Translating molecular insights into clinical success: alkaloid-based therapies for leukemia.

Alkaloids, a diverse class of naturally occurring compounds, have shown significant potential in the treatment of leukemia by targeting key molecular pathways and cellular mechanisms. This review discusses several potent alkaloids, such as homoharringtonine, chaetominine, matrine, and jerantinine B, which induce apoptosis, cell cycle arrest, and autophagy and inhibit signaling pathways including PI3K/Akt/mTOR, MAPK, and NF-κB. For instance, homoharringtonine induces apoptosis in acute myeloid leukemia (AML) cells via the SP1/TET1/5hmC/FLT3/MYC axis, while chaetominine enhances chemosensitivity by inhibiting the PI3K/Akt/Nrf2 pathway. In addition, targeting leukemia stem cells (LSCs) with alkaloids such as zalypsis offers promise due to its ability to induce apoptosis without significantly affecting normal hematopoietic stem cells. The modulation of the immune response, such as the inhibition of NF-κB activation by noscapine, further underscores the potential of alkaloids in overcoming treatment resistance. Various studies have demonstrated the efficacy of alkaloids across different leukemia types. For example, jerantinine B targets AML cells, while vincristine has shown success in lymphocytic leukemia. Clinical trials have also highlighted the benefits of alkaloids, including homoharringtonine, which achieved a 79.9% complete remission rate in AML patients. However, adverse effects such as neutropenia and hepatotoxicity necessitate careful management. Collectively, these findings emphasize the need for further research into alkaloid-based combination therapies to enhance efficacy and minimize toxicity, providing a promising avenue for innovative leukemia treatments.

Flavonoids against depression: a comprehensive review of literature.

Background: Depression is a state of low mood and aversion to activity, which affects a person's thoughts, behavior, motivation, feelings, and sense of wellbeing. Pharmacologic therapies are still the best effective treatment of depression. Still, most antidepressant drugs have low efficacy and delayed onset of therapeutic action, have different side effects, and even exacerbate depression. Such conditions make it possible to look for alternatives. Consequently, we decided to summarize the impact of flavonoids on depression in this review. Methods: We searched scientific databases such as SCOPUS, PubMed, and Google Scholar to find relevant studies until July 2022. Results: A wide variety of natural components have been shown to alleviate depression, one of which is flavonoids. Due to the growing tendency to use natural antidepressant drugs, scientific studies are increasingly being conducted on flavonoids. This study aims to review the latest scientific researches that indicate the antidepressant potential of flavonoids. Various mechanisms include neurotransmitter system modulation and dopaminergic, noradrenergic, and serotonergic pathways regulation in the central nervous system. Different compounds of flavonoids have antidepressant properties in vivo or in vitro experiments or clinical trials and can be used as alternative and complementary treatments for depression. In general, it was observed that there were no severe side effects. Conclusion: Our study proves the antidepressant potential of flavonoids, and considering the limited side effects, they can be used as complementary medicine for depressed patients.

The Role of Alpha-Synuclein in Neurodevelopmental Diseases.

Neurodevelopmental disorders are a group of diseases with cognitive, motor, and emotional development deficits. Alpha-synuclein (α-syn) is a synaptic protein involved in transmission and neurodevelopment. This protein was previously shown to be associated with several disorders, including Parkinson's disease. Furthermore, a close link between neurodevelopmental disorders and Parkinson's has also been found. Changes in synaptic function have been noticed in neurodevelopmental disorders, including autism spectrum disorder. Impaired neurogenesis and related cognitive problems have been associated with altered expression of α-syn. Various studies reported α-syn in different body fluids and tissues such as blood and serum. Alpha-synuclein can help in better understanding the pathogenesis of neurodevelopmental diseases and facilitating their early diagnosis. This review aims to go over the recent advances in the role of α-syn in the pathophysiology of neurodevelopmental disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, and motor and social impairment, and its value as a diagnostic biomarker.

Neuroprotective effects of flavonoids: endoplasmic reticulum as the target.

