Large-scale Human Trials Research Articles

Chemical Composition, Bioactivities, and Applications of Spirulina (Limnospira platensis) in Food, Feed, and Medicine

Spirulina (Limnospira platensis) is a microalga recognised for its rich nutritional composition and diverse bioactive compounds, making it a valuable functional food, feed, and therapeutic agent. This review examines spirulina’s chemical composition, including its high levels of protein, essential fatty acids, vitamins, minerals, and bioactive compounds, such as the phycocyanin pigment, polysaccharides, and carotenoids, in food, feed, and medicine. These compounds exhibit various biological activities, including antioxidant, anti-inflammatory, immunomodulatory, antiviral, anticancer, antidiabetic and lipid-lowering effects. Spirulina’s potential to mitigate oxidative stress, enhance immune function, and inhibit tumour growth positions it as a promising candidate for preventing chronic diseases. Additionally, spirulina is gaining interest in the animal feed sector as a promotor of growth performance, improving immune responses and increasing resistance to diseases in livestock, poultry, and aquaculture. Despite its well-documented health benefits, future research is needed to optimize production/cultivation methods, improve its bioavailability, and validate its efficacy (dose–effect relationship) and safety through clinical trials and large-scale human trials. This review underscores the potential of spirulina to address global health and nutrition challenges, supporting its continued application in food, feed, and medicine.

Perilla Seed Oil: A Review of Health Effects, Encapsulation Strategies and Applications in Food

Perilla (Perilla frutescens L.) is an annual herbaceous plant whose seed oil is rich in unsaturated fatty acids such as alpha-linolenic acid (ALA). This oil exhibits various health benefits, including antioxidant, anti-inflammatory, lipid-lowering, hypoglycemic, neuroprotective and immunomodulatory activities. In addition, incorporating perilla oil into a diet can effectively increase the abundance of beneficial bacteria in the gut microbiota. However, perilla oil is prone to oxidation, which reduces its nutritional value and lowers its bioavailability. To address these issues, encapsulation technologies such as emulsions, oleogels, liposomes and microcapsules have been employed, showing promising results. Nonetheless, further research is needed to fully elucidate the underlying mechanisms of perilla seed oil’s health effects, validate its benefits through large-scale human clinical trials and optimize encapsulation techniques. Future investigations should also explore the synergistic effects of combining perilla seed oil with other functional components and its role in modulating gut microbiota to achieve comprehensive health benefits.

Therapeutic potential of adiponectin in prediabetes: strategies, challenges, and future directions.

Adiponectin, an adipose-derived hormone, plays a pivotal role in glucose regulation and lipid metabolism, with a decrease in circulating adiponectin levels being linked to insulin resistance and prediabetes. This review examines the therapeutic potential of adiponectin in managing prediabetes, elucidating on multiple aspects including its role in glucose and lipid metabolism, influence on insulin sensitivity, and anti-inflammatory properties. Moreover, the paper highlights the latest strategies to augment adiponectin levels, such as gene therapy, pharmacological interventions, dietary modifications, and lifestyle changes. It also addresses the challenges encountered in translating preclinical findings into clinical practice, primarily related to drug delivery, safety, and efficacy. Lastly, the review proposes future directions, underlining the need for large-scale human trials, novel adiponectin analogs, and personalized treatment strategies to harness adiponectin's full therapeutic potential in preventing the transition from prediabetes to diabetes.

Super-Resolution Ultrasound Imaging of Renal Vascular Alterations in Zucker Diabetic Fatty Rats during the Development of Diabetic Kidney Disease.

