Role of Serotonylation and SERT Posttranslational Modifications in Alzheimer's Disease Pathogenesis.

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is implicated mainly in Alzheimer's disease (AD) and reported to be responsible for several processes and roles in the human body, such as regulating sleep, food intake, sexual behavior, anxiety, and drug abuse. It is synthesized from the amino acid tryptophan. Serotonin also functions as a signal between neurons to mature, survive, and differentiate. It plays a crucial role in neuronal plasticity, including cell migration and cell contact formation. Various psychiatric disorders, such as depression, schizophrenia, autism, and Alzheimer's disease, have been linked to an increase in serotonin-dependent signaling during the development of the nervous system. Recent studies have found 5-HT and other monoamines embedded in the nuclei of various cells, including immune cells, the peritoneal mast, and the adrenal medulla. Evidence suggests these monoamines to be involved in widespread intracellular regulation by posttranslational modifications (PTMs) of proteins. Serotonylation is the calcium-dependent process in which 5-HT forms a long-lasting covalent bond to small cytoplasmic G-proteins by endogenous transglutaminase 2 (TGM2). Serotonylation plays a role in various biological processes. The purpose of our article is to summarize historical developments and recent advances in serotonin research and serotonylation in depression, aging, AD, and other age-related neurological diseases. We also discussed several of the latest developments with Serotonin, including biological functions, pathophysiological implications and therapeutic strategies to treat patients with depression, dementia, and other age-related conditions.

Ultrasound-Guided Peripheral Nerve Blocks for Shoulder Dislocation in the Emergency Department: A Systemic Review.

BACKGROUND: Shoulder dislocations are among the most common orthopedic emergencies encountered in the emergency department (ED). Ultrasound-guided peripheral nerve blocks (USG-PNBs) are increasingly being used for acute pain management in the ED, but clinical evidence supporting their utility for shoulder dislocation is limited and often conflicting. OBJECTIVE: The aim of this review was to summarize and evaluate the utility of USG-PNB for analgesia during closed reduction of dislocated shoulders in the ED. METHODS: Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic literature search of the PubMed, Scopus, and Cochrane databases was performed from database inception to September 2022. We included clinical studies examining USG-PNB for pain management of dislocated shoulders in the ED. Information collected from eligible studies included patient demographic characteristics, USG-PNB approach, alternate analgesia techniques, anesthetic regimens, clinical outcomes, and adverse events. RESULTS: Five studies met inclusion criteria, all of which were randomized controlled trials comparing USG-PNB with procedural sedation and analgesia. Pooled patient satisfaction scores were similar for both analgesia methods (3.5 ± 0.6 vs. 3.9 ± 0.6 out of 5; p = 0.76). Patients managed with procedural sedation and analgesia achieved higher rates of overall shoulder reduction (100% vs. 67%; p < 0.001) and successful reduction on the first attempt (86% vs. 48%; p < 0.001). The USG-PNB groups in all but one study had shorter lengths of ED stay. Overall, USG-PNB was associated with a lower risk of adverse events and complications (3.9% vs. 24.9%; p < 0.001), especially adverse respiratory events (0% vs. 14.7%; p < 0.001). CONCLUSIONS: USG-PNBs performed by adequately trained emergency physicians should be considered a safe and effective alternative for analgesia during closed reduction of dislocated shoulders in the ED, particularly in patients with cardiorespiratory comorbidities.

Exosome loaded immunomodulatory biomaterials alleviate local immune response in immunocompetent diabetic mice post islet xenotransplantation.

