Efficacy and safety of neuromodulation for apathy in patients with Alzheimer's disease: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Non-pharmacological interventions, including noninvasive neuromodulation, may alleviate apathy in individuals with Alzheimer's disease. This systematic review and meta-analysis investigated the efficacy and safety of neuromodulation for apathy in elderly patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI). METHODS: The Cochrane Central Register of Controlled Trials, EMBASE, and PubMed databases were searched for randomized controlled trials (RCTs) of neuromodulation for apathy in AD or MCI. The primary outcome was change in apathy based on the Apathy Evaluation Scale. Secondary outcomes were change in global cognition and trial discontinuation. RESULTS: The meta-analysis included four RCTs involving 89 patients (aged 65.6-80.5 years) with apathy in AD or MCI. Findings showed no significant improvement in apathy (SMD = 0.57, 95% CI = -0.22-1.36; P = 0.16) or global cognition (SMD = 0.83, 95% CI = -0.11-1.78; P = 0.08) with neuromodulation compared to sham. Subgroup analyses showed significant improvement in apathy with high-frequency rTMS at 120% RMT compared to sham (SMD = 1.36, [95% CI = 0.61-2.12]; P = 0.0004), but not with rTMS at 80% RMT. For global cognition, high-frequency rTMS resulted in significant enhancement (SMD = 1.34 [95% CI = 0.59-2.10]; P = 0.0005), but no notable difference was observed with tDCS compared to sham. There was no significant difference in trial discontinuation in patients with AD or MCI treated with neuromodulation compared to sham. CONCLUSION: High-frequency rTMS at 120% RMT for four weeks may be efficacious and safe for the treatment of apathy in elderly patients with AD or MCI. High-frequency rTMS may also improve global cognition in these patients. This implies rTMS has potential as an intervention for apathy in AD and MCI. Large well conducted RCTs are warranted to explore this effect further.

Pentamidine Alleviates Inflammation and Lipopolysaccharide-Induced Sepsis by Inhibiting TLR4 Activation via Targeting MD2.

Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) that can recognize lipopolysaccharides (LPS) and initiate the immune response, to protect the body from infection. However, excessive activation of TLR4 induced by LPS leads to substantial release of pro-inflammatory factors, which may bring a cytokine storm in the body and cause severe sepsis. Existing molecules specialized in sepsis therapy are either in clinical trials or show mediocre effects. In this study, pentamidine, an approved drug used in the treatment of trypanosomiasis, was identified as a TLR4 antagonist. Saturation transferred difference (STD)-NMR spectra indicated that pentamidine directly interacted with TLR4's co-receptor myeloid differentiation protein 2 (MD2) in vitro. Cellular thermal shift assay (CETSA) showed that pentamidine binding decreased MD2 stability, which was supported by in silico simulations that pentamidine binding rendered most regions of MD2 more flexible. Pentamidine was found to inhibit the formation of the TLR4/MD2/MyD88 complex and the activation of the TLR4 signaling axes of NF-κB and MAPKs, therefore blocking LPS-induced TLR4 signaling downstream of the pro-inflammatory factors NO, TNF-α, and IL-1ß. The bioisosteric replacement of the methylene group at the center 13' site of pentamidine by the ether oxygen group significantly decreased its interactions with MD2 and abolished its TLR4 antagonist activity. Furthermore, pentamidine enhanced the survival rate of septic mice and exerted an anti-inflammatory effect on organs. All these data provide strong evidence that pentamidine may be an effective drug in alleviating inflammation and sepsis.

Ninety Years of Pentamidine: The Development and Applications of Pentamidine and its Analogs.

Pentamidine, an FDA-approved human drug for many protozoal infections, was initially synthesized in the late 1930s and first reported to be curative for parasitosis in the 1940s. After ninety years of sometimes quiet growth, pentamidine and its derivatives have gone far beyond antibacterial agents, including but not limited to the ligands of DNA minor groove, modulators of PPIs (protein-protein interactions) of the transmembrane domain 5 of lateral membrane protein 1, and the blockers of the SARS-CoV-2 3a channel. This mini-review highlights the development and applications of pentamidine and its analogs, aiming to provide insights for further developing pentamidine derivatives in the following decades.