Individuals with diabetes at risk of developing diabetic kidney disease (DKD) are challenging to identify using currently available clinical methods. Prognostic accuracy and initiation of treatment could be improved by a quantification of the renal microvascular rarefaction and the increased vascular tortuosity during the development of DKD. Super-resolution ultrasound (SRUS) imaging is an in vivo technique capable of visualizing blood vessels at sizes below 75 µm. This preclinical study aimed to investigate the alterations in renal blood vessels' density and tortuosity in a type 2 diabetes rat model, Zucker diabetic fatty (ZDF) rats, as a prediction of DKD. Lean age-matched Zucker rats were used as controls. A total of 36 rats were studied, subdivided into ages of 12, 22, and 40 weeks. Measured albuminuria indicated the early stage of DKD, and the SRUS was compared with the ex vivo micro-computed tomography (µCT) of the same kidneys. Assessed using the SRUS imaging, a significantly decreased cortical vascular density was detected in the ZDF rats from 22 weeks of age compared to the healthy controls, concomitant with a significantly increased albuminuria. Already by week 12, a trend towards a decreased cortical vascular density was found prior to the increased albuminuria. The quantified vascular density in µCT corresponded with the in vivo SRUS imaging, presenting a consistently lower vascular density in the ZDF rats. Regarding vessel tortuosity, an overall trend towards an increased tortuosity was present in the ZDF rats. SRUS shows promise for becoming an additional tool for monitoring and prognosing DKD. In the future, large-scale animal studies and human trials are needed for confirmation.

A novel high throughput assay to quantify Epstein-Barr virus neutralizing antibody activity against B-cell and epithelial cell infections for vaccine and therapeutic developments

Epstein-Barr Virus (EBV) is the causative agent of infectious mononucleosis and has been associated with a variety of malignancies. In vivo, EBV infects B cells and epithelial cells. However, the current EBV neutralization assays, especially those against B cell infection, are low throughput, laborious and lack of sensitivity. In this study, we optimized the EBV-GFP based micro-neutralization assay by selecting the most susceptible cell substrates, Akata 4E3 for B cell and HEK293T for epithelial cell. The newly developed procedure is high throughput. The cell type specific neutralization was confirmed using monoclonal antibodies specific to gp350 and gH/gL/gp42. A panel of human sera was also tested. Natural human EBV seropositive sera could neutralize EBV in both B cell and epithelial cell assays efficiently with a majority of human sera generating near 100% EBV neutralization. The EBV neutralizing antibody titers were highly correlated with antibodies specific to gp350, gH, EBV total proteins, and to a less degree with antibodies against gp42. Collectively, we demonstrated this improved neutralization assay is suitable to evaluating the humoral responses elicited by EBV vaccine candidates in preclinical animal models or in large-scale human trials.

Autophagy takes it all - autophagy inducers target immune aging.

ABSTRACTAutophagy, as the key nutrient recycling pathway, enables eukaryotic cells to adapt to surging cellular stress during aging and, thereby, delays age-associated deterioration. Autophagic flux declines with age and, in turn, decreases in autophagy contribute to the aging process itself and promote senescence. Here, we outline how autophagy regulates immune aging and discuss autophagy-inducing interventions that target senescent immune cells, which are major drivers of systemic aging. We examine how cutting-edge technologies, such as single-cell omics methods hold the promise to capture the complexity of molecular and cellular phenotypes associated with aging, driving the development of suitable putative biomarkers and clinical bioassays. Finally, we debate the urgency to initiate large-scale human clinical trials. We give special preference to small molecule probes and to dietary interventions that can extend healthy lifespan and are affordable for most of the world's population.

Akkermansia muciniphila in inflammatory bowel disease and colorectal cancer.

Akkermansia muciniphila in inflammatory bowel disease and colorectal cancer.

Glucosinolates From Cruciferous Vegetables and Their Potential Role in Chronic Disease: Investigating the Preclinical and Clinical Evidence.

An increasing body of evidence highlights the strong potential for a diet rich in fruit and vegetables to delay, and often prevent, the onset of chronic diseases, including cardiometabolic, neurological, and musculoskeletal conditions, and certain cancers. A possible protective component, glucosinolates, which are phytochemicals found almost exclusively in cruciferous vegetables, have been identified from preclinical and clinical studies. Current research suggests that glucosinolates (and isothiocyanates) act via several mechanisms, ultimately exhibiting anti-inflammatory, antioxidant, and chemo-protective effects. This review summarizes the current knowledge surrounding cruciferous vegetables and their glucosinolates in relation to the specified health conditions. Although there is evidence that consumption of a high glucosinolate diet is linked with reduced incidence of chronic diseases, future large-scale placebo-controlled human trials including standardized glucosinolate supplements are needed.