The incidence of neurological disorders, particularly age-related neurodegenerative pathologies, exhibits an alarming upward trend, while current pharmacological interventions seldom achieve curative outcomes. Despite their diverse clinical presentations, neurological diseases often share a common pathological thread: the aberrant accumulation of misfolded proteins within the endoplasmic reticulum (ER). This phenomenon, known as ER stress, arises when the cell's intrinsic quality control mechanisms fail to cope with the protein-folding burden. Consequently, misfolded proteins accumulate in the ER lumen, triggering a cascade of cellular stress responses. Recognizing this challenge, researchers have intensified their efforts over the past two decades to explore natural compounds that could potentially slow or even reverse these devastating pathologies. Flavonoids constitute a vast and heterogeneous class of plant polyphenols, with over 10,000 identified from diverse natural sources such as wines, vegetables, medicinal plants, and organic products. Flavonoids are generally divided into six different subclasses: anthocyanidins, flavanones, flavones, flavonols, isoflavones, and flavonols. The diverse family of flavonoids, featuring a common phenolic ring backbone adorned with varying hydroxyl groups and additional modifications, exerts its antioxidant activity by inhibiting the formation of ROS, as evidenced by research. Also, studies suggest that polyphenols such as flavonoids can regulate ER stress through apoptosis and autophagy. By understanding these mechanisms, we can unlock the potential of flavonoids as novel therapeutic agents for neurodegenerative disorders. Therefore, this review critically examines the literature exploring the modulatory effects of flavonoids on various steps of the ER stress in neurological disorders.

Pharmacotherapeutic Potential of Bitter Gourd (Momordica charantia) in Age-related Neurological Diseases.

Due to the growth of the elderly population, age-related neurological disorders are an increasing problem. Aging begins very gradually and later leads to several neurological issues such as lower neurotransmitter levels, oxidative stress, neuronal inflammation, and continual neuronal loss. These changes might contribute to brain disorders such as Alzheimer's disease (AD), dementia or mild cognitive impairment, and epilepsy and glioma, and can also aggravate these disorders if they were previously present. Momordica charantia (bitter gourd), a member of the Cucurbitaceae family, is a good source of carbohydrates, proteins, vitamins, and minerals. It is used for diabetes and known for its hypoglycemic and antioxidant effects. In this review, we discuss the pharmaceutical effects of M. charantia on age-related neurological disorders. We searched several databases, including PubMed and Google Scholar, using MeSH terms. We searched articles published up until 2022 regardless of publication language. M. charantia is rich in luteolin, which increases acetylcholine in neurons by binding to enzymes in acetylcholine metabolism pathways, including butyrylcholinesterase and acetylcholinesterase. This binding inhibits the hyperphosphorylation of tau protein by restraining its kinase enzyme. Furthermore, this substance can lower serum cholesterol and has multi-target activity in AD and memory loss. M. charantia can also improve memory by decreasing tau protein and it also has potent antioxidant activity and anti-inflammatory effects. This review highlights that M. charantia has effects on many age-related neurological disorders, and can be a cost-effective supplement with minimal side effects.

Gluten restriction in irritable bowel syndrome, yes or no?: a GRADE-assessed systematic review and meta-analysis.

Background: More than half of patients with irritable bowel syndrome (IBS) report aggravating their symptoms with certain foods. Currently, Low fermentable oligo-, di-, and monosaccharides and polyols diet (LFD) is the most accepted dietary intervention for IBS. Recent randomized controlled trials (RCTs) have been suggested that gluten restriction may reduce the symptoms of patients with IBS. However, the results from these studies are conflicting. This study filled this knowledge gap by evaluating the impact of the gluten-free diet (GFD) on IBS symptoms. Methods: A systematic search was carried out in Pubmed/Medline, Cochrane CENTRAL, Scopus, and Web of Science up to April 2023. A random-effect model was applied to estimate the standardized mean difference (SMD) and 95% confidence interval (95% CI) for each outcome. Results: A total of nine controlled trials were included in the meta-analysis. In contrast to gluten-containing diet, GFD was unable to reduce overall symptoms (SMD - 0.31; 95% CI -0.92, 0.31), bloating (SMD -0.37; 95% CI -1.03, 0.30), and quality of life (SMD -0.12, 95% CI -0.64, 0.39); but had a slight trend to reduce abdominal pain (SMD -0.68; 95% CI -1.36, -0.00). Also, LFD significantly reduced the IBS-Severity score system (SMD 0.66, 95% CI 0.31, 1.01) and improved quality of life (SMD -0.36, 95% CI -0.70, -0.01), compared to GFD. Conclusion: A GFD is not robust enough to be routinely recommended for IBS patients, and its efficacy is significantly lower than that of an LFD. Only a certain subgroup of IBS patients may benefit from GFD; further studies are needed to target this subgroup.

