Global One Health index for zoonoses: A performance assessment in 160 countries and territories.

The One Health (OH) approach is used to control/prevent zoonotic events. However, there is a lack of tools for systematically assessing OH practices. Here, we applied the Global OH Index (GOHI) to evaluate the global OH performance for zoonoses (GOHI-Zoonoses). The fuzzy analytic hierarchy process algorithm and fuzzy comparison matrix were used to calculate the weights and scores of five key indicators, 16 subindicators, and 31 datasets for 160 countries and territories worldwide. The distribution of GOHI-Zoonoses scores varies significantly across countries and regions, reflecting the strengths and weaknesses in controlling or responding to zoonotic threats. Correlation analyses revealed that the GOHI-Zoonoses score was associated with economic, sociodemographic, environmental, climatic, and zoological factors. Additionally, the Human Development Index had a positive effect on the score. This study provides an evidence-based reference and guidance for global, regional, and country-level efforts to optimize the health of people, animals, and the environment.

Towards an actionable One Health approach.

BACKGROUND: Despite the increasing focus on strengthening One Health capacity building on global level, challenges remain in devising and implementing real-world interventions particularly in the Asia-Pacific region. Recognizing these gaps, the One Health Action Commission (OHAC) was established as an academic community for One Health action with an emphasis on research agenda setting to identify actions for highest impact. MAIN TEXT: This viewpoint describes the agenda of, and motivation for, the recently formed OHAC. Recognizing the urgent need for evidence to support the formulation of necessary action plans, OHAC advocates the adoption of both bottom-up and top-down approaches to identify the current gaps in combating zoonoses, antimicrobial resistance, addressing food safety, and to enhance capacity building for context-sensitive One Health implementation. CONCLUSIONS: By promoting broader engagement and connection of multidisciplinary stakeholders, OHAC envisions a collaborative global platform for the generation of innovative One Health knowledge, distilled practical experience and actionable policy advice, guided by strong ethical principles of One Health.

Optimal decision-making in relieving global high temperature-related disease burden by data-driven simulation.

The rapid acceleration of global warming has led to an increased burden of high temperature-related diseases (HTDs), highlighting the need for advanced evidence-based management strategies. We have developed a conceptual framework aimed at alleviating the global burden of HTDs, grounded in the One Health concept. This framework refines the impact pathway and establishes systematic data-driven models to inform the adoption of evidence-based decision-making, tailored to distinct contexts. We collected extensive national-level data from authoritative public databases for the years 2010-2019. The burdens of five categories of disease causes - cardiovascular diseases, infectious respiratory diseases, injuries, metabolic diseases, and non-infectious respiratory diseases - were designated as intermediate outcome variables. The cumulative burden of these five categories, referred to as the total HTD burden, was the final outcome variable. We evaluated the predictive performance of eight models and subsequently introduced twelve intervention measures, allowing us to explore optimal decision-making strategies and assess their corresponding contributions. Our model selection results demonstrated the superior performance of the Graph Neural Network (GNN) model across various metrics. Utilizing simulations driven by the GNN model, we identified a set of optimal intervention strategies for reducing disease burden, specifically tailored to the seven major regions: East Asia and Pacific, Europe and Central Asia, Latin America and the Caribbean, Middle East and North Africa, North America, South Asia, and Sub-Saharan Africa. Sectoral mitigation and adaptation measures, acting upon our categories of Infrastructure & Community, Ecosystem Resilience, and Health System Capacity, exhibited particularly strong performance for various regions and diseases. Seven out of twelve interventions were included in the optimal intervention package for each region, including raising low-carbon energy use, increasing energy intensity, improving livestock feed, expanding basic health care delivery coverage, enhancing health financing, addressing air pollution, and improving road infrastructure. The outcome of this study is a global decision-making tool, offering a systematic methodology for policymakers to develop targeted intervention strategies to address the increasingly severe challenge of HTDs in the context of global warming.

Infectious disease control: from health security strengthening to health systems improvement at global level.