The Use of Botulinum Toxin to Prevent Anastomotic Thrombosis and Promote Flap Survival: A Bridge to Developing Clinical Studies.

Despite the possibility of using botulinum toxin to improve perfusion and prevent vasospasm, only a few studies have examined the use of botulinum toxin in the setting of flap surgery and thrombosis, and the mechanisms have not been fully explained. The primary objective of this study was to provide a comprehensive review of the effectiveness of botulinum toxin in anastomotic thrombosis prevention and surgical flap survival to determine the value of conducting large-scale human trials. Using the SYRCLE and CAMRADES criteria, a systematic review was performed. PubMed, Medline, EmBase, and the Cochrane Library were searched for studies that met our eligibility criteria. Twenty studies were included in the final selection. A total of 397 subjects were included. Eighteen studies used botulinum toxin type A alone, one used botulinum toxin type B alone, and only one used both botulinum toxin type A and botulinum toxin type B. The most commonly used injection technique was a preoperative intradermal injection. The most common procedure performed was a pedicled flap with random pattern skin flaps (65%). The mean injection dose was 28.17 ± 49.21 IU, whereas the mean reported injection time for studies using animal models was 7.4 ± 6.84 days. Similar mechanisms demonstrated in animal models may be replicable in humans, allowing botulinum toxin to be used to prolong flap survival. However, many factors, such as optimal injection techniques, dosages, and long-term outcomes of botulinum use in flap surgery, need to be further assessed before applying this to clinical practice.

Unfolding the Determinants of COVID-19 Vaccine Acceptance in China.

BackgroundChina is at the forefront of global efforts to develop COVID-19 vaccines and has five fast-tracked candidates at the final-stage, large-scale human clinical trials testing phase. Vaccine-promoting policymaking for public engagement is a prerequisite for social mobilization. However, making an informed and judicious choice is a dilemma for the Chinese government in the vaccine promotion context.ObjectiveIn this study, public opinions in China were analyzed via dialogues on Chinese social media, based on which Chinese netizens’ views on COVID-19 vaccines and vaccination were investigated. We also aimed to develop strategies for promoting vaccination programs in China based on an in-depth understanding of the challenges in risk communication and social mobilization.MethodsWe proposed a novel behavioral dynamics model, SRS/I (susceptible-reading-susceptible/immune), to analyze opinion transmission paradigms on Chinese social media. Coupled with a meta-analysis and natural language processing techniques, the emotion polarity of individual opinions was examined in their given context.ResultsWe collected more than 1.75 million Weibo messages about COVID-19 vaccines from January to October 2020. According to the public opinion reproduction ratio (R0), the dynamic propagation of those messages can be classified into three periods: the ferment period (R01=1.1360), the revolution period (R02=2.8278), and the transmission period (R03=3.0729). Topics on COVID-19 vaccine acceptance in China include price and side effects. From September to October, Weibo users claimed that the vaccine was overpriced, making up 18.3% (n=899) of messages; 38.1% (n=81,909) of relevant topics on Weibo received likes. On the contrary, the number of messages that considered the vaccine to be reasonably priced was twice as high but received fewer likes, accounting for 25.0% (n=53,693). In addition, we obtained 441 (47.7%) positive and 295 (31.9%) negative Weibo messages about side effects. Interestingly, inactivated vaccines instigated more heated discussions than any other vaccine type. The discussions, forwards, comments, and likes associated with topics related to inactivated vaccines accounted for 53% (n=588), 42% (n=3072), 56% (n=3671), and 49% (n=17,940), respectively, of the total activity associated with the five types of vaccines in China.ConclusionsMost Chinese netizens believe that the vaccine is less expensive than previously thought, while some claim they cannot afford it for their entire family. The findings demonstrate that Chinese individuals are inclined to be positive about side effects over time and are proud of China’s involvement with vaccine development. Nevertheless, they have a collective misunderstanding about inactivated vaccines, insisting that inactivated vaccines are safer than other vaccines. Reflecting on netizens’ collective responses, the unfolding determinants of COVID-19 vaccine acceptance provide illuminating benchmarks for vaccine-promoting policies.

Applying Immune Instincts and Maternal Intelligence from Comparative Microbiology to COVID-19.

