Exploring the molecular mechanisms of MSC-derived exosomes in Alzheimer's disease: Autophagy, insulin and the PI3K/Akt/mTOR signaling pathway.

Alzheimer's disease (AD) is a devastating neurological condition characterized by cognitive decline, motor coordination impairment, and amyloid plaque accumulation. The underlying molecular mechanisms involve oxidative stress, inflammation, and neuronal degeneration. This study aimed to investigate the therapeutic effects of mesenchymal stem cell-derived exosomes (MSC-exos) on AD and explore the molecular pathways involved, including the PI3K/Akt/mTOR axis, autophagy, and neuroinflammation. To assess the potential of MSC-exos for the treatment of AD, rats were treated with AlCl3 (17 mg/kg/once/day) for 8 weeks, followed by the administration of an autophagy activator (rapamycin), or MSC-exos with or without an autophagy inhibitor (3-methyladenin; 3-MA+ chloroquine) for 4 weeks. Memory impairment was tested, and brain tissues were collected for gene expression analyses, western blotting, histological studies, immunohistochemistry, and transmission electron microscopy. Remarkably, the administration of MSC-exos improved memory performance in AD rats and reduced the accumulation of amyloid-beta (Aß) plaques and tau phosphorylation. Furthermore, MSC-exos promoted neurogenesis, enhanced synaptic function, and mitigated astrogliosis in AD brain tissues. These beneficial effects were associated with the modulation of autophagy and the PI3K/Akt/mTOR signalling pathway, as well as the inhibition of neuroinflammation. Additionally, MSC-exos were found to regulate specific microRNAs, including miRNA-21, miRNA-155, miRNA-17-5p, and miRNA-126-3p, further supporting their therapeutic potential. Histopathological and bioinformatic analyses confirmed these findings. This study provides compelling evidence that MSC-exos hold promise as a potential therapeutic approach for AD. By modulating the PI3K/Akt/mTOR axis, autophagy, and neuroinflammation, MSC-exos have the potential to improve memory, reduce Aß accumulation, enhance neurogenesis, and mitigate astrogliosis. These findings shed light on the therapeutic potential of MSC-exos and highlight their role in combating AD.

Quality by design-based optimization of formulation and process parameters for berberine nanosuspension for enhancing its dissolution rate, bioavailability, and cardioprotective activity.

Berberine (BER) possesses dissolution rate limited oral bioavailability. The present study deciphers the formulation of nanosuspension loaded with BER for enhancing its cardioprotective potential. The nanosuspension was prepared by a liquid antisolvent precipitation technique using sodium lauryl sulfate as a surfactant and polyvinyl pyrrolidone K30 (PVP K30) as a polymer. The optimized formulation showed a particle size of 251.32 ± 4.18 nm, zeta potential of -24.10 ± 1.16 mV, and drug loading capacity of 98.22 ± 2.24%. The results showed about 6.01-fold and 3.54-fold enhancement in the dissolution rate and permeability, respectively, upon loading berberine into nanosuspension. About 8.44-fold increase in Cmax , 27.22-fold increase in AUC0-t , and 27.38-fold increase in AUC0-∞ were observed in the case of BER nanosuspension, compared to its naïve form. The results of particle size, zeta potential, and drug loading showed a nonsignificant change in the response of fresh and aged nanosuspension, which indicated that the formulation was stable. In vitro results on H9C2 cell line indicated a lower cellular proliferation rate after treatment with BER nanosuspension with decreased cytoplasmic expression of angiotensin converting enzyme (ACE) protein. Overall, the results indicated the successful development of BER nanosuspension with an enhanced dissolution rate, permeability, bioavailability, and cardioprotective activity. Practical applications The present study provides the evidence that the formulation of nanosuspension loaded with berberine enhance the cardioprotective activity of berberine. The results of the study supports the improved bioavailability of nanosuspension of berberine showed enhanced cardioprotective activity.

