Biology subjects

De La Cruz, P.

Publications and source records attributed to De La Cruz, P..

5 recordsLinked to original sources

bioRxiv2025

Pulmonary Hypertension Promotes Neuroinflammation and Neurodegeneration

IntroductionPulmonary arterial hypertension (PAH) is associated with neurocognitive deficits and abnormal brain MRI. Little is known about the mechanisms underlying these clinical observations. TDP-43 is a proteinopathy associated with frontotemporal lobar degeneration (FTLD), Alzheimers Disease, and Amyotrophic Lateral Sclerosis (ALS). In this study, we hypothesize PAH will result in gliosis, reduced neuronal density, and increased TDP-43 mislocalization. MethodsSprague Dawley rats were randomly assigned to receive Vehicle (DMSO) Monocrotaline, or Sugen/Hypoxia to induce PH. Right heart catheterization was used to confirm PAH. Brain tissue was fixed and probed for microglia (Iba1), astrocytes (GFAP), neurons (NeuN), and TDP-43. Human PH vs control brain tissue was also probed for NeuN and TDP-43. Results and ConclusionsWe identify an increase in microglia and astrocyte density in the frontal cortex along with reduced neuronal density and neuronal TDP-43 mislocalization in rat models of PH. In addition, human PH frontal cortex demonstrated neuronal TDP-43 mislocalization. This is the first evidence of TDP-43 proteinopathy in PH.

physiology↗

bioRxiv2025

Partial Wwox Loss of Function Increases Severity of Murine Sepsis and Neuroinflammation

RationaleWW domain-containing oxidoreductase (WWOX) is a gene associated implicated in both neurologic and inflammatory diseases and is susceptible to environmental stressors. We hypothesize partial loss of Wwox function will result in increased sepsis severity and neuroinflammation. MethodsWwox WT/P47T mice, generated by CRISPR/Cas9, and Wwox WT/WT mice were treated with intraperitoneal PBS vs LPS (10mg/kg) and euthanized 12 hours post-injection. Open Field Testing (OFT) and Murine Sepsis Severity Scores (MSS) were utilized to measure sickness behavior and sepsis severity, respectively. Brain tissue was analyzed using immunohistochemistry and PCR to measure neuroinflammation and apoptosis. ResultsWwox WT/P47T LPS mice demonstrated a more significant response to sepsis with an increase in sickness behavior, sepsis severity, gliosis, and apoptosis compared to Wwow WT/WT LPS littermates. ConclusionsPartial loss of Wwox function increases risk for severe sepsis and neuroinflammation. Given the susceptibility of WWOX to environmental stressors, this may be a target for future therapeutic interventions.

neuroscience↗

bioRxiv2024

Immune checkpoint inhibitor treatment does not impair ovarian or endocrine function in a mouse model of triple negative breast cancer

BackgroundRepresenting 15-20% of all breast cancer cases, triple negative breast cancer (TNBC) is diagnosed more frequently in reproductive-age women and exhibits higher rates of disease metastasis and recurrence when compared with other subtypes. Few targeted treatments exist for TNBC, and many patients experience infertility and endocrine disruption as a result of frontline chemotherapy treatment. While they are a promising option for less toxic therapeutic approaches, little is known about the effects of immune checkpoint inhibitors on reproductive and endocrine function. ResultsOur findings in a syngeneic TNBC mouse model revealed that therapeutically relevant immunotherapies targeting PD-1, LAG-3, and TIM-3 had no effect on the quality and abundance of ovarian follicles, estrus cyclicity, or hormonal homeostasis. Similarly, in a tumor-free mouse model, we found that ovarian architecture, follicle abundance, estrus cyclicity, and ovulatory efficiency remain unchanged by PD-1 blockade. ConclusionsTaken together, our results suggest that immunotherapy may be a promising component of fertility-sparing therapeutic regimens for patients that wish to retain ovarian and endocrine function after cancer treatment.

cancer biology↗

bioRxiv2023

TRAIL agonists rescue mice from radiation-induced lung injury

Cancer therapy is often limited by toxicity from pneumonitis. This often-lethal side effect is known to be impacted by innate immunity, and in particular the pathways regulated by the TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from the lethal effects of radiation. We found that two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound #10 (TIC10/ONC201), could achieve this goal. Both compounds could completely protect mice from lethality by reducing pneumonitis, alveolar-wall thickness, and oxygen desaturation. At the molecular level, this protection appeared to be due to the inhibition of CCl22, a macrophage-derived chemokine previously associated with radiation pneumonitis and pulmonary fibrosis. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from high doses of radiation exposure has important translational implications. One Sentence SummaryPrevention of lethality, pneumonitis, lung fibrosis and skin dermatitis post-{psi}-irradiation by short- term treatment with innate immune TRAIL pathway agonists

pathology↗

bioRxiv2022

The Requirement of Ubiquitin C-Terminal Hydrolase L1 (UCHL1) in Mouse Ovarian Development and Fertility

Ubiquitin C-Terminal Hydrolase L1 (UCHL1) is a de-ubiquitinating enzyme enriched in neuronal and gonadal tissues known to regulate the cellular stores of mono-ubiquitin and protein turnover. While its function in maintaining proper motor neuron function is well-established, investigation into its role in the health and function of reproductive processes is only just beginning to be studied. Single-cell-sequencing analysis of all ovarian cells from the murine perinatal period revealed that Uchl1 is very highly expressed in the developing oocyte population, an observation which was corroborated by high levels of oocyte-enriched UCHL1 protein expression in oocytes of all stages throughout the mouse reproductive lifespan. To better understand the role UCHL1 may be playing in oocytes, we utilized a UCHL1-deficient mouse line, finding reduced number of litters, reduced litter sizes, altered folliculogenesis, morphologically abnormal oocytes, disrupted estrous cyclicity and apparent endocrine dysfunction in these animals compared to their wild-type and heterozygous littermates. These data reveal a novel role of UCHL1 in female fertility as well as overall ovarian function, and suggest a potentially essential role for the ubiquitin proteasome pathway in mediating reproductive health. Summary sentenceUbiquitin C-Terminal Hydrolase L1 (UCHL1) is required for proper ovarian folliculogenesis, estrous cyclicity, and fertility in the female mouse.

developmental biology↗