Clinical characteristics and prognosis of temporary miller fisher syndrome following COVID-19 vaccination: a systematic review of case studies.

BACKGROUND: Miller Fisher syndrome (MFS) is a subtype of Guillain-Barré syndrome (GBS) which is characterized by the three components of ophthalmoplegia, ataxia, and areflexia. Some studies reported MFS as an adverse effect of the COVID-19 vaccination. We aimed to have a detailed evaluation on demographic, clinical, and para-clinical characteristics of subjects with MFS after receiving COVID-19 vaccines. MATERIALS AND METHODS: A thorough search strategy was designed, and PubMed, Web of Science, and Embase were searched to find relevant articles. Each screening step was done by twice, and in case of disagreement, another author was consulted. Data on different characteristics of the patients and types of the vaccines were extracted. The risk of bias of the studies was assessed using Joanna Briggs Institute (JBI) tools. RESULTS: In this study, 15 patients were identified from 15 case studies. The median age of the patients was 64, ranging from 24 to 84 years. Ten patients (66.6%) were men and Pfizer made up 46.7% of the injected vaccines. The median time from vaccination to symptoms onset was 14 days and varied from 7 to 35 days. Furthermore,14 patients had ocular signs, and 78.3% (11/14) of ocular manifestations were bilateral. Among neurological conditions, other than MFS triad, facial weakness or facial nerve palsy was the most frequently reported side effect that was in seven (46.7%) subjects. Intravenous immunoglobulin (IVIg) was the most frequently used treatment (13/15, 86.7%). Six patients received 0.4 g/kg and the four had 2 g/kg. Patients stayed at the hospital from five to 51 days. No fatal outcomes were reported. Finally, 40.0% (4/15) of patients completely recovered, and the rest experienced improvement. CONCLUSION: MFS after COVID-19 immunization has favorable outcomes and good prognosis. However, long interval from disease presentation to treatment in some studies indicates that more attention should be paid to MFS as the adverse effect of the vaccination. Due to the challenging diagnosis, MFS must be considered in list of the differential diagnosis in patients with a history of recent COVID-19 vaccination and any of the ocular complaints, ataxia, or loss of reflexes, specially for male patients in their 60s and 70s.

Predictors of decline in kidney function in the general population: a decade of follow-up from the Tehran Lipid and Glucose Study.

BACKGROUND AND AIMS: We aimed to assess the potential socio-demographic, clinical, and lifestyle-related risk factors for kidney function decline (KFD), defined as ≥30% estimated glomerular filtration rate (eGFR) decline, in an Iranian cohort study. METHODS: 7190 participants (4049 women) aged 20-90 years with 2-5 eGFR data from examinations (2001-2005 to 2015-2018) were included. Cox proportional hazard models were used to examine the association between potential risk factors and eGFR decline. RESULTS: During 11.5 years of follow-up, 1471 (889 women) participants had incident KFD with a crude incidence rate of 192.1 (182.6-202.2) per 10,000 person-year. Among the total population, older age, female gender, prehypertension, hypertension, diabetes, widowed/divorced states, higher triglycerides (TG), prevalent cardiovascular diseases (CVD), and higher baseline eGFR were significantly associated with higher, while moderate physical activity and a positive family history of diabetes were associated with lower risk of KFD (all p values <.05). Prevalent CVD in women but not men, diabetes, and hypertension among postmenopausal than premenopausal women were significant risk factors of KFD. According to the presence of chronic kidney disease (CKD) at baseline, higher eGFR decreased the risk of KFD in patients with CKD and increased KFD risk in those without CKD (all p for interactions <.05). CONCLUSION: KFD is associated with multiple modifiable risk factors among the Iranian urban population that is affected by gender, menopausal status, and initial kidney function. Interventions targeting these factors might potentially help reduce the burden of KFD.Key messages:Menopausal status may influence the relationship between cardiometabolic risk factors and KFD;The impact of higher baseline eGFR on the risk of KFD differed between subjects with preserved kidney function and CKD patients.The interaction between gender, menopausal status, and baseline kidney function with different risk factors on KFD may help to make renal risk prediction scores to identify those in the general population at risk who may benefit from early prevention.

