Translational research : the journal of laboratory and clinical medicine
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The purinergic P2X3 receptor in the carotid body (CB) is considered a new target for treating hypertension, although approaches for targeted regulating P2X3 receptor expression are lacking. Here, we explored the feasibility of targeted P2X3 receptor down-regulation in CBs by localized low-intensity focused ultrasound (LIFU)-mediated gene delivery to reduce the blood pressure. Thirty-two Kunming canines were randomly assigned to the treatment group (n = 14), negative control group (n = 10), LIFU + cationic microbubbles group (n = 4), and LIFU-only group (n = 4). ⋯ Mean systolic (152.5 ± 3.0 vs 138.0 ± 2.9 mm Hg, P = 0.003) and diastolic (97.8 ± 1.5 vs 87.2 ± 2.3 mm Hg, P= 0.002) blood pressures reduced on day 14 in the treatment group, compared with the baseline values, whereas no effects were observed with LIFU treatment or cationic microbubbles injection alone. Canines treated with this strategy exhibited no local or systemic adverse events. Thus, LIFU-mediated gene delivery to CBs successfully modulated CB function and reduced blood pressure in a canine model, suggesting a new possibility for treating hypertension and further clinical translation.
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The term autologous fecal microbiota transplantation (a-FMT) refers herein to the use of one's feces during a healthy state for later use to restore gut microbial communities after perturbations. Generally, heterologous fecal microbiota transplantation (h-FMT), where feces from a ``healthy" donor is transplanted into a person with illness, has been used to treat infectious diseases such as recurrent Clostridioides difficile infection (CDI), with cure rates of up to 90%. In humans, due to limited response to medicines, h-FMT has become a hallmark intervention to treat CDI. ⋯ FMT response variability could also be due to differences in microbiome composition between donors, recipients, and within individuals, which vary with diet, and environments, across regions. While donor selection has emerged as a key factor in FMT success, the use of heterologous donor stool still places the recipient at risk of exposure to infectious/pathogenic microorganisms. As an implementable solution, herein we review the available literature on a-FMT, and list some considerations on the benefits of a-FMT for IBD.
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Recent innovations in translational research have ushered an exponential increase in the discovery of novel biomarkers, thereby elevating the hope for deeper insights into "personalized" medicine approaches to disease phenotyping and care. However, a critical gap exists between the fast pace of biomarker discovery and the successful translation to clinical use. This gap underscores the fundamental biomarker conundrum across various acute and chronic disorders: how does a biomarker address a specific unmet need? Additionally, the gap highlights the need to shift the paradigm from a focus on biomarker discovery to greater translational impact and the need for a more streamlined drug approval process. ⋯ Accordingly, this review discusses the current state of ARDS biomarkers in the context of the drug development pipeline and highlight gaps between biomarker discovery and clinical implementation while proposing potential paths forward. We discuss potential ARDS biomarkers by category and by context of use, highlighting progress in the development continuum. We conclude by discussing challenges to successful translation of biomarker candidates to clinical impact and proposing possible novel strategies.
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Sepsis is defined as a dysregulated inflammatory response, which ultimately results from a perturbed interaction of both an altered immune system and the biomass and virulence of involved pathogens. This response has been tied to the intestinal microbiota, as the microbiota and its associated metabolites play an essential role in regulating the host immune response to infection. In turn, critical illness as well as necessary health care treatments result in a collapse of the intestinal microbiota diversity and a subsequent loss of health-promoting short chain fatty acids, such as butyrate, leading to the development of a maladaptive pathobiome. These perturbations of the microbiota contribute to the dysregulated immune response and organ failure associated with sepsis. Several case series have reported the ability of fecal microbiota transplant (FMT) to restore the host immune response and aid in recovery of septic patients. Additionally, animal studies have revealed the mechanism of FMT rescue in sepsis is likely related to the ability of FMT to restore butyrate producing bacteria and alter the innate immune response aiding in pathogen clearance. However, several studies have reported lethal complications associated with FMT, including bacteremia. Therefore, FMT in the treatment of sepsis is and should remain investigational until a more detailed mechanism of how FMT restores the host immune response in sepsis is determined, allowing for the development of more fine-tuned microbiota therapies.
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Much of the population is now faced with an enormous burden of age-associated chronic diseases. Recent discoveries in geroscience indicate that healthspan in model organisms such as mice can be manipulated by targeting cellular senescence, a hallmark mechanism of aging, defined as an irreversible proliferative arrest that occurs when cells experience oncogenic or other diverse forms of damage. ⋯ Therapeutically targeting senescent cells in mice can prevent, delay, or alleviate each of these conditions. Therefore, senotherapeutic approaches, including senolytics and senomorphics, that either selectively eliminate senescent cells or interfere with their ability to promote tissue dysfunction, are gaining momentum as potential realistic strategies to abrogate human senescence to thereby compress morbidity and extend healthspan.