Proton Pump Inhibitors and Cancer Risk: A Comprehensive Review of Epidemiological and Mechanistic Evidence.

Background: Proton pump inhibitors (PPIs) are commonly prescribed long-acting drugs used to treat acid reflux, gastroesophageal reflux disease (GERD), and peptic ulcers. Recently, concerns have been raised about their safety, particularly due to the association between long-term PPI use and cancer development. Multiple comprehensive studies have consistently suggested a noteworthy link between prolonged PPI usage and an increased risk of developing gastric, esophageal, colorectal, and pancreatic cancers, yet the precise underlying mechanism remains elusive. Methods: First, we review the extensive body of research that investigates the intricate relationship between cancer and PPIs. Then, we predict PPI toxicity using the prodrug structures with the ProTox-II webserver. Finally, we predict the relative risk of cancer for each PPI, using PubMed citation counts of each drug and keywords related to cancer. Results: Our review indicates that prolonged PPI use (exceeding three months) is significantly associated with an elevated risk of cancer, while shorter-term usage (less than three months) appears to pose a comparatively lower risk. Our review encompasses various proposed mechanisms, such as pH and microbiome alterations, vitamin and mineral malabsorption, hypergastrinemia, and enterochromaffin-like cell proliferation, while ProTox-II also suggests aryl hydrocarbon receptor binding. Potentially, the PubMed citations count suggests that the PPIs omeprazole and lansoprazole are more associated with cancer than pantoprazole and esomeprazole. In comparison, the H2R blocker, famotidine, is potentially less associated with cancer than PPIs, and may serve as a safer alternative treatment for periods beyond 3 months. Conclusions: Despite the well-established cancer risk associated with PPIs, it is notable that these medications continue to be widely prescribed for periods longer than 3 months. Thus, it is of paramount importance for clinicians and patients to thoughtfully evaluate the potential risks and benefits of long-term PPI usage and explore alternative treatments before making informed decisions regarding their medical management.

Evaluation of Stages, Treatment Protocols, and Outcomes of Colorectal Cancer among West Bank Patients.

Background: Colorectal cancer (CRC) is the second most widespread cancer among Palestinian patients. As cancer care improves in hospitals across the West Bank, services like palliative care, targeted therapy, bone marrow transplantation, and individualized therapy are still limited. This study aimed to assess the CRC stages, treatment protocols, and survival rates of patients in the West Bank. Methodology: This retrospective study collected data from the medical records of Al-Najah University Hospital (NUH), which specializes in the care of cancer patients. Patients with confirmed CRC (stages I-IV) undergoing surgical or medical treatment were included in the study. Data collection was standardized by using a data collection form to gather information from the medical records included in the study. All statistical analyses were performed using SPSS (version v27), and survival was assessed using a regression analysis of the number of days from the time of diagnosis to the most recent visit against the type of treatment (e.g., surgery, chemotherapy, radiotherapy). Results: A sample of 252 patients with CRC from NUH was collected, including 143 males and 109 females aged between 27 and 86 years, with the average age being 60.6 ± 11.4 years. The sample included 183 patients (72.6%) diagnosed with colon cancer only, 29 patients (11.5%) diagnosed with rectal cancer only, and 40 patients (15.9%) diagnosed with both. Diagnosis took place at CRC stage I for 3 patients (1.2%), stage II for 33 patients (13.1%), stage III for 57 patients (22.6%), and stage IV for 159 patients (63.1%). Surgery was the most prevailing mode of treatment for 230 patients (91.3%), while 227 patients (90.1%) received chemotherapy treatment, and 38 patients (15.1%) received radiotherapy. Of the 252 patients, 40 patients (15.8%) received FOLFOX (i.e., folinic acid, fluorouracil, oxaliplatin), and 25 patients (9.9%) received FOLFIRI (i.e., folinic acid, fluorouracil, irinotecan), while the 187 remaining patients (74.2%) were treated with capecitabine, oxaliplatin, bevacizumab, cetuximab, regorafenib, cisplatin, etoposide, gemcitabine, or a combination thereof. The sample was categorized into six outcomes: (1) death, (2) cure, (3) disease progression, (4) disease recurrence, (5) under-treatment, and (6) unknown. Mortality was high, with 104 patients (41.3%) dying within a short time after diagnosis, and may have been attributable to delayed diagnosis. Surgical treatment had a positive impact on increasing the survival years, and it was significant (p = 0.033). Conclusions: A high percentage of patients were diagnosed in advanced CRC stages. The treatment modes were adopted from general international guidelines; however, the cure rates were low, and mortality was high. More studies need to be undertaken to investigate the actual application of chemotherapy protocols, and survival would benefit from the involvement of clinical pharmacists in the chemotherapy protocol selection, dosing, frequency, and follow-up. The present study advocates for greater public awareness of CRC and attests to the merits of screening by primary care professionals, which can help to avoid this serious illness and to promote a better prognosis.

