Targeting cancer signaling pathways by natural products: Exploring promising anti-cancer agents

Cancer is one of the leading causes of death and significantly burdens the healthcare system. Due to its prevalence, there is undoubtedly an unmet need to discover novel anticancer drugs. The use of natural products as anticancer agents is an acceptable therapeutic approach due to accessibility, applicability, and reduced cytotoxicity. Natural products have been an incomparable source of anticancer drugs in the modern era of drug discovery. Along with their derivatives and analogs, natural products play a major role in cancer treatment by modulating the cancer microenvironment and different signaling pathways. These compounds are effective against several signaling pathways, mainly cell death pathways (apoptosis and autophagy) and embryonic developmental pathways (Notch pathway, Wnt pathway, and Hedgehog pathway). The historical record of natural products is strong, but there is a need to investigate the current role of natural products in the discovery and development of cancer drugs and determine the possibility of natural products being an important source of future therapeutic agents. Many target-specific anticancer drugs failed to provide successful results, which accounts for a need to investigate natural products with multi-target characteristics to achieve better outcomes. The potential of natural products to be promising novel compounds for cancer treatment makes them an important area of research. This review explores the significance of natural products in inhibiting the various signaling pathways that serve as drivers of carcinogenesis and thus pave the way for developing and discovering anticancer drugs.This study was supported by Sidra Medicine Precision Program funding to Ajaz A. Bhat (5081012003) and Mohammad Haris (5081012002)

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Genetics of glutamate and its receptors in autism spectrum disorder

Autism spectrum disorder (ASD) is a neurodevelopmental impairment characterized by deficits in social interaction skills, impaired communication, and repetitive and restricted behaviors that are thought to be due to altered neurotransmission processes. The amino acid glutamate is an essential excitatory neurotransmitter in the human brain that regulates cognitive functions such as learning and memory, which are usually impaired in ASD. Over the last several years, increasing evidence from genetics, neuroimaging, protein expression, and animal model studies supporting the notion of altered glutamate metabolism has heightened the interest in evaluating glutamatergic dysfunction in ASD. Numerous pharmacological, behavioral, and imaging studies have demonstrated the imbalance in excitatory and inhibitory neurotransmitters, thus revealing the involvement of the glutamatergic system in ASD pathology. Here, we review the effects of genetic alterations on glutamate and its receptors in ASD and the role of non-invasive imaging modalities in detecting these changes. We also highlight the potential therapeutic targets associated with impaired glutamatergic pathways.Other Information Published in: Molecular Psychiatry License: https://creativecommons.org/licenses/by/4.0See article on publisher's website: http://dx.doi.org/10.1038/s41380-022-01506-w</p