Since the twenty first century, the outbreaks of global infectious diseases have caused several public health emergencies of international concern, imposing an enormous impact on population health, the economy, and social development. The COVID-19 pandemic has once again exposed deficiencies in existing global health systems, emergency management, and disease surveillance, and highlighted the importance of developing effective evaluation tools. This article outlines current challenges emerging from infectious disease control from the perspective of global health, elucidated through influenza, malaria, tuberculosis, and neglected tropical diseases. The discordance among government actors and absent data sharing platforms or tools has led to unfulfilled targets in health system resilience and a capacity gap in infectious disease response. The current situation calls for urgent action to tackle these threats of global infectious diseases with joined forces through more in-depth international cooperation and breaking governance barriers from the purview of global health. Overall, a systematic redesign should be considered to enhance the resilience of health systems, which warrants a great need to sustain capacity-building efforts in emergency preparedness and response and raises an emerging concern of data integration in the concept of One Health that aims to address shared health threats at the human-animal-environment interface.

Assessing food security performance from the One Health concept: an evaluation tool based on the Global One Health Index.

BACKGROUND: Food systems instantiate the complex interdependencies across humans, physical environments, and other organisms. Applying One Health approaches for agri-food system transformation, which adopts integrated and unifying approaches to optimize the overall health of humans, animals, plants, and environments, is crucial to enhance the sustainability of food systems. This study develops a potential assessment tool, named the global One Health index-Food Security (GOHI-FS), aiming to evaluate food security performance across countries/territories from One Health perspective and identify relevant gaps that need to be improved for sustainable food systems. METHODS: We comprehensively reviewed existing frameworks and elements of food security. The indicator framework of GOHI-FS was conceptualized following the structure-process-outcome model and confirmed by expert advisory. Publicly available data in 2020 was collected for each indicator. The weighting strategy was determined by the Fuzzy Analytical Hierarchy Process. The data for each indicator was normalized and aggregated by weighted arithmetic mean. Linear regressions were performed to evaluate the associations of GOHI-FS with health and social-economic indicators. RESULTS: The GOHI-FS includes 5 first-level indicators, 19 second-level indicators and 45 third-level indicators. There were 146 countries/territories enrolled for evaluation. The highest average score of first-level indicators was Nutrition (69.8) and the lowest was Government Support and Response (31.3). There was regional heterogeneity of GOHI-FS scores. Higher median scores with interquartile range (IQR) were shown in North America (median: 76.1, IQR: 75.5-76.7), followed by Europe and Central Asia (median: 66.9, IQR: 60.1-74.3), East Asia and the Pacific (median: 60.6, IQR: 55.5-68.7), Latin America and the Caribbean (median: 60.2, IQR: 57.8-65.0), Middle East and North Africa (median: 56.6, IQR: 52.0-62.8), South Asia (median: 51.1, IQR: 46.7-53.8), and sub-Saharan Africa (median: 41.4, IQR: 37.2-46.5). We also found significant associations between GOHI-FS and GDP per capita, socio-demographic index, health expenditure and life expectancy. CONCLUSIONS: GOHI-FS is a potential assessment tool to understand the gaps in food security across countries/territories under the One Health concept. The pilot findings suggest notable gaps for sub-Saharan Africa in numerous aspects. Broad actions are needed globally to promote government support and response for food security.

Tackling global health security by building an academic community for One Health action.

BACKGROUND: One Health approach is crucial to tackling complex global public health threats at the interface of humans, animals, and the environment. As outlined in the One Health Joint Plan of Action, the international One Health community includes stakeholders from different sectors. Supported by the Bill & Melinda Gates Foundation, an academic community for One Health action has been proposed with the aim of promoting the understanding and real-world implementation of One Health approach and contribution towards the Sustainable Development Goals for a healthy planet. MAIN TEXT: The proposed academic community would contribute to generating high-quality scientific evidence, distilling local experiences as well as fostering an interconnected One Health culture and mindset, among various stakeholders on different levels and in all sectors. The major scope of the community covers One Health governance, zoonotic diseases, food security, antimicrobial resistance, and climate change along with the research agenda to be developed. The academic community will be supported by two committees, including a strategic consultancy committee and a scientific steering committee, composed of influential scientists selected from the One Health information database. A workplan containing activities under six objectives is proposed to provide research support, strengthen local capacity, and enhance global participation. CONCLUSIONS: The proposed academic community for One Health action is a crucial step towards enhancing communication, coordination, collaboration, and capacity building for the implementation of One Health. By bringing eminent global experts together, the academic community possesses the potential to generate scientific evidence and provide advice to local governments and international organizations, enabling the pursuit of common goals, collaborative policies, and solutions to misaligned interests.