C. elegans as an in vivo model system for the phenotypic drug discovery for treating paraquat poisoning.

BACKGROUND: Paraquat (PQ) is an effective and widely used herbicide and causes numerous fatalities by accidental or voluntary ingestion. However, neither the final cytotoxic mechanism nor effective treatments for PQ poisoning have been discovered. Phenotypic drug discovery (PDD), which does not rely on the molecular mechanism of the diseases, is having a renaissance in recent years owing to its potential to address the incompletely understood complexity of diseases. Herein, the C. elegans PDD model was established to pave the way for the future phenotypic discovery of potential agents for treating PQ poisoning. METHODS: C. elegans were treated with PQ-containing solid medium followed by statistical analysis of worm survival, pharyngeal pumping, and movement ability. Furthermore, coenzyme Q10 (CoQ10) was used to test the C. elegans model of PQ poisoning by measuring the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), mitochondrial morphology, and worm survival rate. Additionally, we used the classic mice model of PQ intoxication to evaluate the validity of the C. elegans model of PQ poisoning by measuring the effect of CoQ10 as a potential antidote for PQ poisoning. RESULTS: In the C. elegans model of PQ poisoning, 5 mg/mL PQ increased the levels of ROS, MDA content, mitochondrial fragments, which significantly shortened the lifespan, while CoQ10 alleviated these phenotypes. In the mice model of PQ poisoning, CoQ10 increased the chance of survival in PQ poisoned mice while reducing ROS, MDA content in lung tissue and inhibiting PQ-induced lung edema. Moreover, CoQ10 alleviated the lung morphopathological changes induced by PQ. CONCLUSION: Here we established a C. elegans model of PQ poisoning, whose validity was confirmed by the classic mice model of PQ intoxication.

Dissecting the Role of N-Glycan at N413 in Toll-like Receptor 3 via Molecular Dynamics Simulations.

Toll-like receptor 3 (TLR3) is an endosomal receptor involved in initiating immune responses upon viral infection by directly recognizing double-stranded RNA (dsRNA). As one of the most heavily glycosylated TLR family members, the role of glycan at N413 of TLR3 in ligand recognition has been in debate for decades. Herein, to investigate the role of glycans in TLR3, specifically at amino acid residue N413, molecular dynamic simulations were performed. The loop region of LRR12 (residues 323-355), which protrudes from the dsRNA binding TLR3 lateral surface was found to be vital for interacting with dsRNA via the formation of hydrogen bonds. The glycan at N413 not only prevented dsRNA from being exposed to the bulk water during the binding process but further stabilized dsRNA in the TLR3 binding site. When N413 was in the glycosylated form, the binding free energy of TLR3 interacting with dsRNA was significantly lower than that of TLR3 in the N413 unglycosylated form. Additionally, as the glycan at N413 functioned to alter the dynamics of the dsRNA binding process, its flexibility was meanwhile influenced by dsRNA. In all, these results demonstrate that the size, length, and branch of glycan at N413 affect the thermodynamics and dynamics of TLR3 recognition with dsRNA. This study further extends our understanding of the biological role of glycans in the innate immune recognition of dsRNA by TLR3 and provides a new perspective for modulating TLR3 function.

Nicotine prevents in vivo Aß toxicity in Caenorhabditis elegans via SKN-1.

OBJECTIVE: Nicotine, a main active compound in tobacco, has been shown to attenuate amyloid-ß (Aß) mediated neurotoxicity. However, the detailed underlying mechanisms remains to be elucidated. In this study, nematode Caenorhabditis elegans (C. elegans) had been chosen as the model animal for dissecting the role of nicotine in the prevention of Aß-induced toxicity in vivo. METHODS: CL2120 and CL4176 transgenic worms of Alzheimer's disease (AD) models were treated with different concentrations of nicotine, and worm paralysis was monitored. Next, the effects of nicotine on Aß deposits, Aß oligomers, reactive oxygen species (ROS) and the oxidative stress resistance in worms were measured. Moreover, the pathway responsible for nicotine alleviating Aß-induced toxicity in vivo was explored by observing the oxidative stress resistance of skn-1 or daf-16 mutants in the presence of nicotine. Furthermore, the worm paralysis and Aß deposits were further checked in CL4176 worms with skn-1 RNA interference under the condition of nicotine. RESULTS: Nicotine (5 µM) attenuated AD-like symptoms of worm paralysis in CL2120 and CL4176 transgenic C. elegans. Nicotine did not inhibit Aß aggregation in vitro, however it suppressed Aß deposits and reduced the Aß oligomers to alleviate the toxicity induced by Aß overexpression in C. elegans. Although nicotine did not possess apparent intrinsic anti-oxidative activity, it decreased in vivo reactive oxygen species (ROS). Nicotine enhanced the oxidative stress resistance of C. elegans, which was mediated by SKN-1 but not DAF-16 signaling. Furthermore, skn-1 RNAi abrogated the effect of nicotine reducing Aß deposits in vivo and completely blocked nicotine preventing Aß induced worm paralysis. CONCLUSIONS: Nicotine reduces Aß oligomer formation and alleviates Aß-induced paralysis of C. elegans, which is mediated by SKN-1 signaling.