New data specific to COVID-19 are emerging quickly on key issues of immunity and prevention, but past research in coronavirology and for other human pathogens (e.g., Mycoplasma pneumoniae) has been available and of great relevance. Considerable study of endemic human coronaviruses has shown that neutralizing antibody correlates with protection, but effective clinical protection is variable for subsequent virus exposure. Animal coronavirus research has emphasized the importance of local mucosal protection (especially IgA) and systemic responses. Animal model and human post-infection studies for SARS-CoV and MERS-CoV are largely corroborative. Whether for passive therapeutic strategies or vaccination, these findings provide a template for COVID-19. Many approaches to vaccination have emerged, and there may be more than one vaccine that will be applied, but individualized obstacles and concerns for administration, efficacy, and safety are inevitable. Regardless of safeguards or promises that may be understood from laboratory or vertebrate experiments, observations from large-scale human trials will ultimately prove to shape the medical future. Focus on common mucosal immunity can be underrated, and equally or more, focus on lactogenic immunity may be underestimated. In understanding both passive immunity and protection, the body is already primed to educate us with decisions of what constitutes protection and harm. This review provides key insights that drive hypotheses into how the instinct of immunity and the intelligence of the maternal component of the common mucosal immune system has already guided us and may continue to do so effectively into a bright and safe future.

Cyproheptadine for Serotonin Toxicity: an Updated Systematic Review and Grading of Evidence

Serotonin toxicity (ST) is a serious clinical entity caused by drug-induced serotonin excess in the central nervous system. Animal studies and some human data indicate that activation of specific serotonin receptor subtypes, namely 5-HT1A and 5-HT2A, are involved in ST pathophysiology, suggesting that serotonin antagonists could be used to treat ST. However, to date, high-quality evidence for the clinical utility of the most commonly employed serotonin antagonist, cyproheptadine, is lacking. This systematic review provides a clinical update on the evidence regarding use cyproheptadine for treating ST and compiles cyproheptadine treatment recommendations from recent review articles. Published articles concerning the use of cyproheptadine for treating ST are exclusively case reports and case series (n = 151); most provide very low-quality evidence (i.e., grade D, n = 148) and the remaining few provide low-quality evidence (i.e., grade C, n = 3). Most recent review articles (n = 18) acknowledge this low level of evidence and propose cyproheptadine as an optional treatment, whereas others recommend its use in the clinical setting. Although ST has been recognized as a clinical entity for decades, rigorous trials demonstrating the therapeutic efficacy of cyproheptadine are lacking, warranting large-scale prospective human trials of antiserotonergic agents using a coordinated multicenter approach.

Medical management of cataracts: promising or pointless?

Cataracts are a significant and common cause of reversible blindness, for which definitive management is by surgical removal. However, a lack of ophthalmologists and funding means many do not have access to such procedures worldwide. Therefore, a less invasive and cheaper alternative is desirable. This paper aims to provide a brief overview of the physiology and risk factors of cataract formation, as well as discussing current evidence regarding prevention and management of cataracts non-surgically. This review finds there are numerous promising prevention strategies to reduce the likelihood of a cataract developing. These include aldose reductase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), and vitamin supplementation. However, further large-scale human trials are required for definitive medical prevention strategies. There is also almost no data on alternative management of established cataract as opposed to prevention of cataract development. This identifies a key gap in the literature requiring further investigation.

Cancer prevention by different forms of tocopherols

Low vitamin E nutritional status has been suggested to increase cancer risk. However, recent large-scale human trials with high doses of alpha-tocopherol (α-T) have produced disappointing results. This points out the need for a better understanding of the biological activities of different forms of tocopherols. Using a tocopherol mixture that is rich in γ-T (γ-TmT), we demonstrated the inhibition of colon carcinogenesis in mice, and the inhibition is associated with decreased levels of 8-isoprostane, nitrotyrosine, prostaglandin E2 and leukotriene B4. Dietary 0.3% γ-TmT also inhibited chemically induced lung tumorigenesis in the A/J mice as well as the growth of lung cancer cells in xenograft or allograft tumors; the inhibition was associated with a reduction of oxidative/nitrosative stress. δ-T was found to be more active than γ-T in the inhibition of cancer cell growth in culture and lung cancer xenograft tumors as well as in azoxymethane-induced colon aberrant crypt foci formation in rats, whereas α-T was ineffective. Analysis of the levels of tocopherols and their metabolites in blood and tissues suggests that metabolites of δ-T and γ-T contribute to their inhibitory activity. These studies demonstrate the broad cancer preventive activity of γ-TmT and higher activity of δ-T.