China's application of the One Health approach in addressing public health threats at the human-animal-environment interface: Advances and challenges.

Background: Due to emerging issues such as global climate change and zoonotic disease pandemics, the One Health approach has gained more attention since the turn of the 21st century. Although One Health thinking has deep roots and early applications in Chinese history, significant gaps exist in China's real-world implementation at the complex interface of the human-animal-environment. Methods: We abstracted the data from the global One Health index study and analysed China's performance in selected fields based on Structure-Process-Outcome model. By comparing China to the Belt & Road and G20 countries, the advances and gaps in China's One Health performance were determined and analysed. Findings: For the selected scientific fields, China generally performs better in ensuring food security and controlling antimicrobial resistance and worse in addressing climate change. Based on the SPO model, the "structure" indicators have the highest proportion (80.00%) of high ranking and the "outcome" indicators have the highest proportion (20.00%) of low ranking. When compared with Belt and Road countries, China scores above the median in almost all indicators (16 out of 18) under the selected scientific fields. When compared with G20 countries, China ranks highest in food security (scores 72.56 and ranks 6th), and lowest in climate change (48.74, 11th). Conclusion: Our results indicate that while China has made significant efforts to enhance the application of the One Health approach in national policies, it still faces challenges in translating policies into practical measures. It is recommended that a holistic One Health action framework be established for China in accordance with diverse social and cultural contexts, with a particular emphasis on overcoming data barriers and mobilizing stakeholders both domestically and globally. Implementation mechanisms, with clarified stakeholder responsibilities and incentives, should be improved along with top-level design.

Allergic bronchopulmonary aspergillosis with marked peripheral blood eosinophilia and pulmonary eosinophilia: A case report.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is an immune-related pulmonary disease caused by sensitization of airway by Aspergillus fumigatus. The disease manifests as bronchial asthma and recurring pulmonary shadows, which may be associated with bronchiectasis. The diagnosis of ABPA mainly depends on serological, immunological, and imaging findings. Pathological examination is not necessary but may be required in atypical cases to exclude pulmonary tuberculosis, tumor, and other diseases through lung biopsy. CASE SUMMARY: An 18-year-old man presented with recurrent wheezing, cough, and peripheral blood eosinophilia. Chest computed tomography showed pulmonary infiltration. There was a significant increase in eosinophils in bronchoalveolar lavage fluid. There was no history of residing in a parasite-endemic area or any evidence of parasitic infection. Pathologic examination of bronchoalveolar lavage fluid excluded fungal and mycobacterial infections. The patient was receiving medication for comorbid diseases, but there was no temporal correlation between medication use and clinical manifestations, which excluded drug-induced etiology. Histopathological examination of lung biopsy specimen showed no signs of eosinophilic granulomatosis with polyangiitis, IgG4-related diseases, or tumors. The diagnosis of ABPA was considered based on the history of asthma and the significant increase in serum Aspergillus fumigatus-specific immunoglobulin (Ig)E. Eosinophil-related diseases were excluded through pathological biopsy, which showed typical pathological manifestations of ABPA. CONCLUSION: The possibility of ABPA should be considered in patients with poorly controlled asthma, especially those with eosinophilia, lung infiltration shadows, or bronchiectasis. Screening for serum IgE, Aspergillus fumigatus-specific IgE and IgG, and alveolar lavage can help avoid misdiagnosis.

