMPACT STATEMENTWhat is already known on this subject? Asia has the highest incidence of cervical cancer (58.2%). Poly(adenosine diphosphate-ribose) polymerases (PARPs) are family of enzymes involved in single-strand break (SSB) and double-strand break (DSB) repair pathways. Niraparib is an effective inhibitor of both PARP-1 and PARP-2 and has the ability to cross the blood-brain barrier.What the results of this study add? Our study demonstrated that the combination of niraparib and radiotherapy can significantly enhance the cytotoxicity induced by radiotherapy. The inhibition effect of radiotherapy combined with niraparib on the tumour growth of mice was prominent, thereby establishing the radio-sensitisation activity of niraparib.What are the implications of these findings for clinical practice and/or further research? Niraparib can improve the cytotoxic effect of radiotherapy by increasing the formation of DSBs and up regulating the expression of apoptotic protein in HeLa cells.

Relative effectiveness of bivalent COVID-19 vaccine: a systematic review and meta-analysis.

Objective: The rapid development of COVID-19 bivalent vaccines (BVs) has encompassed both the original virus strains and the variant strain. However, the effectiveness of BVs is largely unknown. Therefore, we conducted a systematic review and meta-analysis of the effectiveness of BVs. Methods: Literature research was conducted through PubMed, Cochrane Library, Embase, and Web of Science up until November 4, 2023. Both randomized control trials and observational studies were considered for inclusion. Pooled estimates were calculated using a random effects model. The Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias in cohort and case-control studies. Results: A total of 1,174 articles were reviewed and 22 eligible studies were included. All included studies were observational (15 cohort studies, 7 case-control studies). The total number of participants was 39,673,160, and the number of people vaccinated with BVs as an intervention group was 11,585,182. Two mRNA BVs were mainly involved, including the ancestral strain and the BA.1 or BA.4-5 variants. Meta-analysis results showed, compared with the monovalent vaccines (MVs), the relative effectiveness (rVE) of the BVs in COVID-19-associated infections/symptomatic infections, illnesses, hospitalizations, and deaths was 30.90% [95% confidence interval (CI), 8.43-53.37], 39.83% (95% CI, 27.34-52.32), 59.70% (95% CI, 44.08-75.32), and 72.23% (95% CI, 62.08-82.38), respectively. For those aged 50 years and older, BVs provided an additional 49.69% (95% CI, 41.44-57.94) effective protection compared with MVs. During the dominance period of the omicron XBB variant strain, BVs provided an additional 47.63% (95% CI, 27.45-67.82) effective protection compared with MVs. Conclusion: Our findings show that the rVE of BVs in preventing COVID-19-associated infections, symptomatic infections, illnesses, hospitalizations, and deaths is higher compared to MVs. Particularly for people over 50 years of age and during the Omicron variant XBB dominance phase, BVs provided superior protection. Therefore, BVs may have a broader application in the prevention and control of coronaviruses variant.

Drug-induced hypersensitivity syndrome with high procalcitonin levels due to piperacillin/tazobactam and meropenem: A case report.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and life-threatening adverse drug reaction. It is characterized by a long latency period with rash, hematological abnormalities, and visceral damage. Clinical manifestations of DRESS vary. Thus, accurate clinical diagnosis and identification are essential to ensure timely treatment commencement for improving prognosis and speeding up recovery. We report the case of a 66-year-old male patient with a drug reaction induced by a beta-lactam antibiotic, piperacillin/tazobactam (Pip/Taz). This resulted in the manifestation of both eosinophilic and systemic symptoms. Ten days after the Pip/Taz treatment commencement, the patient developed hyperthermia and elevated serum procalcitonin (PCT), leading to a misdiagnosis of an exacerbated infection. Meropenem treatment was then started. However, after 72 h, the patient developed a generalized rash, eosinophilia, hematological abnormalities, and visceral damage. Moreover, PCT levels were significantly elevated. All these symptoms were associated with DRESS. The sensitizing drug was discontinued, and glucocorticoids were administered, resulting in gradual subsiding of symptoms and decreases in serum PCT levels. Clinicians should be aware that elevated PCT serum levels may be a diagnostic biomarker for DRESS, which requires specific treatment. Furthermore, studies are warranted to further evaluate and elucidate the role of PCT in response to DRESS.

Usefulness of AFP, PIVKA-II, and Their Combination in Diagnosing Hepatocellular Carcinoma Based on Upconversion Luminescence Immunochromatography.