Landscape of circulating diagnostic biomarkers in pancreatic malignancies

: Pancreatic cancer remains the most lethal adult cancer in the US that is in large part due to the lack of effective early detection biomarkers. Although a variety of blood based technologies have been developed, each of these assays have different advantages and disadvantages. Here, we will review the landscape of blood based biomarkers in the context of pancreatic cancer early detection. Tumor biomarkers (CA19-9, CEA) are widely used, but often have limited specificity to cancer, and panel-based approaches combining multiple serum proteins may prove more promising in early detection of pancreatic cancer. Metabolic markers, including the substrates, intermediates, and by-products of aberrant pathways can also be quantified and used as biomarkers, particularly since pancreatic cancer almost universally exploits KRAS mutations leading aberration activation of the MEK/ERK/AKT pathways. More recent approaches have also attempted to use cell-free DNA released from tumor cells into the bloodstream to directly sequence and identify mutations and serve as a ‘liquid biopsy.’ Alternatively, approaches are being used to capture rare circulating epithelial cells that have entered into the bloodstream (circulating tumor cells, or CTCs) even in pre-neoplastic lesions. Extracellular vesicles (EVs) found in plasma are a new emerging source of tumor enriched cargo (DNA, RNA, proteins) providing a multi-prong approach towards early tumor detection. Although many of these approaches are promising, they need to be validated in large-scale human trials using appropriate controls. Altogether, the complementary performance characteristics of different biomarkers point to a combination of these technologies as the future of a pancreatic cancer early detection liquid biopsy.

Radiation enteritis: from diagnosis to management.

As cancer treatments improve more patients than ever are living for longer with the side effects of these treatments. Radiation enteritis is a heterogenous condition with significant morbidity. The present review aims to provide a broad overview of the condition with particular attention to the diagnosis and management of the condition. Radiation enteritis appears to be more prevalent than originally thought because of patient underreporting and a lack of clinician awareness. Patient-related and treatment-related risk factors have now been identified and should be modified where possible. Medical and surgical factors have been explored, but manipulation of the gut microbiota offers one of the most exciting recent developments in disease prevention. Diagnosis and treatment are best approached in a systematic fashion with particular attention to the exclusion of recurrent malignancy and other gastrointestinal conditions. Surgery and endoscopy both offer opportunities for management of the complications of radiation enteritis. Experimental therapies offer hope for future management of radiation enteritis but large-scale human trials are needed. Radiation enteritis is an important clinical problem, but awareness is lacking amongst patients and physicians. Clinical guidelines would allow standardised management which may improve the burden of the disease for patients.

Non-intrusive vital sign monitoring using an intelligent pillow based on a piezoelectric ceramic sensor

Performing real-time monitoring for human vital signs during sleep at home is of vital importance to achieve timely detection and rescue. However, the existing smart equipment for monitoring human vital signs suffers the drawbacks of high complexity, high cost, and intrusiveness, or low accuracy. Thus, it is of great need to develop a simplified, nonintrusive, comfortable and low cost real-time monitoring system during sleep. In this study, a novel intelligent pillow was developed based on a low-cost piezoelectric ceramic sensor. It was manufactured by locating a smart system (consisting of a sensing unit i.e. a piezoelectric ceramic sensor, a data processing unit and a GPRS communication module) in the cavity of the pillow made of shape memory foam. The sampling frequency of the intelligent pillow was set at 1000 Hz to capture the signals more accurately, and vital signs including heart rate, respiratory rate and body movement were derived through series of well established algorithms, which were sent to the user’s app. Validation experimental results demonstrate that high heart-rate detection accuracy (i.e. 99.18%) was achieved in using the intelligent pillow. Besides, human tests were conducted by detecting vital signs of six elder participants at their home, and results showed that the detected vital signs may well predicate their health conditions. In addition, no contact discomfort was reported by the participants. With further studies in terms of validity of the intelligent pillow and large-scale human trials, the proposed intelligent pillow was expected to play an important role in daily sleep monitoring.