Assessment of integrated patterns of human-animal-environment health: a holistic and stratified analysis.

BACKGROUND: Data-driven research is a very important component of One Health. As the core part of the global One Health index (GOHI), the global One Health Intrinsic Drivers index (IDI) is a framework for evaluating the baseline conditions of human-animal-environment health. This study aims to assess the global performance in terms of GOH-IDI, compare it across different World Bank regions, and analyze the relationships between GOH-IDI and national economic levels. METHODS: The raw data among 146 countries were collected from authoritative databases and official reports in November 2021. Descriptive statistical analysis, data visualization and manipulation, Shapiro normality test and ridge maps were used to evaluate and identify the spatial and classificatory distribution of GOH-IDI. This paper uses the World Bank regional classification and the World Bank income groups to analyse the relationship between GOH-IDI and regional economic levels, and completes the case studies of representative countries. RESULTS: The performance of One Health Intrinsic Driver in 146 countries was evaluated. The mean (standard deviation, SD) score of GOH-IDI is 54.05 (4.95). The values (mean SD) of different regions are North America (60.44, 2.36), Europe and Central Asia (57.73, 3.29), Middle East and North Africa (57.02, 2.56), East Asia and Pacific (53.87, 5.22), Latin America and the Caribbean (53.75, 2.20), South Asia (52.45, 2.61) and sub-Saharan Africa (48.27, 2.48). Gross national income per capita was moderately correlated with GOH-IDI (R2 = 0.651, Deviance explained = 66.6%, P < 0.005). Low income countries have the best performance in some secondary indicators, including Non-communicable Diseases and Mental Health and Health risks. Five indicators are not statistically different at each economic level, including Animal Epidemic Disease, Animal Biodiversity, Air Quality and Climate Change, Land Resources and Environmental Biodiversity. CONCLUSIONS: The GOH-IDI is a crucial tool to evaluate the situation of One Health. There are inter-regional differences in GOH-IDI significantly at the worldwide level. The best performing region for GOH-IDI was North America and the worst was sub-Saharan Africa. There is a positive correlation between the GOH-IDI and country economic status, with high-income countries performing well in most indicators. GOH-IDI facilitates researchers' understanding of the multidimensional situation in each country and invests more attention in scientific questions that need to be addressed urgently.

Effects of polysaccharides-riched Prunus mume fruit juice concentrate on uric acid excretion and gut microbiota in mice with adenine-induced chronic kidney disease.

The present study aimed to determine the effects of polysaccharides-riched Prunus mume fruit juice concentrate (PFC) on uric acid (UA) excretion and the gut microbiota in mice with chronic kidney disease (CKD). C57BL/6 mice were randomly allocated to four groups: two that were fed AIN93M diet, one of which was administered 500 mg/kg PFC, and two that were fed AIN93M diet containing 0.2% adenine, one of which was administered 500 mg/kg PFC. PFC promoted UA excretion, which may have been mediated through increases in the protein expression of ATP-binding cassette transporter G2 (ABCG2), organic anion transporter 1 (OAT1), organic carnitine transporter 2 (OCTN2), and reductions in the protein expression of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) in kidneys of CKD mice. ABCG2 expression in the intestine was also increased by PFC administration. Additionally, PFC significantly increased large intestinal short-chain fatty acids (SCFAs) concentrations, and the number of gut microbial species, and reduced the abundance of the genera Bacteroides, Pseudoflavonifractor, Helicobacter, Clostridium_IV and Allobaculum, which have a negative effect on UA excretion. In conclusion, PFC may promote UA excretion in CKD mice by altering the expression of urate transporters and regulating the gut microbiota.

Early diagnosis of intracranial atherosclerotic large vascular occlusion: A prediction model based on DIRECT-MT data.