Addressing the Discrepancies Between Animal Models and Human Alzheimer's Disease Pathology: Implications for Translational Research.

Animal models, particularly transgenic mice, are extensively used in Alzheimer's disease (AD) research to emulate key disease hallmarks, such as amyloid plaques and neurofibrillary tangles formation. Although these models have contributed to our understanding of AD pathogenesis and can be helpful in testing potential therapeutic interventions, their reliability is dubious. While preclinical studies have shown promise, clinical trials often yield disappointing results, highlighting a notable gap and disparity between animal models and human AD pathology. Existing models frequently overlook early-stage human pathologies and other key AD characteristics, thereby limiting their application in identifying optimal therapeutic interventions. Enhancing model reliability necessitates rigorous study design, comprehensive behavioral evaluations, and biomarker utilization. Overall, a nuanced understanding of each model's neuropathology, its fidelity to human AD, and its limitations is essential for accurate interpretation and successful translation of findings. This article analyzes the discrepancies between animal models and human AD pathology that complicate the translation of findings from preclinical studies to clinical applications. We also delve into AD pathogenesis and attributes to propose a new perspective on this pathology and deliberate over the primary limitations of key experimental models. Additionally, we discuss several fundamental problems that may explain the translational failures and suggest some possible directions for more effective preclinical studies.

Enhancing cognitive function in older adults: dietary approaches and implications.

Natural aging encompasses physiological and psychological changes that impact overall health and quality of life. Mitigating these effects requires physical and mental exercise, coupled with proper nutrition. Notably, protein malnutrition emerges as a potential risk factor for senile dementia, with insufficient intake correlating with premature cognitive decline. Adequate protein intake in the elderly positively associates with memory function and lowers cognitive impairment risk. Considering diet as a modifiable risk factor for cognitive decline, extensive research has explored diverse dietary strategies to prevent dementia onset in older adults. However, conclusive results remain limited. This review aims to synthesize recent evidence on effective dietary approaches to enhance cognitive function and prognosis in older individuals. Specifically, the study evaluates complex multicomponent programs, protein-rich diets, and branched-chain amino acid supplementation. By addressing the nexus of nutrition and cognitive health, this review contributes to understanding viable interventions for promoting cognitive well-being in aging populations.

Combined Hormonal Contraception during Breastfeeding-A Survey of Physician's Recommendations.

Until breastfeeding is established, progesterone-only pill (POP) use is preferable over combined hormonal contraception (CHC), as the latter potentially reduces milk production. Yet, POPs are often associated with breakthrough bleeding (BTB), and irregular spotting is often a reason for their cessation. Conversely, CHC is less associated with BTB but is not usually prescribed, even if breastfeeding has been established, despite its verified safety profile. Here, we surveyed physicians' perception of CHC safety during breastfeeding through an online questionnaire (N = 112). Physicians were asked if they would prescribe CHC to a woman three months postpartum, breastfeeding fully, and suffering from BTB while using POPs. Half of the physicians responded they would, 28% would not until six months postpartum, while 14% would not during breastfeeding. Of the physicians that would prescribe CHC, 58% would without any reservation, 24% would only after discussing milk reduction with the patient, 9% would use a pill with a lower hormonal dose, and 9% would only prescribe CHC 3 months postpartum. The main risk associated with CHC during breastfeeding, as perceived by physicians, is a potential decrease in breast milk production (88%). While some physicians consider CHC unsafe during breastfeeding, most health organizations consider CHC compatible with breastfeeding 5-6 weeks after birth. Thus, there is a gap in the attitude and knowledge of physicians about the safety profile of CHC, and only half acknowledge that the risk of BTB justifies the use of CHC instead of POPs while breastfeeding three months postpartum. We highlight the importance of physician's education, advocate CHC breastfeeding compatibility if breastfeeding has been established (i.e., 30 days postpartum), and underline the importance of discussing the option of CHC with patients in case POPs have unwanted side effects.

