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Vascular inflammation and fibrosis are hallmarks of hypertension and contribute to the development of cardiovascular disease and cognitive impairment. However, current anti-hypertensive drugs do not treat the underlying tissue damage, such as inflammation-associated fibrosis. Human amnion epithelial cells have several properties amenable for treating vascular pathology. This study tested the effect of amnion epithelial cells on vascular pathology and cognitive impairment during hypertension. Male C57Bl6 mice (8-12 weeks) were administered vehicle (saline; n = 58) or angiotensin II (0.7 mg/kg/d, n = 56) subcutaneously for 14 d. After surgery, a subset of mice were injected with 10 6 amnion epithelial cells intravenously. Angiotensin II infusion increased systolic blood pressure, aortic pulse wave velocity, accumulation of aortic leukocytes, and aortic mRNA expression of collagen subtypes compared to vehicle-infused mice (n = 9-11, P < 0.05). Administration of amnion epithelial cells attenuated these effects of angiotensin II (P < 0.05). Angiotensin II-induced cognitive impairment was prevented by amnion epithelial cell therapy (n = 7-9, P < 0.05). In the brain, amnion epithelial cells modulated some of the inflammatory genes that angiotensin II promoted differential expression of (n = 6, p-adjusted < 0.05). These findings suggest that amnion epithelial cells could be explored as a potential therapy to inhibit vascular pathology and cognitive impairment during hypertension., (© 2024. The Author(s).)

Background: Thrombolytic agents such as tissue plasminogen activator (tPA) are the only drug class approved to treat ischemic stroke and are usually administered within 4.5 h. However, only ~20% of ischemic stroke patients are eligible to receive the therapy. We previously demonstrated that early intravenous administration of human amnion epithelial cells (hAECs) can limit brain inflammation and infarct growth in experimental stroke. Here, we have tested whether hAECs exert cerebroprotective effects in combination with tPA in mice., Methods: Male C57Bl/6 mice were subjected to middle cerebral artery occlusion for 60 min followed by reperfusion. Immediately following reperfusion, vehicle (saline, n  = 31) or tPA (10 mg/kg; n  = 73) was administered intravenously. After 30 min of reperfusion, tPA-treated mice were injected intravenously with either hAECs (1×10 6 ; n  = 32) or vehicle (2% human serum albumin; n  = 41). A further 15 sham-operated mice were treated with vehicle ( n  = 7) or tPA + vehicle ( n  = 8). Mice were designated to be euthanised at 3, 6 or 24 h post-stroke ( n  = 21, 31, and 52, respectively), and brains were collected to assess infarct volume, blood-brain barrier (BBB) disruption, intracerebral bleeding and inflammatory cell content., Results: There was no mortality within 6 h of stroke onset, but a high mortality occurred in tPA + saline-treated mice between 6 h and 24 h post-stroke in comparison to mice treated with tPA + hAECs (61% vs. 27%, p  = 0.04). No mortality occurred within 24 h of sham surgery in mice treated with tPA + vehicle. We focused on early infarct expansion within 6 h of stroke and found that infarction was ~50% larger in tPA + saline- than in vehicle-treated mice (23 ± 3 mm 3 vs. 15 ± 2 mm 3 , p  = 0.02) but not in mice receiving tPA + hAECs (13 ± 2 mm 3 , p  < 0.01 vs. tPA + saline) in which intracerebral hAECs were detected. Similar to the profiles of infarct expansion, BBB disruption and intracerebral bleeding in tPA + saline-treated mice at 6 h was 50-60% greater than in vehicle-treated controls (2.6 ± 0.5 vs. 1.6 ± 0.2, p  = 0.05) but not after tPA + hAECs treatment (1.7 ± 0.2, p  = 0.10 vs. tPA + saline). No differences in inflammatory cell content were detected between treatment groups., Conclusion: When administered following tPA in acute stroke, hAECs improve safety and attenuate infarct growth in association with less BBB disruption and lower 24 h mortality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Barreto-Arce, Kim, Chan, Lim, Drummond, Ma, Phan, Sobey and Zhang.)

Background: We proposed a Phase I dose escalation trial to assess the safety of allogeneic human amniotic epithelial cells (hAECs) in stroke patients with a view to informing the design for a Phase II trial., Methods: The design is based on 3 + 3 dose escalation design with additional components for measuring MR signal of efficacy as well as the effect of hAECs (2-8 × 10 6 /kg, i.v.) on preventing immunosuppression after stroke., Results: Eight patients (six males) were recruited within 24 h of ischemic stroke onset and were infused with hAECs. We were able to increase the dose of hAECs to 8 × 10 6 cells/kg (2 × 10 6 /kg, n = 3; 4 × 10 6 /kg, n = 3; 8 × 10 6 /kg, n = 2). The mean age is 68.0 ± 10.9 (mean ± SD). The frequencies of hypertension and hyperlipidemia were 87.5%, diabetes was 37.5%, atrial fibrillation was 50%, ischemic heart disease was 37.5% and ever-smoker was 25%. Overall, baseline NIHSS was 7.5 ± 3.1, 7.8 ± 7.2 at 24 h, and 4.9 ± 5.4 at 1 week ( n = 8). The modified Rankin scale at 90 days was 2.1 ± 1.2. Supplemental oxygen was given in five patients during hAEC infusion. Using pre-defined criteria, two serious adverse events occurred. One patient developed recurrent stroke and another developed pulmonary embolism whilst in rehabilitation. For the last four patients, infusion of hAECs was split across separate infusions on subsequent days to reduce the risk for fluid overload., Conclusion: Our Phase I trial demonstrates that a maximal dose of 2 × 10 6 /kg hAECs given intravenously each day over 2 days (a total of 4 × 10 6 /kg) is safe and optimal for use in a Phase II trial., Clinical Trial Registration: ClinicalTrials.gov, identifier ACTRN12618000076279P., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Phan, Lim, Chan, McDonald, Gan, Zhang, Barreto Arce, Vuong, Thirugnanachandran, Clissold, Ly, Singhal, Hervet, Kim, Drummond, Wallace, Ma and Sobey.)

Objective: To assess the effect of bovine lactoferrin (bLf) on the invasion of Salmonella enterica ser. Typhimurium to HEp-2 cells., Materials and Methods: HEp-2 monolayers were infected with 106 colony forming unit (CFU) of bacteria in the absence and presence of 1 and 10 mg/mL of bLf (iron-saturated) and incubated 1.5 hours at 37°C. Two treatments were evaluated: pre- infection (HEp-2 cells were incubated with bLf one hour prior to infection with Salmonella) and post-infection (bLf was added 15 minutes after the infection). Invasiveness of Salmonella was determined throgh quantification of CFU recovered from inside the HEp-2 cells (after treatment with 100 μg/mL and 10 μg/mL of gentamicin and Triton X -100)., Results: In the pre-infection treatment, we observed a decrease of 23% of Salmonella invasion when HEp-2 cells were pre incubated with 1 mg/mL of bLf (2.8x105 vs 2.1x105, p=0.04) and 50% when them were pre-incubated with 10 mg/mL of bLf (2.8x105 vs 1.4x105, p=0.04). In post-infection treatment, no changes were observed in the invasiveness of Salmonella., Conclusion: The results indicated that bLf reduces the invasiveness of Salmonella enterica ser. Typhimurium to HEp-2 cells in the pre-infection treatment.