Reactive oxygen species (ROS) are linked with numerous cellular functions, including cell differentiation, proliferation, angiogenesis, and apoptosis. ROS are the main signaling molecule that participates in an essential function in developing inflammatory diseases such as cancer and neurodegenerative diseases. Oxidative stress and chronic inflammation are the most crucial factors engaged in the progression of about 15–20% of cancers worldwide (60). The constant inflammatory cell employment, frequent production of ROS, and pro-inflammatory mediators, which persisted the proliferation of genomically unbalanced cells, help the neoplastic transformation and eventually result in cancer metastasis and invasion (61). The inequity between the production and clearance of ROS/RNS aids the progression of the tumor chiefly via stimulating genomic instability. CA blocks lipoxygenase action and represses LPO (62, 63). CA entirely inhibits ROS production and the xanthine oxidase system (62). CA might enhance the cytotoxic activities of M1 macrophages and block cancer growth; inhibitory action on TAMs can be induced by its antioxidative action. However, the anticancer action of CA has been the effect of the synergistic actions of diverse mechanisms through which CA performs on proliferation, survival, angiogenesis, and immunomodulation (64–66). CA competently inhibited the incidence of TAMs and noticeably repressed tumorigenesis in mouse tumor models. Hence, targeting TAMs via antioxidants might be a potentially effective method for tumor treatment (64).

The amount of such ROS-mediated injuries was revealed to be more widespread in the areas of the brain where Aβ is rich (67, 68). The antioxidant defense in the AD brain was found to repeatedly reduce as the disease progressed (69–71). Mitochondrial dysfunction is the main cause of ROS-induced pathologies far too frequent in AD (72). Thus, drugs targeting several mechanisms of ROS/oxidative stress-induced cellular injuries could have therapeutic potential for AD. Hence, a study (73) has examined the anti-AD potential of CA in an in vitro acrolein-mediated toxicity model utilizing HT22 mouse hippocampal cells. However, the study has revealed that pretreatment of cells with CA drastically reduced the acrolein-mediated neurotoxicity, ROS gathering, and GSH reduction. The acrolein-mediated MAPKs and GSK3β/Akt signalings have been altered via CA, recommending their probable mechanisms by such results. The improvement of memory via CA (10–50 mg/kg) in the global cerebral ischemia-reperfusion damage in the rat is partly because of antioxidant results, as a reduced MDA and considerable SOD activities have been detected to be reduced in the hippocampus’s subsequent treatment with CA (22). The defensive result of CA against spatial learning and memory role failure via chronic aluminum excess has been revealed to be accompanied by the reverse of the reduced SOD actions and enhanced MDA contents (21). However, the association between cognitive decline and oxidative stress is fine as demonstrated in most of the work by researchers (74) who utilized streptozotocin-mediated investigational dementia in rats like an AD model.

Antioxidants perform by blocking or decreasing the results regulated via free radicals and oxidizing compounds (75). The phenolic acids are distinguished via the existence of a benzene ring, a carboxylic acid group, and one/more hydroxyl/methoxy groups of the molecule that confers antioxidant functions (76). CA has been revealed for producing defensive results on α-tocopherol in low-density lipoprotein (77, 78). CA is an antioxidant, which may decrease oxidative stress made in the body because of free radicals. Hence, oxidative stress is described as an inequity between the making of ROS and antioxidant protection (79, 80).

In consequence of this inequity, oxidative stress is frequently responded with the progression of several human diseases including cancer (81, 82). Antioxidants perform by inhibiting the effects regulated via free radicals and oxidizing compounds (75). CA was found to be an α-tocopherol defensive in LDL (77). Additionally, its grouping with other products, including chlorogenic and caftaric acids, explained high potent antioxidant action in various systems (83, 84). CA is among the hydroxycinnamates used to increase dietary products’ constancy (85, 86). The antioxidant promise of CA is influenced by factors including the nature of oil, food processing, constituents, and the ratio of antioxidants and lipid constituents (86, 87). However, novel dihydro-CA amides were proven to have brilliant free radical scavenging capabilities accessed via the DPPH technique; an outstanding potential was identified for protecting polyunsaturated oils (88). The addition of CA was documented to increase the solidity of different oils via the blockage of lipid oxidation (85, 87, 89).