Partogram of Grandmultiparous Parturients: A Multicenter Cohort Study.

Sparse and conflicting data exist regarding the normal partogram of grand-multiparous (GMP, defined as parity of 6+) parturients. Customized partograms may potentially lower cesarean delivery rates for protraction disorders in this population. In this study, we aim to construct a normal labor curve of GMP women and compare it to the multiparous (MP, defined as parity of 2-5) partogram. We conducted a multicenter retrospective cohort analysis of deliveries between the years 2003 and 2019. Eligible parturients were the trials of labor of singletons ≥37 + 0 weeks in cephalic presentation with ≥2 documented cervical examinations during labor. Exclusion criteria were elective cesarean delivery without a trial of labor, preterm labor, major fetal anomalies, and fetal demise. GMP comprised the study group while the MP counterparts were the control group. A total of 78,292 deliveries met the inclusion criteria, comprising 10,532 GMP and 67,760 MP parturients. Our data revealed that during the first stage of labor, cervical dilation progressed at similar rates in MPs and GMPs, while head descent was a few minutes faster in GMPs compared to MPs, regardless of epidural anesthesia. The second stage of labor was faster in GMPs compared to MPs; the 95th percentile of the second stage duration of GMPs (48 min duration) was 43 min less than that of MPs (91 min duration). These findings remained similar among deliveries with and without epidural analgesia or labor induction. We conclude that GMPs' and MPs' cervical dilation progression in the active phase of labor was similar, and the second stage of labor was shorter in GMPs, regardless of epidural use. Thus, GMPs' uterus function during labor corresponds, and possibly surpasses, that of MPs. These findings indicate that health providers can use the standard partogram of the active phase of labor when caring for GMP parturients.

The Risk of Breakthrough Bleeding Justifies the Use of Combined Hormonal Contraception Over Progesterone-Only Pills While Breastfeeding.

Breakthrough bleeding is a side effect of progesterone-only pills (POPs) in 40% of women, and is reduced to 10% with combined hormonal contraceptives (CHCs). In addition, breakthrough bleeding is reduced if POP is supplemented with norethisterone. As breakthrough bleeding is responsible for a quarter of women stopping the pill, it is vital to realize that CHC is an alternative to POP-even during lactation. CHCs are considered safe during lactation, do not reduce milk production, nor impede infant development. Nevertheless, CHCs are often not prescribed for lactating mothers due to this misconception that they reduce milk production. Among Orthodox Jews, breakthrough bleeding frequently results in stopping POP, as Jewish religious law prohibits any physical contact of the mother with her partner during active bleeding, and for 7 days after bleeding. When such bleeding occurs, not choosing a CHC alternative, results in couples risking discontinuation of POP, and in conceiving within a year of the previous birth, with its increased risk of preterm labor and birth defects. To measure how physicians respond to the presumed dilemma of balancing the risk of breakthrough bleeding versus the concern of reduction of milk production, we conducted a preliminary online survey. Physicians were asked if they would prescribe CHC instead of POP to breastfeeding mothers, 3 months postpartum with breakthrough bleeding. Half of the physicians responded they would prescribe CHC, whereas close to half of the physicians responded that they would not. The main reasons given by the respondents for avoiding CHC was a concern regarding possible milk reduction. These results confirm a significant degree of a lack of updated pharmacological information regarding the options of oral contraceptive use for lactating mothers, particularly for those where breakthrough bleeding has major behavioral and religious consequences. Thus, we contend that the risk of breakthrough bleeding justifies the more routine use of CHC in lieu of POP in lactating mothers.

