Strong Binding of Phytochemicals to the Catalytic Domain of Tyrosine Hydroxylase as a Trojan Horse Decreases Dopamine in Dopaminergic Cells: Pharmaceutical Considerations in Schizophrenia and Parkinson's Disease.

BACKGROUND: Imbalances in dopamine levels result in neurological and psychological disorders such as elevated dopamine in Parkinson's disease. OBJECTIVE: Despite a considerable number of advertisements claiming Aloe-vera's effectiveness in PD treatment, it has hidden long-term disadvantages for healthy people and PD patients. METHODS: In the present investigation, the impacts of Aloe-vera on dopaminergic cells were evaluated. RESULTS: The results indicated that the focal adhesion kinase (FAK) enhancement was in line with the Bax/Bcl2 ratio decrement, reactive oxygen specious (ROS) production, and nonsignificant alteration in the sub-G1phase of the cell cycle. It led to glial cell-derived neurotrophic factor (GDNF) upregulation but did not significantly change the BDNF level involved in depression and motor impairment recovery. These events apparently resulted in the enhancement in dopaminergic cell viability and neurite length and attenuated PI+ cells. However, it also induced neuronal nitric oxide synthase (nNOS) overexpression and nitric oxide (NO) and lactate dehydrogenase (LDH) production. Notably, docking results of the catalytic domain in tyrosine hydroxylase (TH) with the Aloe-vera constituents showed strong binding of most Aloe-vera constituents with the catalytic domain of TH, even stronger than L-tyrosine as an original substrate. Following the docking results, Aloe-vera downregulated TH protein and attenuated dopamine. CONCLUSION: It can be hypothesized that Aloe-vera improves PD symptoms through enhancement in antiapoptotic markers and neurotrophic factors, while it suppresses TH and dopamine in the form of a Trojan horse, later resulting in the future deterioration of the disease symptoms. The results provide cues to pharmaceutical companies to use the active components of Aloe-vera as putative agents in neurological and psychiatric disorders and diseases to decrease dopamine in patients with enhanced dopamine levels.

Fingolimod Nanoemulsions at Different Particle Sizes Define the Fate of Spinal Cord Injury Recovery.

Spinal cord injury (SCI) is a debilitating condition for which no definitive treatment has yet been identified. Notably, it influences other tissues through inflammatory reactions and metabolic disturbances. Therefore, fingolimod (FTY-720), as an FDA-approved inflammatory modulator, would be promising. In the present study, nanocarriers with two distinct monodisperse particle sizes of 60 (nF60) and 190 (nF190) nm were prepared via low-(stirring) and high-energy (probe ultrasound) emulsion oil in water (O/W) methods. Larger nanocarriers showed higher EE% and sustained-release profile than smaller nanocarriers. Neural stem cell (NSC) viability and lactate dehydrogenase (LDH) release were studied in the presence of nanocarriers and free FTY-720. The results indicated that nanocarriers and free FTY-720 enhanced NSC viability compared with the control group. However, nF190 induced significantly less cell membrane damage than nF60. Nanocarriers and free FTY-720 enhanced motor neuron recovery in SCI rats, while body weight and return to bladder reflux by nF190 were significantly higher than those in the nF60 group. Return to bladder reflux might be due to the role of FTY-720 in the regulation of detrusor muscle tone and preservation of the integrity of vessels by acting on endothelial cells. Moreover, nF190 gained higher soleus muscle weight than the free drugs; probably decreasing proinflammatory cytokines in the soleus diminishes muscular atrophy in SCI rats. In summary, it might be said that larger nanocarriers with sustained-release profile and less cell membrane damage seem to be more efficient than smaller ones to manage SCI and enhance bladder reflux. These data will help pharmaceutical companies select the correct particle size for nanodrugs and develop more efficient drug formulations to treat SCI.

Can we Succeed in the Fight Against SARS-CoV-2 with its Emerging New Variants?

In 2019, the whole world came together to confront a life-threatening virus named SARS-CoV-2, causing COVID-19 illness. The virus infected the human host by attaching to the ACE2 and CD147 receptors in some human cells, resulting in cytokine storm and death. The new variants of the virus that caused concern are Alpha, Beta, Gamma, Delta, and Epsilon, according to the WHO label. However, Pango lineages designated them as B.1.1.7, B.1.351, P.1, B.1.617.2, and B.1.429. Variants may be progressively formed in one chronic COVID-19 patient and transmitted to others. They show some differences in cellular and molecular mechanisms. Mutations in the receptor-binding domain (RBD) and N-terminal domain (NTD) lead to alterations in the host's physiological responses. They show significantly higher transmissibility rates and viral load while evading neutralizing antibodies at different rates. These effects are through mutations, deletion, and conformational alterations in the virus, resulting in the enhanced affinity of RBD to PD of ACE2 protein, virus entry, and spike conformational change. In the clinical laboratory, new variants may diagnose from other variants using specific primers for RBD or NTD. There are some controversial findings regarding the efficacy of the developed vaccines against the new variants. This research aimed to discuss the cellular and molecular mechanisms beyond COVID-19 pathogenesis, focusing on the new variants. We glanced at why the mutations and the ability to transmit the virus increase and how likely the available vaccines will be effective against these variants.

The World Against Versatile SARS-Cov-2 Nanomachines: Mythological or Reality?

Nanomachines hold promise for the next generation of emerging technology; however, nanomachines are not a new concept. Viruses, nature's nanomachines, have already existed for thousands of years. In 2019, the whole world had to come together to confront a life-threatening nanomachine named "SARS-CoV-2", which causes COVID-19 illness. SARS-CoV-2, a smart nanomachine, attaches itself to the ACE2 and CD147 receptors present on the cell surfaces of the lungs, kidneys, heart, brain, intestines, testes, etc. and triggers pathogenesis. Cell entry triggers a cascade of inflammatory responses resulting in tissue damage, with the worst affected cases leading to death. SARS-CoV-2 influences several receptors and signalling pathways; therefore, finding a biomaterial that caps these signalling pathways and ligand sites is of interest. This research aimed to compare the similarities and differences between COVID-19 and its elderly sisters, MERS and SARS. Furthermore, we glanced at emerging therapeutics that carry potential in eliminating SARS-CoV-2, and the tissue damage it causes. Simple prophylactic and therapeutic strategies for the treatment of COVID- 19 infection have been put forward.

The effect of carrier type on bone regeneration of demineralized bone matrix in vivo.

Demineralized bone matrix (DBM) is a bone substitute biomaterial used as an excellent grafting material. Some factors such as carrier type might affect the healing potential of this material. The background data discuss the present status of the field: Albumin as a main protein in blood and carboxymethyl cellulose (CMC) were applied frequently in the DBM gels. We investigated the bone-repairing properties of 2 DBMs with different carriers. Bone regeneration in 3 groups of rat calvaria treated with DBM from the Iranian Tissue Bank Research and Preparation Center, DBM from Hans Biomed Corporation, and an empty cavity was studied. Albumin and CMC as carriers were used. The results of bone regeneration in the samples after 1, 4, and 8 weeks of implantation were compared. The block of the histologic samples was stained with hematoxylin and eosin, and the percentage area of bone formation was calculated using the histomorphometry method. The results of in vivo tests showed a significantly stronger new regenerated bone occupation in the DBM with albumin carrier compared with the one with CMC 8 weeks after the implantation. The 2 types of DBM had a significant difference in bone regeneration. This difference is attributed to the type of carriers. Albumin could improve mineralization and bioactivity compared with CMC.