UV radiation is the reason for biological alterations, including photoaging, and injures normal lymphocytes, consequential in their death. CA achieves notable consideration as a potential photoprotective agent (90) and also is present in skincare products due to its antioxidant action. Depending on the exposure time, dose, wavelength, and area exposed, the UV radiation may cause premature skin aging, skin burns, skin cell DNA injury, and skin tumor (91, 92). Though lymphocytes were pretreated with CA for 30 minutes while being irradiated with UVB, a photoprotective result of CA was identified in terms of reduced LPO and decreased DNA injury illustrating the viability of lymphocytes (93). Hence, the photoprotective result of CA might be because of GSH metabolism, which displays free radical scavenging. CA was detected for protecting phospholipidic membranes (94, 95) and opposed vitamins C and E depletion by the membrane (96). CA was found to have photoprotective action against UVB both in vitro and in vivo (97, 98). CA pretreatment causes a significant reduction in g radiation-motivated DNA injury in cultured lymphocytes (97). However, ischemia/reperfusion (I/R) damage may be caused by ROS (99). Reported models might be used to study defensive results of antioxidants administered before the induction of I/R damage (100, 101). CA was proven to have defensive capabilities against I/R injury in rats’ small intestine (99, 102, 103).

In response to a stimulus including tissue injury, inflammation expands. It is a physiologic process that might contribute to cancer progression via several intermediates (104). Many modulators involve inflammation to tumor progression, including NF-kB, COX-2, TNF-a, IL-6, Nrf2, iNOS, NFAT, and HIF-1α (104–106). CA illustrated its inhibitory action on NO-making that also sturdily blocked the creation of COX -2 and iNOS (107). Therapeutic agents that target NF-κB and COX-2 can help repress cancer angiogenesis (60, 64, 108, 109). CA powerfully hinders ceramide-mediated NF-κB action (110) and UVB-mediated COX-2 expression (109, 111). Hence, numerous studies have recognized CA to be an inducer of cell death in tumor cells and to be able to perform cancer growth blockage and failure in animals (112–114). The role of CA in inflammation, cancer progression, and other pathways is illustrated in Figure 1.

However, the activation of cells under pathological conditions was revealed for contributing to the progression of numerous neurodegenerative diseases. The discharge of pro-inflammatory mediators in the brain stimulated through various stimulants, including Aβ, was exhibited to account for the inflammatory constituent of neuronal loss in AD (117–119). CA and its derivatives’ recognized anti-inflammatory result are of prospective benefit in combating AD through these agent candidates.

In addition, activation of Nrf2 has been explained for inhibiting inflammatory gene expression (120, 121) by signaling crosstalk linking the HO-1 (122). Kim et al. (123) have illustrated that Nrf2-induced HO-1 introduction of CAPE is correlated with its anti-inflammatory and antioxidant mechanisms. Hence, there is a relationship between CA derivatives’ antioxidant and anti-inflammatory effect and their therapeutic promise to AD through their multifunctional results. A research (22) has confirmed that the enhanced NF-κB, p65, and 5-LOX correlated with the global cerebral ischemia-reperfusion neuronal injury and memory failure in rats is inverted through CA (10–50 mg/kg) treatment. However, CA (50 mg/kg) also improved neuronal loss and infarct volume 24 h after ischemia (124). The anti-inflammatory result of other CA esters in microglial cells was connected to the induction of HO-1 (105, 125).

One of the deadliest malignancies among women is breast cancer. The migration rate inhibition of breast tumor is treated via CA (130). CA decreased MDA-MB-231 and MCF-7 cell growth, repressing breast tumors’ proliferation (131). The experimental and clinical findings reveal a variety of antitumor functions of CA against ER⁺ and ER¯ breast tumors, which can sensitize cancer cells to tamoxifen and decrease breast tumor growth (131, 132). This study illustrates that CA mimics the activities of antiestrogens and modifies main growth regulatory signaling ER/cyclin D1 and IGF-IR/pAkt, resulting in damaged cell-cycle development and decreased cellular proliferation (131). CA exhibits a potent antiradical and antioxidant activity in breast tumors, acting by diverse mechanisms. It is a potential and practical clinical move toward presenting less toxicity for healthy cells and more action toward their malignant counterparts (133). CA decreases IL-12-making and NF-κB activation. However, it hinders with the TLR4 pathway via disrupting the TLR4/MD2 complex. Decreased regulation of TRIF, TLR4, and IRAK4 expression provokes apoptosis in breast cancers (10).

Prostate cancer (PCa) is the most frequent cancer in developed countries (116, 134), resistant to cell death. Due to this resistance, it is necessary to develop a novel therapeutic approach; phenolic acids have revealed a relationship with a reduced risk of PCa (135, 136). CA has been linked with a lesser risk of advanced PCa. However, more intake of CA can be connected with decreased risk of PCa (137). CA treatment reduced Skp2 and Akt1 expression in LNCaP cancers as compared with control (138). NF-κB is constitutively stimulated in PCa cells and inhibition of NF-κB action that links with the repression of invasion, angiogenesis, and metastasis. IκBα inactivates the NF-κB transcription via fronting the nuclear signals of NF-κB proteins and keeps them inactive in the cytoplasm (137). CAPE is an NF-κB inhibitor as well as a 5α reductase inhibitor. It is potent for the treatment of PCa. CAPE may block NF-κB activation in PC-3, and it inhibits NF-κB activation (139).