Identifying Hub Genes Associated with Neoadjuvant Chemotherapy Resistance in Breast Cancer and Potential Drug Repurposing for the Development of Precision Medicine.

Breast cancer is the second leading cause of morbidity and mortality in women worldwide. Despite advancements in the clinical application of neoadjuvant chemotherapy (NAC), drug resistance remains a major concern hindering treatment efficacy. Thus, identifying the key genes involved in driving NAC resistance and targeting them with known potential FDA-approved drugs could be applied to advance the precision medicine strategy. With this aim, we performed an integrative bioinformatics study to identify the key genes associated with NAC resistance in breast cancer and then performed the drug repurposing to identify the potential drugs which could use in combination with NAC to overcome drug resistance. In this study, we used publicly available RNA-seq datasets from the samples of breast cancer patients sensitive and resistant to chemotherapy and identified a total of 1446 differentially expressed genes in NAC-resistant breast cancer patients. Next, we performed gene co-expression network analysis to identify significantly co-expressed gene modules, followed by MCC (Multiple Correlation Clustering) clustering algorithms and identified 33 key hub genes associated with NAC resistance. mRNA-miRNA network analysis highlighted the potential impact of these hub genes in altering the regulatory network in NAC-resistance breast cancer cells. Further, several hub genes were found to be significantly involved in the poor overall survival of breast cancer patients. Finally, we identified FDA-approved drugs which could be useful for potential drug repurposing against those hub genes. Altogether, our findings provide new insight into the molecular mechanisms of NAC resistance and pave the way for drug repurposing techniques and personalized treatment to overcome NAC resistance in breast cancer.

Virtual Screening for FDA-Approved Drugs That Selectively Inhibit Arginase Type 1 and 2.

Arginases are often overexpressed in human diseases, and they are an important target for developing anti-aging and antineoplastic drugs. Arginase type 1 (ARG1) is a cytosolic enzyme, and arginase type 2 (ARG2) is a mitochondrial one. In this study, a dataset containing 2115-FDA-approved drug molecules is virtually screened for potential arginase binding using molecular docking against several ARG1 and ARG2 structures. The potential arginase ligands are classified into three categories: (1) Non-selective, (2) ARG1 selective, and (3) ARG2 selective. The evaluated potential arginase ligands are then compared with their clinical use. Remarkably, half of the top 30 potential drugs are used clinically to lower blood pressure and treat cancer, infection, kidney disease, and Parkinson's disease thus partially validating our virtual screen. Most notable are the antihypertensive drugs candesartan, irbesartan, indapamide, and amiloride, the antiemetic rolapitant, the anti-angina ivabradine, and the antidiabetic metformin which have minimal side effects. The partial validation also favors the idea that the other half of the top 30 potential drugs could be used in therapeutic settings. The three categories greatly expand the selectivity of arginase inhibition.

Autoimmune Disease Classification Based on PubMed Text Mining.

Autoimmune diseases (AIDs) are often co-associated, and about 25% of patients with one AID tend to develop other comorbid AIDs. Here, we employ the power of datamining to predict the comorbidity of AIDs based on their normalized co-citation in PubMed. First, we validate our technique in a test dataset using earlier-reported comorbidities of seven knowns AIDs. Notably, the prediction correlates well with comorbidity (R = 0.91) and validates our methodology. Then, we predict the association of 100 AIDs and classify them using principal component analysis. Our results are helpful in classifying AIDs into one of the following systems: (1) gastrointestinal, (2) neuronal, (3) eye, (4) cutaneous, (5) musculoskeletal, (6) kidneys and lungs, (7) cardiovascular, (8) hematopoietic, (9) endocrine, and (10) multiple. Our classification agrees with experimentally based taxonomy and ranks AID according to affected systems and gender. Some AIDs are unclassified and do not associate well with other AIDs. Interestingly, Alzheimer's disease correlates well with other AIDs such as multiple sclerosis. Finally, our results generate a network classification of autoimmune diseases based on PubMed text mining and help map this medical universe. Our results are expected to assist healthcare workers in diagnosing comorbidity in patients with an autoimmune disease, and to help researchers in identifying common genetic, environmental, and autoimmune mechanisms.