OBJECTIVES: To evaluate the prognostic values of serum PIVKA-II (prothrombin induced by vitamin K absence-II) and α-fetoprotein (AFP) and the combination of these analytes for identifying hepatocellular carcinoma (HCC), and to analyze the correlation between biomarkers and clinicopathological features of HCC. METHODS: The levels of PIVKA-II and AFP in 331 case individuals were determined by upconverting phosphor technology-based immune lateral flow (UPT-LF) assay. We used the ROC curve to determine the diagnostic value; the relationships between the biomarkers and clinicopathological features of HCC also were analyzed. RESULTS: AFP and PIVKA-II have good diagnostic performance in the diagnosis of HCC; the best AUC was 0.76, 0.74. High levels of PIVKA-II were more advantageous than AFP in predicting tumor size, portal-vein embolism, and vascular invasion (all P <.05). CONCLUSION: Levels of PIVKA-II and AFP showed good diagnostic value for HCC, but the level of PIVKA-II was more closely related to the clinicopathological features of HCC.

Electrospun Scaffold of Collagen and Polycaprolactone Containing ZnO Quantum Dots for Skin Wound Regeneration.

Nanofibers (NFs) have been widely used in tissue engineering such as wound healing. In this work, the antibacterial ZnO quantum dots (ZnO QDs) have been incorporated into the biocompatible poly (ε-caprolactone)/collagen (PCL/Col) fibrous scaffolds for wound healing. The as-fabricated PCL-Col/ZnO fibrous scaffolds exhibited good swelling, antibacterial activity, and biodegradation behaviors, which were beneficial for the applications as a wound dressing. Moreover, the PCL-Col/ZnO fibrous scaffolds showed excellent cytocompatibility for promoting cell proliferation. The resultant PCL-Col/ZnO fibrous scaffolds containing vascular endothelial growth factor (VEGF) also exhibited promoted wound-healing effect through promoting expression of transforming growth factor-ß (TGF-ß) and the vascular factor (CD31) in tissues in the early stages of wound healing. This new electrospun fibrous scaffolds with wound-healing promotion and antibacterial property should be convenient for treating wound healing. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s42235-021-00115-7.

Transdermal delivery of multifunctional CaO2@Mn-PDA nanoformulations by microneedles for NIR-induced synergistic therapy against skin melanoma.

The development of multifunctional nanoformulations (NFs) include several features in a single nanosystem for these devices to overcome the disadvantages of inefficiency and undesirable toxicity of traditional therapies and provide new opportunities in the management of tumors. Herein, multifunctional CaO2@Mn-PDA NFs with a core-shell structure, integrating the photothermal conversion properties of Mn-PDA, the chemodynamic properties of doped Mn ions, and relieving hypoxia in the tumor microenvironment (TME) were developed. The as-fabricated CaO2@Mn-PDA NFs were embedded in microneedles (MNs) for transdermal delivery into tumor sites, leading to the generation of a new minimally invasive and synergistic therapeutic strategy against skin melanoma. Under near-infrared (NIR) light irradiation, the CaO2@Mn-PDA NFs exhibited a synergistic therapeutic effect, including photothermal therapy (PTT), chemodynamic therapy (CDT), and modulating hypoxia due to their high photothermal conversion efficiency, boosted intracellular production of reactive oxygen species, excellent chemodynamic reactions, etc. Therefore, the developed MN platform, which can build implanted multifunctional characteristics for on-demand NIR-induced synergistic therapy, have a bright future in tumor suppression.

[Microneedles in diagnosis and treatment: a review].

Microneedles have been developed rapidly in the field of transdermal administration in the past few decades. In recent years, the development of microelectronics technology has expanded the applications of microneedles by combining with microelectronic systems, especially in biological diagnosis and treatment. Different types of microneedles have been designed to extract blood and tissue fluids for detection, or as electrodes to directly detect blood sugar, melanoma and pH in real-time in vivo, both show good prospects for real-time detection applications. In this paper, we review the design of materials and structure of microelectronic-based microneedles, and discuss their advances in biological diagnosis.

Bioactivity-guided discovery of quality control markers in rhizomes of Curcuma wenyujin based on spectrum-effect relationship against human lung cancer cells.