Lung cancer is the leading cause of malignancy-related death worldwide (140). NSCLC is reported to comprise more than 85% of all lung cancers, and approximately 60% of NSCLC presents with advanced stage at the time of diagnosis (140, 141). However, chemotherapy to NSCLC is inadequate because of adverse effects of drug resistance and it contributes small to survival (142). CA may prevent oxidative stress-induced exposure to UVB and DNA injury in lymphocytes (93). A study has illustrated the defensive effect of CA on PTX-mediated apoptosis in A549 cells by the NF-κB pathway (143). Another study has found that a dose of CA (600 μM) drastically stimulates apoptosis in H1299 and A549 cells and has a potential function in modulating and increasing PTX-mediated cell death of NSCLC in in vivo and in vitro MAPK signaling. However, the combined treatment of CA with PTX reduced the proliferation of H1299 cells except for not normal Beas-2b cells. CA blocked H1299 cell growth via stimulating apoptosis, and PTX and CA combined created a synergistic antitumor result in H1299 cells (144). The effects of chemopreventive agents on TGF-β-mediated invasive phenotype utilizing A549 cells as a model scheme have been examined using CAPE as a therapeutic drug. CAPE efficiently repressed TGF-β-increased cell motility and TGF-β-mediated Akt activation and a specific PI3K/Akt signaling inhibitor, LY294002 (145, 146).

Because of the strong resistance of melanoma to conventional chemotherapy, numerous studies focused on novel treatment approaches and coadjuvants were investigated. Studies representing an inhibitory effect of CA on cell migration and invasion with potential activity in decreasing metastases in tumor cells are attracting more attention and are increasingly frequent in the scientific data (129). Additionally, research explains the potential of CA in decreasing proliferation, growth, and cell viability in numerous cancers, and a capability to induce via apoptosis (129, 147). Results illustrated a reduction in cell viability, inhibition of colony formation, cell cycle modulation, and modifications in the gene expression of caspases following CA treatment (148). However, these results recommend an anticancer effect of CA on SK-Mel-28 cells. CA might play a key function in inhibiting cancer progression in melanoma cells (148) and efficiently blocked melanin-making in B16 melanoma cells (149). However, CAPE is recommended for suppressing ROS-mediated DNA damage in A2058 cells compared to other potential defensive agents (150).

Oral cancer is the most general kind of head and neck cancer. Hence, more than 90% of oral cancers are OSCC (151–153). Pro- and anti-apoptotic Bcl-2 proteins are involved in oral cancer (154–156). The migration rate of OSCC may be drastically blocked via the biological action of CA (157). Treatment with CAPE prevents the expression and activity of COX-2 in OSCC (158). CAPE treatment can inhibit the activity and plenty of COX-2 and EGFR. Administration of CAPE may inhibit and hinder the progression of oral tumors (159). Hence, CAPE is sturdily efficient against oral cancer cells. It prevents the COX-2 and EGFR activities and proliferation, growth, survival, and metastasis, and it hampers with the PI3K-Akt pathway and Skp2 in oral tumor (159).

HCC is a leading form of liver cancer, distinguished by being a malignant main solid tumor that differs from hepatocytes (160, 161). CA performs in HCC via its strong antioxidant capability, which inhibits ROS-making, decreases oxidative stress, and is very general in liver cancer (162, 163). CA performs as a primary as well as secondary antioxidant. It may act in the angiogenesis of HCC cells by decreasing the phosphorylation of JNK-1 and reducing the activation of HIF-1α. Animal studies treated with CA and CAPE proved the endorsed repression of cancer growth in HepG2 and the reduction of cancer invasion on a metastatic position in the liver. However, CA and CAPE prevent and obstruct the MMP-9 action via blocking NF-κB function (11, 164). In vitro and in vivo investigations have revealed that CA exerted its antihepatocarcinoma result, dependent on a variety of mechanisms including cell death via induction of TRAIL signaling and the activation of caspase 9, liberation of cyt-c, and creation of the apoptosome (32). Hence, CA is an anticancer agent for inhibiting HCC (165). CA was established to be a stimulant of HO-1, GCLC, and GCLM expression by the Nrf2/ERK pathway, and it can be an efficient chemoprotective agent to defend liver injury against oxidative harm (166).

