Design, Synthesis, and Antitumor Evaluation of an Opioid Growth Factor Bioconjugate Targeting Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) presents a formidable challenge with high lethality and limited effective drug treatments. Its heightened metastatic potential further complicates the prognosis. Owing to the significant toxicity of current chemotherapeutics, compounds like [Met5]-enkephalin, known as opioid growth factor (OGF), have emerged in oncology clinical trials. OGF, an endogenous peptide interacting with the OGF receptor (OGFr), plays a crucial role in inhibiting cell proliferation across various cancer types. This in vitro study explores the potential anticancer efficacy of a newly synthesized OGF bioconjugate in synergy with the classic chemotherapeutic agent, gemcitabine (OGF-Gem). The study delves into assessing the impact of the OGF-Gem conjugate on cell proliferation inhibition, cell cycle regulation, the induction of cellular senescence, and apoptosis. Furthermore, the antimetastatic potential of the OGF-Gem conjugate was demonstrated through evaluations using blood platelets and AsPC-1 cells with a light aggregometer. In summary, this article demonstrates the cytotoxic impact of the innovative OGF-Gem conjugate on pancreatic cancer cells in both 2D and 3D models. We highlight the potential of both the OGF-Gem conjugate and OGF alone in effectively inhibiting the ex vivo pancreatic tumor cell-induced platelet aggregation (TCIPA) process, a phenomenon not observed with Gem alone. Furthermore, the confirmed hemocompatibility of OGF-Gem with platelets reinforces its promising potential. We anticipate that this conjugation strategy will open avenues for the development of potent anticancer agents

Re-evaluation of the interrelationships among the behavioral tests in rats exposed to chronic unpredictable mild stress

<div><p>The chronic unpredictable mild stress model of depression has been widely used as an experimental tool to investigate human psychopathology. Our objective was to provide an update on the validity and reliability of the chronic unpredictable mild stress model, by analyzing the interrelationships among the indexes using stepwise discriminant analysis and Pearson correlation coefficient to examine the possible combinations. We evaluated the depressive rats in both the presence and the absence of chronic unpredictable mild stress, using weight change, percentage of sucrose preference, coat state, splash test, open-field test, elevated plus-maze test, forced swimming test, and Morris water maze test. The results showed that 6-week-long chronic unpredictable mild stress produces significant depression and anxiety-like behavior. The combination of body weight change, percentage of sucrose preference, coat state score, open-field score, grooming latency of splash test, immobility time in force swimming test, and platform crossing in the Morris water maze test can effectively discriminate between normal and chronic unpredictable mild stress rats. Strong interrelationships were noted among these indexes in both open-field test and elevated plus-maze test. In conclusion, there might be certain criteria for the combination of behavioral endpoints, which is advantageous to more effectively and reliably assess the chronic unpredictable mild stress induced depression model.</p></div

Variables entered and inclusion parameters.

<p>Variables entered and inclusion parameters.</p

CUMS schedule.

<p>CUMS schedule.</p

Results of the percentage of time and entries in the open arms in elevated plus-maze test of rats submitted to 6-week CUMS (mean ± SD, n = 40).

<p>A: Time spent in open arms(%); B: Entries of open arms(%).**p < 0.01 vs control.</p

Results of the latency and time of grooming behavior following a 10% sucrose solution spray in the splash test of rats submitted to 6-week CUMS(mean ± SD, n = 40).A: Grooming latency(sec); B: Grooming time(%).

<p>**p < 0.01 vs control.</p

Results of horizontal movement, rearing, grooming behaviors, feces, latency (sec), total scores in the open-field test of rats submitted to 6-week CUMS (mean± SD, n = 40).

<p>Results of horizontal movement, rearing, grooming behaviors, feces, latency (sec), total scores in the open-field test of rats submitted to 6-week CUMS (mean± SD, n = 40).</p

Results of forced swimming test of rats submitted to 6-week CUMS (mean ± SD, n = 40).

<p>**p < 0.01 vs control.</p

Preliminary work and general procedure of this study.

<p>Preliminary work and general procedure of this study.</p