Co-carcinogenic effects of vitamin E in prostate

A large number of basic researches and observational studies suggested the cancer preventive activity of vitamin E, but large-scale human intervention trials have yielded disappointing results and actually showed a higher incidence of prostate cancer although the mechanisms underlying the increased risk remain largely unknown. Here we show through in vitro and in vivo studies that vitamin E produces a marked inductive effect on carcinogen-bioactivating enzymes and a pro-oxidant status promoting both DNA damage and cell transformation frequency. First, we found that vitamin E in the human prostate epithelial RWPE-1 cell line has the remarkable ability to upregulate the expression of various phase-I activating cytochrome P450 (CYP) enzymes, including activators of polycyclic aromatic hydrocarbons (PAHs), giving rise to supraphysiological levels of reactive oxygen species. Furthermore, our rat model confirmed that vitamin E in the prostate has a powerful booster effect on CYP enzymes associated with the generation of oxidative stress, thereby favoring lipid-derived electrophile spread that covalently modifies proteins. We show that vitamin E not only causes DNA damage but also promotes cell transformation frequency induced by the PAH-prototype benzo[a]pyrene. Our findings might explain why dietary supplementation with vitamin E increases the prostate cancer risk among healthy men.

Ischaemic postconditioning: cardiac protection after the event.

Ischaemic heart disease remains the leading cause of death worldwide. Novel approaches to improve morbidity and mortality in this population are essential. Cardiac ischaemic postconditioning - the technique of applying alternating cycles of sublethal myocardial ischaemia and reperfusion after a sustained insult - is one cardioprotective strategy that can reduce reperfusion injury. Infarct size reduction and improvements in left ventricular ejection fraction have been demonstrated with mechanical or pharmacological postconditioning, both after spontaneous acute myocardial infarction, and associated with cardiac surgery. Nonetheless, the benefits of postconditioning can be easily attenuated. For maximal benefit, postconditioning demands a particular patient population (large area at risk, with little collateral blood flow), timely application and the measurement of appropriate clinical endpoints. Furthermore, confounders such age, sex and medication, as well as a plethora of co-morbidities common in patients with ischaemic heart disease, all impact on the efficacy of postconditioning. This fragility requires the security of outcomes from large-scale human trials to ensure robust applicability to everyday clinical practice, and to provide assurance of an impact on long-term clinical outcome. This review highlights the development of current postconditioning algorithms, the findings from current proof-of-concept trials, and the barriers that may limit its broad uptake into clinical practice.

Endocannabinoids and the Cardiovascular System in Health and Disease.

The endocannabinoid system is widely distributed throughout the cardiovascular system. Endocannabinoids play a minimal role in the regulation of cardiovascular function in normal conditions, but are altered in most cardiovascular disorders. In shock, endocannabinoids released within blood mediate the associated hypotension through CB(1) activation. In hypertension, there is evidence for changes in the expression of CB(1), and CB(1) antagonism reduces blood pressure in obese hypertensive and diabetic patients. The endocannabinoid system is also upregulated in cardiac pathologies. This is likely to be cardioprotective, via CB(2) and CB(1) (lesser extent). In the vasculature, endocannabinoids cause vasorelaxation through activation of multiple target sites, inhibition of calcium channels, activation of potassium channels, NO production and the release of vasoactive substances. Changes in the expression or function of any of these pathways alter the vascular effect of endocannabinoids. Endocannabinoids have positive (CB(2)) and negative effects (CB(1)) on the progression of atherosclerosis. However, any negative effects of CB(1) may not be consequential, as chronic CB(1) antagonism in large scale human trials was not associated with significant reductions in atheroma. In neurovascular disorders such as stroke, endocannabinoids are upregulated and protective, involving activation of CB(1), CB(2), TRPV1 and PPARα. Although most of this evidence is from preclinical studies, it seems likely that cannabinoid-based therapies could be beneficial in a range of cardiovascular disorders.