BACKGROUND: Due to the diversity of the ingredients, the complexity of the mechanism of action, the uncertainty of the effective ingredients, coupled with the multiple species and multiple growing areas, the quality control (QC) of Traditional Chinese Medicines (TCMs) is challenging. Discovering and identifying effective compounds from the complex extracts of TCMs and then establishing a scientific QC method is the key to the holistic QC of TCMs. PURPOSE: To develop an anti-lung-cancer-guided spectrum-effect relationship approach for the discovery of QC markers of the rhizome of Curcuma wenyujin (WEZ) and establish a bioactive compounds-based holistic QC method. METHODS: The chemical profiling of the volatile oil (WVO) from 42 batches of WEZ collected from different growing areas was performed by GC-MS. The anti-lung cancer activity of different WVO samples was determined by CCK-8 assay against human lung cancer cells (A549). The apoptosis and cell cycle analysis under different concentrations of WVO were detected by flow cytometry. SIMCA-P software was used to perform multivariate statistical analysis on the chemical composition of different WVO samples and to find the different components. Active compounds were screened using a PLSR model of the spectrum-effect relationship. Bioactive compounds-based fingerprint and quantification of the leading bioactive compounds were developed by GC-MS and GC-FID, respectively. RESULTS: Seventy-eight compounds were detected in WVO and 54 were successfully identified. The multivariate statistical analysis uncovered that WVO components and the anti-A549 activity of WVO at the concentration of 60 nl/ml differ greatly according to the origin of the plant. The WVO at the concentration of 60 nl/ml (IC50) increased A549 cells apoptosis significantly with late and early apoptosis of 15.61% and 7.80%, and the number of cells in the G2/M phase were also increased significantly under this concentration. The spectrum-effect relationship analysis revealed that 44 compounds were positively correlated with their activities, and the result was verified by A549 cell viability assay. Sixteen positively correlated compounds were further selected as QC markers according to their relative amount > 0.5% and anticancer activity. Finally, the 16 QC markers-based GC-MS fingerprint was established to holistically control the quality of WEZ, and a GC-FID method was developed for the quantification of leading bioactive compounds, ß-elemene and ß-caryophyllene. CONCLUSION: Based on an anti-lung-cancer-guided spectrum-effect relationship approach, the bioactive compounds-based holistic QC method was successfully developed for WEZ, which could provide a valuable reference for the QC of TCMs.

Fabrication of Rapidly Separable Microneedles for Transdermal Delivery of Metformin on Diabetic Rats.

In this work, the rapidly separable microneedles (MNs) consisted of needle-tips and supporting bases have been fabricated by a step-by-step coating method. Poly (vinyl alcohol) (PVA) have been used to prepare the needle-tips of MNs in which they are capped on the solvable supporting bases consisted of sodium bicarbonate, poly (vinyl pyrolidone) (PVP), and tartaric acid (TA) (NaHCO3/PVP/TA). After insertion into the skin, the needle-tips can be separated rapidly from the patches within 90 s due to the generation of air bubbles in the supporting bases by the reaction between NaHCO3 and TA after absorption of tissue fluid, leading to the needle-tips remaining in the skin tissue. Metformin, a hypoglycemic drug, encapsulated in the needle-tips of MNs can be released due to swelling and decomposition of PVA by the absorption of tissue fluid. To investigate the pharmacological effect via transdermal delivery route, metformin-loaded MNs are applied on the diabetic SD rats induced by streptozotocin (STZ). They exhibit a longer hypoglycemic effect in vivo than that of subcutaneous injection. These results indicated the as-fabricated rapidly separable MNs present a promising platform for transdermal delivery of drugs against diabetic patients.

Autophagy promotes oncolysis of an adenovirus expressing apoptin in human bladder cancer models.

As a potential cancer therapy, we developed a recombinant adenovirus named Ad-VT, which was designed to express the apoptosis-inducing gene (apoptin) and selectively replicate in cancer cells via E1a manipulation. However, how it performs in bladder cancer remains unclear. We examined the antitumor efficacy of Ad-VT in bladder cancers using CCK-8 assays and xenograft models. Autophagy levels were evaluated by western blotting, MDC staining, and RFP-GFP-LC3 aggregates' analyses. Here, we report the selective replication and antitumor efficacy (viability inhibition and apoptosis induction) of Ad-VT in bladder cancer cells. Using xenograft tumor models, we demonstrate that its effects are tumor specific resulting in the inhibition of tumor growth and improvement of the survival of mice models. Most Importantly, Ad-VT induced a complete autophagy flux leading to autophagic cancer cell death through a signaling pathway involving AMPK, raptor and mTOR. Finally, we suggest that treatment combination of Ad-VT and rapamycin results in a synergistic improvement of tumor control and survival compared to monotherapy. This study suggests that Ad-VT can induce selective autophagic antitumor activities in bladder cancer through the AMPK-Raptor-mTOR pathway, which can be further improved by rapamycin.