Aims: This study aimed to build a prediction model to early diagnose intracranial atherosclerosis (ICAS)-related large vascular occlusion (LVO) in acute ischemic stroke patients before digital subtractive angiography. Methods: Patients enrolled in the DIRECT-MT trial (NCT03469206) were included in our secondary analysis and distributed into ICAS-LVO and non-ICAS-LVO groups. We also retrieved demographic data, medical histories, clinical characteristics, and pre-operative imaging data. Hypothesis testing was used to compare data of the two groups, and univariate logistic regression was used to identify the predictors of ICAS-LVO primarily. Then, we used multivariate logistic regression to determine the independent predictors and formulate the prediction model. Model efficacy was estimated by the area under the receiver operating characteristic (ROC) curve (AUC) and diagnostic parameters generated from internal and external validations. Results: The subgroup analysis included 45 cases in the ICAS-LVO group and 611 cases in the non-ICAS-LVO group. Variates with p < 0.1 in the comparative analysis were used as inputs in the univariate logistic regression. Next, variates with p < 0.1 in the univariate logistic regression were used as inputs in the multivariate logistic regression. The multivariate logistic regression indicated that the atrial fibrillation history, hypertension and smoking, occlusion located at the proximal M1 and M2, hyperdense artery sign, and clot burden score were related to the diagnosis of ICAS-LVO. Then, we constructed a prediction model based on multivariate logistics regression. The sensitivity and specificity of the model were 84.09 and 74.54% in internal validation and 73.11 and 71.53% in external validation. Conclusion: Our current prediction model based on clinical data of patients from the DIRECT-MT trial might be a promising tool for predicting ICAS-LVO.

Assessment of performance for a key indicator of One Health: evidence based on One Health index for zoonoses in Sub-Saharan Africa.

BACKGROUND: Zoonoses are public health threats that cause severe damage worldwide. Zoonoses constitute a key indicator of One Health (OH) and the OH approach is being applied for zoonosis control programmes of zoonotic diseases. In a very recent study, we developed an evaluation system for OH performance through the global OH index (GOHI). This study applied the GOHI to evaluate OH performance for zoonoses in sub-Saharan Africa. METHODS: The framework for the OH index on zoonoses (OHIZ) was constructed including five indicators, 15 subindicators and 28 datasets. Publicly available data were referenced to generate the OHIZ database which included both qualitative and quantitative indicators for all sub-Sahara African countries (n = 48). The GOHI algorithm was used to estimate scores for OHIZ. Indicator weights were calculated by adopting the fuzzy analytical hierarchy process. RESULTS: Overall, five indicators associated with weights were generated as follows: source of infection (23.70%), route of transmission (25.31%), targeted population (19.09%), capacity building (16.77%), and outcomes/case studies (15.13%). Following the indicators, a total of 37 sub-Sahara African countries aligned with OHIZ validation, while 11 territories were excluded for unfit or missing data. The OHIZ average score of sub-Saharan Africa was estimated at 53.67/100. The highest score was 71.99 from South Africa, while the lowest score was 40.51 from Benin. It is also worth mentioning that Sub-Sahara African countries had high performance in many subindicators associated with zoonoses, e.g., surveillance and response, vector and reservoir interventions, and natural protected areas, which suggests that this region had a certain capacity in control and prevention or responses to zoonotic events. CONCLUSIONS: This study reveals that it is possible to perform OH evaluation for zoonoses in sub-Saharan Africa by OHIZ. Findings from this study provide preliminary research information in advancing knowledge of the evidenced risks to strengthen strategies for effective control of zoonoses and to support the prevention of zoonotic events.

Towards a global One Health index: a potential assessment tool for One Health performance.