Foreign body response (FBR) to biomaterials compromises the function of implants and leads to medical complications. Here, we report a hybrid alginate microcapsule (AlgXO) that attenuated the immune response after implantation, through releasing exosomes derived from human Umbilical Cord Mesenchymal Stem Cells (XOs). Upon release, XOs suppress the local immune microenvironment, where xenotransplantation of rat islets encapsulated in AlgXO led to >170 days euglycemia in immunocompetent mouse model of Type 1 Diabetes. In vitro analyses revealed that XOs suppressed the proliferation of CD3/CD28 activated splenocytes and CD3+ T cells. Comparing suppressive potency of XOs in purified CD3+ T cells versus splenocytes, we found XOs more profoundly suppressed T cells in the splenocytes co-culture, where a heterogenous cell population is present. XOs also suppressed CD3/CD28 activated human peripheral blood mononuclear cells (PBMCs) and reduced their cytokine secretion including IL-2, IL-6, IL-12p70, IL-22, and TNFα. We further demonstrate that XOs mechanism of action is likely mediated via myeloid cells and XOs suppress both murine and human macrophages partly by interfering with NFκB pathway. We propose that through controlled release of XOs, AlgXO provide a promising new platform that could alleviate the local immune response to implantable biomaterials.

Controlled Release of Stem Cell Secretome Attenuates Inflammatory Response against Implanted Biomaterials.

Inflammatory response against implanted biomaterials impairs their functional integration and induces medical complications in the host's body. To suppress such immune responses, one approach is the administration of multiple drugs to halt inflammatory pathways. This challenges patient's adherence and can cause additional complications such as infection. Alternatively, biologics that regulate multiple inflammatory pathways are attractive agents in addressing the implants immune complications. Secretome of mesenchymal stromal cells (MSCs) is a multipotent biologic, regulating the homeostasis of lymphocytes and leukocytes. Here, it is reported that alginate microcapsules loaded with processed conditioned media (pCM-Alg) reduces the infiltration and/or expression of CD68+ macrophages likely through the controlled release of pCM. In vitro cultures revealed that alginate can dose dependently induce macrophages to secrete TNFα, IL-6, IL-1ß, and GM-CSF. Addition of pCM to the cultures attenuates the secretion of TNFα (p = 0.023) and IL-6 (p < 0.0001) by alginate or lipopolysaccharide (LPS) stimulations. Mechanistically, pCM suppressed the NfκB pathway activation of macrophages in response to LPS (p < 0.0001) in vitro and cathepsin activity (p = 0.005) in response to alginate in vivo. These observations suggest the efficacy of using MSC-derived secretome to prevent or delay the host rejection of implants.

Reduction of lymphocele rate in patients undergoing sentinel node biopsy for melanoma by intraoperative placement of plant-based hemostatic powder: Results of a prospective trial.

BACKGROUND: Lymphocele is a complication of sentinel node biopsy (SNB) for melanoma. Plant-based hemostatic powder (PBHP) may have a lymphostatic benefit. We studied whether PBHP placed intraoperatively could reduce lymphocele rates. METHODS: We performed an open label, prospective, IRB -approved, before- and-after, matched control trial of PBHP placed into the wound in patients undergoing SNB of groin or axillary nodes for melanoma staging. Patient/tumor features and lymphocele rates were compared by standard statistical tests. RESULTS: 66 control and 66 treatment (49 axillary and 17 groin in each arm) SNBs were performed in 61 and 55 patients, respectively, for a total 132 SNBs in 116 patients. Patient and tumor features were similar between groups. Nineteen lymphoceles occurred (14.4%); lymphocele rates were 22.2% (14/66) in the control group and 7.6% (5/66) in the treatment group (p = 0.026). The reduction in lymphocele rates between arms was greater for axillary than for groin sites (87.5% vs. 33%); the axillary reduction was statistically significant (p = 0.030). CONCLUSIONS: Intra-operative placement of PBHP reduced the rate of lymphoceles in patients undergoing SNB for melanoma.