Norethisterone Reduces Vaginal Bleeding Caused by Progesterone-Only Birth Control Pills.

(1) Background: Progesterone-only pills (POP) are widely used contraceptives. About 40% of women taking these pills report vaginal bleeding/spotting; 25% find this a reason for cessation. To date, no effective remedy has been described. We aimed to examine the therapeutic approaches offered by health providers. (2) Methods: A prospective questionnaire-based study of women experiencing vaginal bleeding due to POP, comparing the effectiveness of prescribed therapies. Women were recruited through social networks, and subsequently divided into groups according to the treatment offered: (1) POP with norethisterone (n = 36); (2) double dose POP (n = 19); (3) single dose POP (continuing initial treatment, n = 57); and (4) different POP formula (n = 8). Women rated bleeding quantity and frequency at four intervals, at weeks 0, 2, 4, and 6. (3) Results: Women who added 5 mg norethisterone acetate reported a significant decrease in bleeding frequency compared to the other groups, observed after 2, 4, and 6 weeks (p-values 0.019, 0.002, and 0.002, respectively). Women also reported an overall decrease in combined bleeding quantity and frequency (p-values 0.028, 0.003, and 0.005, respectively). There was no difference in the rate of side effects among groups. (4) Conclusions: Adding 5 mg norethisterone acetate (Primolut-nor) to progesterone-only pills significantly reduces bleeding and spotting associated with POP contraception.

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Text-Mining Approach to Identify Hub Genes of Cancer Metastasis and Potential Drug Repurposing to Target Them.

Metastasis accounts for the majority of cancer-related deaths. Despite decades of research, the prevention and suppression of metastasis remain an elusive goal, and to date, only a few metastasis-related genes have been targeted therapeutically. Thus, there is a strong need to find potential genes involved in key driver traits of metastasis and their available drugs. In this study, we identified genes associated with metastasis and repurposable drugs that potentially target them. First, we use text mining of PubMed citations to identify candidate genes associated with metastatic processes, such as invadopodia, motility, movement, metastasis, invasion, wound healing, EMT (epithelial to mesenchymal transition), and podosome. Next, we annotated the top genes involved in each process as a driver, tumor suppressor, or oncogene. Then, a total of 185 unique cancer genes involved in metastasis-related processes were used for hub gene analysis using bioinformatics tools. Notably, a total of 77 hub genes were identified. Further, we used virtual screening data of druggable candidate hub genes involved in metastasis and identified potential drugs that can be repurposed as anti-metastatic drugs. Remarkably, we found a total of 50 approved drugs that have the potential to be repurposed against 19 hub genes involved in metastasis-related processes. These 50 drugs were also found to be validated in different cancer cell lines, such as dasatinib, captopril, leflunomide, and dextromethorphan targeting SRC, MMP2, PTK2B, and RAC1 hub genes, respectively. These repurposed drugs potentially target metastasis, provide pharmacodynamic insight, and offer a window of opportunity for the development of much-needed antimetastatic drugs.

Resistance to Antimalarial Monotherapy Is Cyclic.