BACKGROUND: A One Health approach has been increasingly mainstreamed by the international community, as it provides for holistic thinking in recognizing the close links and inter-dependence of the health of humans, animals and the environment. However, the dearth of real-world evidence has hampered application of a One Health approach in shaping policies and practice. This study proposes the development of a potential evaluation tool for One Health performance, in order to contribute to the scientific measurement of One Health approach and the identification of gaps where One Health capacity building is most urgently needed. METHODS: We describe five steps towards a global One Health index (GOHI), including (i) framework formulation; (ii) indicator selection; (iii) database building; (iv) weight determination; and (v) GOHI scores calculation. A cell-like framework for GOHI is proposed, which comprises an external drivers index (EDI), an intrinsic drivers index (IDI) and a core drivers index (CDI). We construct the indicator scheme for GOHI based on this framework after multiple rounds of panel discussions with our expert advisory committee. A fuzzy analytical hierarchy process is adopted to determine the weights for each of the indicators. RESULTS: The weighted indicator scheme of GOHI comprises three first-level indicators, 13 second-level indicators, and 57 third-level indicators. According to the pilot analysis based on the data from more than 200 countries/territories the GOHI scores overall are far from ideal (the highest score of 65.0 out of a maximum score of 100), and we found considerable variations among different countries/territories (31.8-65.0). The results from the pilot analysis are consistent with the results from a literature review, which suggests that a GOHI as a potential tool for the assessment of One Health performance might be feasible. CONCLUSIONS: GOHI-subject to rigorous validation-would represent the world's first evaluation tool that constructs the conceptual framework from a holistic perspective of One Health. Future application of GOHI might promote a common understanding of a strong One Health approach and provide reference for promoting effective measures to strengthen One Health capacity building. With further adaptations under various scenarios, GOHI, along with its technical protocols and databases, will be updated regularly to address current technical limitations, and capture new knowledge.

Research advances in the clinical application of esketamine.

Esketamine is dextrorotatory ketamine, which is an enantiomer of ketamine. Compared with ketamine, it has the advantages of a fast metabolism, fewer side effects, and strong pharmacological effects, so it is more suitable for clinical use. Esketamine has a powerful analgesic effect and has little effect on breathing. It has a wide range of applications in the fields of pediatric anesthesia, conscious sedation anesthesia, and emergency analgesia. In addition, it is also used for pain that is difficult to relieve with conventional drugs and to prevent postoperative pain. Various routes of administration are also suitable for patients who need short-term analgesia and sedation. As a drug, esketamine inevitably brings some side effects when it is used clinically. In this article, by introducing the mechanism of action and pharmacological characteristics of esketamine, its clinical application is reviewed, and it provides a reference for the more reasonable and safe clinical application of esketamine.

Study on the effect of sevoflurane on the cognitive function of aged rats based on the activation of cortical microglia.

Postoperative cognitive dysfunction (POCD) is a common clinical manifestation that is a severe complication characterized by decreased learning ability and deterioration of memory following anesthesia and surgery. However, the precise mechanisms of POCD are not completely understood. Rats were divided into blank control group (Con, n = 12) and sevoflurane group (Sev, n = 12). Morris water maze test was performed to evaluate the ability of learning and memory in two groups of rats; immunohistochemical staining was used to detect the expression of ion calcium-binding adaptor molecule-1 (Iba-1) in rat prefrontal cortex (PFC); Western blot analysis was applied respectively to investigate Iba-1, inducible nitric oxide synthase (iNOS), arginase-1 (ARG1), inflammatory cytokines interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) expression; The expression of iNOS, ARG1, IL-1ß, and TNF-α in sera of rats was detected by enzyme-linked immunosorbent assay. We found that sevoflurane induced learning and memory impairment assessed by morris water maze test, anesthesia up-regulated the expression of iNOS, IL-1ß and TNF-α inflammasome in microglia, as indicated by increased activation of Iba-1 and reduced the level of ARG1 in the PFC. We conclude that the cognitive function of rats after inhaling anesthesia was likely associated with M1/M2 polarization of microglia, which was triggered by sevoflurane.

Human Amylin: From Pathology to Physiology and Pharmacology.