Mechanisms of Control of Mycobacterium tuberculosis by NK Cells: Role of Glutathione.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), continues to be one of the most prevalent infectious diseases in the world. There is an upward trend in occurrence due to emerging multidrug resistant strains and an increasingly larger proportion of immunocompromised patient populations as a result of the acquired immunodeficiency syndrome pandemic. The complex and often deadly combination of multidrug resistant M. tb (MDR-M. tb) along with human immunodeficiency virus (HIV) puts a significant number of people at high risk for pulmonary and extra-pulmonary TB without sufficient therapeutic options available. Natural killer (NK) cells and macrophages are major components of the body's innate immune system, contributing significantly to the body's ability to synergistically inhibit the growth of M. tb in immune compromised individuals lacking a sufficient T cell response. Direct mechanisms of control are largely through the secretory products perforin, granulysin, and granzymes, as well as multiple membrane-bound death receptors that facilitate target directed lysis. NK cells also have a role in indirectly stimulating an immune response through activation of macrophages and monocytes with multiple signaling pathways, including both reactive oxygen species and reactive nitrogen species. Glutathione (GSH) has been shown to play a part in inhibiting the growth of intracellular M. tb through bacteriostatic mechanisms. Enhancing cellular GSH through several cytokines and N-acetyl cysteine has been shown to increase these effects, at least in part, through their action on NK cells. Taken together, there is substantial evidence for a mechanistic correlation between NK cell activity and functionality in combating M. tb in HIV infection mediated through adequate GSH production and use.

An elucidation of neutrophil functions against Mycobacterium tuberculosis infection.

We characterized the functions of neutrophils in response to Mycobacterium tuberculosis (M. tb) infection, with particular reference to glutathione (GSH). We examined the effects of GSH in improving the ability of neutrophils to control intracellular M. tb infection. Our findings indicate that increasing the intracellular levels of GSH with a liposomal formulation of GSH (L-GSH) resulted in reduction in the levels of free radicals and increased acidification of M. tb containing phagosomes leading to the inhibition in the growth of M. tb. This inhibitory mechanism is dependent on the presence of TNF-α and IL-6. Our studies demonstrate a novel regulatory mechanism adapted by the neutrophils to control M. tb infection.

Characterization of dendritic cell and regulatory T cell functions against Mycobacterium tuberculosis infection.

Glutathione (GSH) is a tripeptide that regulates intracellular redox and other vital aspects of cellular functions. GSH plays a major role in enhancing the immune system. Dendritic cells (DCs) are potent antigen presenting cells that participate in both innate and acquired immune responses against microbial infections. Regulatory T cells (Tregs) play a significant role in immune homeostasis. In this study, we investigated the effects of GSH in enhancing the innate and adaptive immune functions of DCs against Mycobacterium tuberculosis (M. tb) infection. We also characterized the functions of the sub-populations of CD4+T cells such as Tregs and non-Tregs in modulating the ability of monocytes to control the intracellular M. tb infection. Our results indicate that GSH by its direct antimycobacterial activity inhibits the growth of intracellular M. tb inside DCs. GSH also increases the expressions of costimulatory molecules such as HLA-DR, CD80 and CD86 on the cell surface of DCs. Furthermore, GSH-enhanced DCs induced a higher level of T-cell proliferation. We also observed that enhancing the levels of GSH in Tregs resulted in downregulation in the levels of IL-10 and TGF- ß and reduction in the fold growth of M. tb inside monocytes. Our studies demonstrate novel regulatory mechanisms that favor both innate and adaptive control of M. tb infection.

The application of surface engineered silica for the treatment of sugar containing wastewater.

The removal of sucrose and fructose from water at various high concentrations by surface engineered silica (SES) was studied using dissolved sugar in pure water. The results indicate that sugar at concentrations of up to 800 g/L can be removed by SES at a relatively high dose of 250 to 300 g/L. Based on these results, process water from a soft drink filling station which was contaminated by sugar, flavour components, Escherichia coli, Pseudomonas aeruginosa bacteria and Candida pelliculosa yeast were treated to study the performance of SES using actual process water samples by analysing turbidity, biological oxygen demand (BOD), UV absorption, and various other standard parameters, and microbial tests. The study shows that at a dose of 100 g/L of SES bacterial contamination as well as turbidity, BOD and UV absorption can be significantly reduced. However, the study found the yeast species Candida pelliculosa could not be removed from the water samples.