Baclofen as a therapeutic option for gastroesophageal reflux disease: A systematic review of clinical trials.

Background: The main components of gastroesophageal reflux disease (GERD) management include a combination of medications and lifestyle modifications; Nevertheless, based on the severity of symptoms and their response to medications, other treatments could be considered. Baclofen has been demonstrated in studies to relieve GERD symptoms. The current study aimed to precisely address the effects of baclofen on the treatment of GERD and its characteristics. Methods: A systematic search was carried out in Pubmed/Medline, Cochrane CENTRAL, Scopus, Google Scholar, Web of Science, and clinicaltrials.gov up to December 10, 2021. The search terms included baclofen, GABA agonists, GERD, and reflux. Results: We selected 26 papers that matched the inclusion criteria after examining 727 records. Studies were classified into four categories based on the study population and reported outcomes: (1) adults, (2) children, (3) patients with gastroesophageal reflux-induced chronic cough, (4) hiatal hernia patients. The results revealed that baclofen can significantly improve reflux symptoms and pH-monitoring and manometry findings to different degrees in all four mentioned categories; although its effect on pH-monitoring parameters seems less significant than the other parameters. Mild neurological and mental status deterioration were the most reported side effects. However, side effects occurred in a portion of less than 5% of short-term users and nearly 20% of long-term users. Conclusion: In PPI-resistant patients, a trial of adding baclofen to the PPI may be helpful. Baclofen therapies may be more beneficial for symptomatic GERD patients who also report concurrent conditions including alcohol use disorder, non-acid reflux, or obesity. Systematic review registration: https://clinicaltrials.gov/.

From kitchen to clinic: Pharmacotherapeutic potential of common spices in Indian cooking in age-related neurological disorders.

Aging is described as an advanced time-related collection of changes that may negatively affect with the risk of several diseases or death. Aging is a main factor of several age-related neurological disorders, including neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and dementia), stroke, neuroinflammation, neurotoxicity, brain tumors, oxidative stress, and reactive oxygen species (ROS). Currently available medications for age-related neurological disorders may lead to several side effects, such as headache, diarrhea, nausea, gastrointestinal (GI) diseases, dyskinesia, and hallucinosis. These days, studies on plant efficacy in traditional medicine are being conducted because herbal medicine is affordable, safe, and culturally acceptable and easily accessible. The Indian traditional medicine system called Ayurveda uses several herbs and medicinal plants to treat various disorders including neurological disorders. This review aims to summarize the data on the neuroprotective potential of the following common Indian spices widely used in Ayurveda: cumin (Cuminum cyminum (L.), Apiaceae), black cumin (Nigella sativa (L.), Ranunculaceae), black pepper (Piper nigrum (L.), Piperaceae), curry leaf tree (Murraya koenigii (L.), Spreng Rutaceae), fenugreek (Trigonella foenum-graecum (L.), Fabaceae), fennel (Foeniculum vulgare Mill, Apiaceae), cardamom (Elettaria cardamomum (L.) Maton, Zingiberaceae), cloves (Syzygium aromaticum (L.) Merr. & L.M.Perry, Myrtaceae), and coriander (Coriandrum sativum (L.), Apiaceae) in age-related neurological disorders.

Pharmacotherapeutic potential of pomegranate in age-related neurological disorders.

Age-related neurological disorders [AND] include neurodegenerative diseases [NDDs] such as Alzheimer's disease [AD] and Parkinson's disease [PD], which are the most prevalent types of dementia in the elderly. It also includes other illnesses such as migraine and epilepsy. ANDs are multifactorial, but aging is their major risk factor. The most frequent and vital pathological features of AND are oxidative stress, inflammation, and accumulation of misfolded proteins. As AND brain damage is a significant public health burden and its incidence is increasing, much has been done to overcome it. Pomegranate (Punica granatum L.) is one of the polyphenol-rich fruits that is widely mentioned in medical folklore. Pomegranate is commonly used to treat common disorders such as diarrhea, abdominal pain, wound healing, bleeding, dysentery, acidosis, microbial infections, infectious and noninfectious respiratory diseases, and neurological disorders. In the current review article, we aimed to summarize the data on the pharmacotherapeutic potentials of pomegranate in ANDs.