A combination index and glycoproteomics-based approach revealed synergistic anticancer effects of curcuminoids of turmeric against prostate cancer PC3 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Herbal medicines (HMs) often exert integration effects, including synergistic, additive and antagonistic effects, in such ways that they act on multiple targets and multiple pathways on account of their multiple components. Turmeric, made from the rhizome of Curcuma longa L., is a well-known HM prescribed in the polyherbal formulas for cancer treatment in traditional Chinese medicines (TCMs). However, neither the multiple anticancer compounds of turmeric nor the integration effects of these components are fully known. AIM OF THE STUDY: This work aims to develop a systematic approach to reveal the integration effect mechanisms of multiple anticancer compounds in turmeric against prostate cancer PC3 cells. MATERIALS AND METHODS: Combination index and omics technologies were applied to profile the integration effect mechanisms of bioactive compounds in proportions naturally found in turmeric. PC3 cell line (a prostate cancer cell line) fishing and high resolution mass spectrometry were employed to screen and identify the anticancer compounds from turmeric. The combinations which contain different cell-bound compounds in natural proportions were prepared for further evaluation of anti-cancer activity by using cell viability assays, and assessment of cell apoptosis and cell cycle analysis. Combination index analysis was applied to study the integration effects of the anticancer compounds in their natural proportions. Finally, quantitative glycoproteomics/proteomics and Western blot were implemented to reveal the potential synergistic effect mechanisms of the anticancer compounds based on their natural proportions in turmeric. RESULTS: Three curcuminoids (curcumin, CUR; demethoxycurcumin, DMC; bisdemethoxycurcumin, BDMC) in turmeric were discovered and shown to possess significant synergistic anticancer activities. Combination index analysis revealed an additive effect of CUR combined with DMC or BDMC and a slight synergistic effect of DMC combined with BDMC in natural proportions in turmeric, while a combination of all three curcuminoids (CUR, DMC and BDMC) at a ratio of 1:1:1 yielded superior synergistic effects. Interestingly, the presence of BDMC and DMC are essential for synergistic effect. Glycoproteomics and proteomics demonstrated that different curcuminoids regulate various protein pathways, such as ribosome, glycolysis/gluconeogenesis, biosynthesis of amino acids, and combination of CUR + DMC + BDMC showed the most powerful effects on down-regulation of protein expression. CONCLUSIONS: Our analytical approach provides a systematic understanding of the holistic activity and integration effects of the anti-cancer compounds in turmeric and three curcuminoids of turmeric showed a synergistic effect on PC3 cells.

[UPLC quantitative fingerprint research on Gardeniae Fructus based on chemical pattern recognition technology].

Twenty-six batches of Gardeniae Fructus from different producing area were collected for the development of the fingerprint, and the main components of Gardeniae Fructus were identified by liquid chromatography-mass spectrometry. The producing areas of Gardeniae Fructus were distinguished by chemical pattern recognition technology, and the index components of Gardeniae Fructus were quantitated. An UPLC wavelength switching method was adopted, and the separation was carried out on a Waters Acquity UPLC HASS C_(18)(2.1 mm×100 mm, 1.7 µm) column using the mobile phase of acetonitrile-0.5% formic acid water for gradient elution. Principal component analysis(PCA) and orthogonal partial least square discriminant analysis(OPLS-DA) were used for the data ana-lysis. The results showed that the similarity of 26 batches of Gardeniae Fructus was more than 0.89, and ten common peaks were defined. Sixteen compounds including monoterpenes, iridoids and diterpenoids were identified by reference identification, literature comparison and high-resolution mass spectrometry data analysis. The distinguishment of origin of Gardeniae Fructus was realized by PCA and OPLS-DA analysis, and two quality differential markers were screened as geniposide and crocin Ⅰ. The contents of crocin Ⅰ, crocin Ⅱ and geniposide in Gardeniae Fructus from different places were different. These results will provide reference for the geographical origin traceability of Gardeniae Fructus.

Analysis of the WHO ICTRP for novel coronavirus clinical trial registrations.

Up-to-date information on the current progress made in the research and development to control the global COVID-19 pandemic is important. The study aimed to analyze the clinical trial characteristics and vaccine development progress of the new Coronavirus Disease 2019 (COVID-19) registered with the World Health Organization International Clinical Trial Registry Platform (WHO ICTRP).A comprehensive search of COVID-19 clinical trials since the establishment of the ICTRP to June 11, 2020, was conducted to record and analyze relevant characteristics. Chi-Squared test was used to compare the statistical differences between different research types, interventions, and sources.A total of 3282 COVID-19 clinical trials in 17 clinical trial registration centers were registered with the WHO ICTRP. The main research sources for the present study were ClinicalTrials.gov and ChiCTR. There were significant differences in the parameters of study location (P = .000), number of participants (P = .000), study duration (P = .001), research stage (P = .000), randomization procedure (P = .000), and blinding method (P = .000) between the 2 registration sources. There were significant differences in all the parameters between different kinds of intervention methods. Hydroxychloroquine, plasma therapy, and Xiyanping injection were the high-frequency research drugs used. Ten different vaccine studies were registered under phases I-II.Amongst the studies researched, heterogeneity existed for various parameters. Differences in the type of study, interventions, and registration sources of the studies led to significant differences in certain parameters of the COVID-19 clinical trials. The statistics of high-frequency drugs and the progress of vaccine trials may provide an informative reference for the prevention and control of COVID-19.