The histopathological hallmark of type 2 diabetes is islet amyloid implicated in the developing treatment options. The major component of human islet amyloid is 37 amino acid peptide known as amylin or islet amyloid polypeptide (IAPP). Amylin is an important hormone that is co-localized, copackaged, and co-secreted with insulin from islet ß cells. Physiologically, amylin regulates glucose homeostasis by inhibiting insulin and glucagon secretion. Furthermore, amylin modulates satiety and inhibits gastric emptying via the central nervous system. Normally, human IAPP is soluble and natively unfolded in its monomeric state. Pathologically, human IAPP has a propensity to form oligomers and aggregate. The oligomers show misfolded α-helix conformation and can further convert themselves to ß-sheet-rich fibrils as amyloid deposits. The pathological findings and physiological functions of amylin have led to the introduction of pramlintide, an amylin analog, for the treatment of diabetes. The history of amylin's discovery is a representative example of how a pathological finding can translate into physiological exploration and lead to pharmacological intervention. Understanding the importance of transitioning from pathology to physiology and pharmacology can provide novel insight into diabetes mellitus and Alzheimer's disease.

Antibacterial activities of a series of novel 5-O-(4', 6'-O-dimodified)-mycaminose 14-membered ketolides.

A series of novel 5-O-(4',6'-O-dimodified)-mycaminose 14-membered ketolides were assessed for their in vitro antibacterial activities against a panel of sensitive and resistant pathogens. Compound 1 and compound 2, two ester analogs, showed the best antibacterial activities against several macrolide-sensitive and macrolide-resistant strains. These results indicated that introducing ester to 6-OH and a small volume ether substituent to the 4-OH of mycaminose could improve the antibacterial activities of ketolides.

Synthesis and Antibacterial Activity of Novel 4″-O-desosaminyl clarithromycin derivatives with 11, 12-arylalkyl side chains.

A series of novel 4″-O-desosaminyl clarithromycin derivatives with 11, 12-arylalkyl side chains was synthesized by coupling 6-deoxy-desosamine donors (18, 19) with 4″-OH of compounds 5a-c. The activities of the target compounds were tested against a series of macrolide-sensitive and macrolide-resistant pathogens. Some of them showed activities against macrolide sensitive and resistant pathogens, and compounds 21d and 21e displayed significant improvement of activities against resistant pathogens.

Cordycepin induces apoptosis in human pancreatic cancer cells via the mitochondrial-mediated intrinsic pathway and suppresses tumor growth in vivo.

BACKGROUND: Cordycepin, the main active ingredient of a traditional Chinese herbal remedy - extracted from Cordyceps sinensis - has been demonstrated as a very effective anti-inflammatory and antitumor drug. The present study investigated its antitumor effect on pancreatic cancer, a highly aggressive cancer with extremely poor prognosis due to malignancy, and clarified its underlying mechanism both in vitro and in vivo. METHODS: The antitumor viability of cordycepin on human pancreatic cancer MIAPaCa-2 and Capan-1 cells was determined by colony formation assays. Annexin V/PI double staining and flow cytometry assay were used to investigate whether cordycepin induced apoptosis and cell cycle arrest. The mitochondrial membrane potential (ΔΨm) was analyzed by Rhodamine 123 staining, and expression of related proteins evaluated by Western blot and immunohistochemistry, both on pancreatic cancer cells and tumor xenografts to reveal the potential mechanism for the effect of cordycepin. Furthermore, the in vivo efficacy was examined on nude mice bearing MIAPaCa-2 cell tumors treated by intraperitoneal injection of cordycepin (0, 15, and 50 mg/kg/d) for 28 days. RESULTS: Cordycepin inhibited cell viability, proliferation and colony formation ability and induced cell cycle arrest and early apoptosis of human pancreatic cancer cells (MIAPaCa-2 and Capan-1) in a dose- and time-dependent manner. The same effect was also observed in vivo. Decrease of ΔΨm and upregulation of Bax, cleaved caspase-3, cleaved caspase-9, and cleaved PARP as well as downregulation of Bcl-2 both in vitro and in vivo indicated that the mitochondria-mediated intrinsic pathway was involved in cordycepin's antitumor effect. CONCLUSION: Our data showed that cordycepin inhibited the activity of pancreatic cancer both in vitro and in vivo by regulating apoptosis-related protein expression through the mitochondrial pathway and suggest that cordycepin may be a promising therapeutic option for pancreatic cancer.