Protective Effect of Triclosan in Monocrotaline-Induced Pulmonary Arterial Hypertension: FASN Inhibition a Novel Approach.

Background: Novel pharmacological approaches are needed to improve the outcomes of patients with idiopathic pulmonary hypertension. Fatty acid synthase (FASN) inhibitors have shown beneficial effects in preclinical models of pulmonary arterial hypertension (PAH), because of their role in the regulation of pulmonary artery vasoconstrictor tone and remodeling. Objective: We compared a Triclosan (FASN inhibitor), for the first time with the dual endothelin receptor antagonist, macitentan, in a monocrotaline-induced rat pulmonary hypertension model. Methods: Different methods (hemodynamics, histology of right ventricle and pulmonary vessels, and circulating biomarkers) showed consistently that 30 mg/kg daily of Triclosan (FASN inhibitor) and 10 mg/kg daily of macitentan slowed the progression of PAH both at the functional and structural levels. Results: Treatments started on day 14 after monocrotaline injection and lasted 14 days. The findings of all experimental methods show that the FASN inhibitor has more similar effects as compared to macitentan. Conclusion: Our study reveals that inhibition of FAS decreases RV hypertrophy and improves cardiac function associated with PAH with the regulation of metabolic functions and governs further studies to establish "FASN inhibitor as a potential therapeutic approach" for the management of PAH.

Recent Advances Towards Treatment of HIV: Synthesis and SAR Studies.

In the present study, authors want to encourage the research exertions through structureactivity relationship for the identification of effective molecules for the treatment of Human immunodeficiency virus because nowadays AIDS is considered as one of the main causes of death in human beings. A diversity of biological resources has been searched and developed for the treatment of HIV but unfortunately, until now, no medicine is found to be fully effective and safe for the cure of patients. Human immunodeficiency virus is a type of lentivirus which causes the infection of HIV and once it enters the human body, it stays for a longer period of time triggering immunodeficiency syndrome. For searching and developing new potent and effective anti-HIV molecules, medicinal chemists have engaged in countless targets with the structure-activity relationship (SAR) of molecules and on this basis, many antiretroviral therapies have been developed to cure HIV infection. Most of these new searched molecules have been found to be clinically active against various types of AIDS patient and auxiliary research in this area may lead to better treatment in the near future. This article encompasses and highlights the recent advancement of innumerable inhibitors laterally through synthetic, semi-synthetic and structure-activity relationship approaches.

3D Printing Technology in Drug Delivery: Recent Progress and Application.

BACKGROUND: 3D printing technology is a new chapter in pharmaceutical manufacturing and has gained vast interest in the recent past as it offers significant advantages over traditional pharmaceutical processes. Advances in technologies can lead to the design of suitable 3D printing device capable of producing formulations with intended drug release. METHODS: This review summarizes the applications of 3D printing technology in various drug delivery systems. The applications are well arranged in different sections like uses in personalized drug dosing, complex drugrelease profiles, personalized topical treatment devices, novel dosage forms and drug delivery devices and 3D printed polypills. RESULTS: This niche technology seems to be a transformative tool with more flexibility in pharmaceutical manufacturing. Typically, 3D printing is a layer-by-layer process having the ability to fabricate 3D formulations by depositing the product components by digital control. This additive manufacturing process can provide tailored and individualized dosing for treatment of patients different backgrounds with varied customs and metabolism pattern. In addition, this printing technology has the capacity for dispensing low volumes with accuracy along with accurate spatial control for customized drug delivery. After the FDA approval of first 3D printed tablet Spritam, the 3D printing technology is extensively explored in the arena of drug delivery. CONCLUSION: There is enormous scope for this promising technology in designing various delivery systems and provides customized patient-compatible formulations with polypills. The future of this technology will rely on its prospective to provide 3D printing systems capable of manufacturing personalized doses. In nutshell, the 3D approach is likely to revolutionize drug delivery systems to a new level, though need time to evolve.