Malaria is a prevalent parasitic disease that is estimated to kill between one and two million people-mostly children-every year. Here, we query PubMed for malaria drug resistance and plot the yearly citations of 14 common antimalarials. Remarkably, most antimalarial drugs display cyclic resistance patterns, rising and falling over four decades. The antimalarial drugs that exhibit cyclic resistance are quinine, chloroquine, mefloquine, amodiaquine, artesunate, artemether, sulfadoxine, doxycycline, halofantrine, piperaquine, pyrimethamine, atovaquone, artemisinin, and dihydroartemisinin. Exceptionally, the resistance of the two latter drugs can also correlate with a linear rise. Our predicted antimalarial drug resistance is consistent with clinical data reported by the Worldwide Antimalarial Resistance Network (WWARN) and validates our methodology. Notably, the cyclical resistance suggests that most antimalarial drugs are sustainable in the end. Furthermore, cyclic resistance is clinically relevant and discourages routine monotherapy, in particular, while resistance is on the rise. Finally, cyclic resistance encourages the combination of antimalarial drugs at distinct phases of resistance.

Effects of Chronic Arginase Inhibition with Norvaline on Tau Pathology and Brain Glucose Metabolism in Alzheimer's Disease Mice.

Alzheimer's disease (AD) is an insidious neurodegenerative disorder representing a serious continuously escalating medico-social problem. The AD-associated progressive dementia is followed by gradual formation of amyloid plaques and neurofibrillary tangles in the brain. Though, converging evidence indicates apparent metabolic dysfunctions as key AD characteristic. In particular, late-onset AD possesses a clear metabolic signature. Considerable brain insulin signaling impairment and a decline in glucose metabolism are common AD attributes. Thus, positron emission tomography (PET) with glucose tracers is a reliable non-invasive tool for early AD diagnosis and treatment efficacy monitoring. Various approaches and agents have been trialed to modulate insulin signaling. Accumulating data point to arginase inhibition as a promising direction to treat AD via diverse molecular mechanisms involving, inter alia, the insulin pathway. Here, we use a transgenic AD mouse model, demonstrating age-dependent brain insulin signaling abnormalities, reduced brain insulin receptor levels, and substantial energy metabolism alterations, to evaluate the effects of arginase inhibition with Norvaline on glucose metabolism. We utilize fluorodeoxyglucose whole-body micro-PET to reveal a significant treatment-associated increase in glucose uptake by the brain tissue in-vivo. Additionally, we apply advanced molecular biology and bioinformatics methods to explore the mechanisms underlying the effects of Norvaline on glucose metabolism. We demonstrate that treatment-associated improvement in glucose utilization is followed by significantly elevated levels of insulin receptor and glucose transporter-3 expression in the mice hippocampi. Additionally, Norvaline diminishes the rate of Tau protein phosphorylation. Our results suggest that Norvaline interferes with AD pathogenesis. These findings open new avenues for clinical evaluation and innovative drug development.

Towards a Consensus on Alzheimer's Disease Comorbidity?

Alzheimer's disease (AD) is often comorbid with other pathologies. First, we review shortly the diseases most associated with AD in the clinic. Then we query PubMed citations for the co-occurrence of AD with other diseases, using a list of 400 common pathologies. Significantly, AD is found to be associated with schizophrenia and psychosis, sleep insomnia and apnea, type 2 diabetes, atherosclerosis, hypertension, cardiovascular diseases, obesity, fibrillation, osteoporosis, arthritis, glaucoma, metabolic syndrome, pain, herpes, HIV, alcoholism, heart failure, migraine, pneumonia, dyslipidemia, COPD and asthma, hearing loss, and tobacco smoking. Trivially, AD is also found to be associated with several neurodegenerative diseases, which are disregarded. Notably, our predicted results are consistent with the previously published clinical data and correlate nicely with individual publications. Our results emphasize risk factors and promulgate diseases often associated with AD. Interestingly, the comorbid diseases are often degenerative diseases exacerbated by reactive oxygen species, thus underlining the potential role of antioxidants in the treatment of AD and comorbid diseases.

Invasion and Metastasis as a Central Hallmark of Breast Cancer.

Hanahan and Weinberg introduced the "hallmarks of cancer" and typified essential biological abilities acquired by human cancer. Since then, a growing understanding of hallmark principles associated with breast cancer has assisted knowledge-based therapeutics development; however, despite the rapidly increasing number of targeted therapeutics, enduring disease-free responses for most forms of breast cancer is rare. Invasion and metastasis are the most defining feature of breast cancer malignancy and the leading cause of patient mortality. Hence, we propose a modified hallmarks model adapted to breast cancer, in which invasion and metastasis are shifted to the center of attention, thereby emphasizing it as a potentially superior therapeutic target. Although the scientific community highly appreciates the importance of the invasion and metastasis hallmark, as can be demonstrated by the growing number of publications on breast cancer metastasis, very few clinical trials concentrate on testing anti-metastasis inhibitors and even fewer trials focus on inhibitors for breast cancer metastasis. Here, we discuss the obstacles of applying research on invasion and metastasis therapeutics into the clinic and present current developments that could provide a potential solution to this dilemma.

Alzheimer's disease as a chronic maladaptive polyamine stress response.

Polyamines are nitrogen-rich polycationic ubiquitous bioactive molecules with diverse evolutionary-conserved functions. Their activity interferes with numerous genes' expression resulting in cell proliferation and signaling modulation. The intracellular levels of polyamines are precisely controlled by an evolutionary-conserved machinery. Their transient synthesis is induced by heat stress, radiation, and other traumatic stimuli in a process termed the polyamine stress response (PSR). Notably, polyamine levels decline gradually with age; and external supplementation improves lifespan in model organisms. This corresponds to cytoprotective and reactive oxygen species scavenging properties of polyamines. Paradoxically, age-associated neurodegenerative disorders are characterized by upsurge in polyamines levels, indicating polyamine pleiotropic, adaptive, and pathogenic roles. Specifically, arginase overactivation and arginine brain deprivation have been shown to play an important role in Alzheimer's disease (AD) pathogenesis. Here, we assert that a universal short-term PSR associated with acute stimuli is beneficial for survival. However, it becomes detrimental and maladaptive following chronic noxious stimuli, especially in an aging organism. Furthermore, we regard cellular senescence as an adaptive response to stress and suggest that PSR plays a central role in age-related neurodegenerative diseases' pathogenesis. Our perspective on AD proposes an inclusive reassessment of the causal relationships between the classical hallmarks and clinical manifestation. Consequently, we offer a novel treatment strategy predicated upon this view and suggest fine-tuning of arginase activity with natural inhibitors to preclude or halt the development of AD-related dementia.

Modified Snake α-Neurotoxin Averts ß-Amyloid Binding to α7 Nicotinic Acetylcholine Receptor and Reverses Cognitive Deficits in Alzheimer's Disease Mice.

Alzheimer's disease (AD) is the most common cause of senile dementia and one of the greatest medical, social, and economic challenges. According to a dominant theory, amyloid-ß (Aß) peptide is a key AD pathogenic factor. Aß-soluble species interfere with synaptic functions, aggregate gradually, form plaques, and trigger neurodegeneration. The AD-associated pathology affects numerous systems, though the substantial loss of cholinergic neurons and α7 nicotinic receptors (α7AChR) is critical for the gradual cognitive decline. Aß binds to α7AChR under various experimental settings; nevertheless, the functional significance of this interaction is ambiguous. Whereas the capability of low Aß concentrations to activate α7AChR is functionally beneficial, extensive brain exposure to high Aß concentrations diminishes α7AChR activity, contributes to the cholinergic deficits that characterize AD. Aß and snake α-neurotoxins competitively bind to α7AChR. Accordingly, we designed a chemically modified α-cobratoxin (mToxin) to inhibit the interaction between Aß and α7AChR. Subsequently, we examined mToxin in a set of original in silico, in vitro, ex vivo experiments, and in a murine AD model. We report that mToxin reversibly inhibits α7AChR, though it attenuates Aß-induced synaptic transmission abnormalities, and upregulates pathways supporting long-term potentiation and reducing apoptosis. Remarkably, mToxin demonstrates no toxicity in brain slices and mice. Moreover, its chronic intracerebroventricular administration improves memory in AD-model animals. Our results point to unique mToxin neuroprotective properties, which might be tailored for the treatment of AD. Our methodology bridges the gaps in understanding Aß-α7AChR interaction and represents a promising direction for further investigations and clinical development.