CA has been known for its antioxidant function in normal cells and pro-oxidant function in tumor cells. Hence, this pro-oxidant-induced oxidative DNA break and its downstream pathway stimulate cancer cell death (167, 168). CA treatment has altered ROS and modified MMP in ME-180 and HeLa cells (167, 169). The enhanced apoptotic morphological alterations in CA-treated cells were examined in ME-180 and HeLa cells. CA possesses an antitumor effect via its pro-oxidant function. It considerably decreases the proliferation of HeLa cells in a concentration-dependent manner. The morphological proof of cell death such as nuclei fragmentation has been noticeably detected after exposure to CA by flow cytometry. CA reduces the levels of uncleaved caspase-3 and Bcl-2 and provokes cleaved caspase-3 and p53 (170).

CA stimulates apoptosis via blocking Bcl-2 action, leading to the liberation of cyt-c and following caspase-3 activation, representing the fact that CA induces cell death by the mitochondrial apoptotic pathway. CA has a potent anticancer effect and can be a promising chemotherapeutic agent (170). It interrelates synergistically with 5−FU, leading to a decline of apoptosis in HeLa cells with the lowest quantity of hemolytic activity (171). CDDP and CA have been selected, and their CxCa antitumor action has been calculated in combination. In CaSki and HeLa cells, a combination index <1 to CDDP and CFC showed the synergistic growth/survival inhibition that drastically enhanced caspase−3, −7, and −9 expression. CFC can be an aspirant antitumor agent and, when exploited in combination, might enhance the therapeutic efficiency of CDDP (172). Synergistic results of CA-cisplatin stimulate apoptosis in cervical cancer cells by the mitochondrial pathway (172).

Colorectal cancer (CRC) is the third leading cause of malignancy-related death in the United States. Huge common CRC cases may be attributed to environmental reasons, as they account for more than 70% of all occurrences (173). Some features of western dietary outlines can also persuade the risk of CRC. However, adiposity and high insulin levels in obese subjects are associated with an enhanced risk of CRC (174). CA has been revealed to have potential antitumor effects in cell cultures and animal models and might play a defensive role against CRC (175). CA prevents the growth of colon cancer and is a potent antitumor agent that enhances AMPK activation and induces apoptosis in CRC cells. However, the structure of CA may be utilized for the rational plan of novel inhibitors, which target human CRC (176). A meta-analysis documented a decreased occurrence of colon cancer in more versus no- or less-coffee-taking subjects in case-control investigations, but not in cohort studies to CRC (177). CA consumption decreases the risk of colon cancer. It sturdily repressed MEK1 and TOPK actions and bound to either MEK1 or TOPK. CA blocked ERKs phosphorylation, AP-1, and NF-κB and consequently prevented TPA-, EGF-, and H-Ras-mediated neoplastic transformation of JB6 P+ cells. CA targets MEK1 and TOPK for suppressing colon cancer metastasis as well as neoplastic cell transformation (15). It endorses apoptosis in HCT-116 and SW-480 in a dose-dependent way (176). Treatment with CA inhibited PDK1, Akt, and mTOR phosphorylation.

CA-blocks UVB-irradiation mediated more expression of MMP-1 and -9 in human skin fibroblasts. CA-affected abdominal skin repressed UVA-irradiation-mediated ROS; CA was found in the skin after oral ingestion (178). CA pretreatment decreased the cytotoxicity of HaCaT after UVA irradiation and repressed UVA-irradiation-mediated MMP-1 action and mRNA oxidant creation. CA upregulated the GSH content and mRNA of γglutamate-cysteine ligase, and mRNA catalase and glutathione peroxidase expression in UVA-irradiated cells. CA generated defensive effects on UVA-irradiation-induced MMP-1 induction in HaCaT, probably as it restored the antioxidant protection system on cellular and molecular levels (178, 179). However, CA showed weak collagenolytic action; topically concerned CA defended the skin from UVB-irradiation-mediated erythema. In vitro and in vivo research revealed that CA can be effectively utilized as a topical defensive agent against UV-irradiation-mediated skin injury (178).

CA attenuates the local immune repression provoked via UVB irradiation and blocks the UVB-irradiation-mediated IL-10 promoter, IL-10 mRNA expression, and protein-making in mouse skin (178, 180). CA can present IL-10-making by interfering with prostaglandin E2 production connected to stimulating the UVB-irradiation-mediated immune repressive cytokine system. CA considerably prevented the UVB-irradiation-mediated activation of MAPK pathway AP-1 and NF-κB. It may have a therapeutic potential as a topical defensive agent against the adverse effects of UVB radiation (181, 182). CA blocked the TPA-dependent motivation of DNA synthesis and enhanced the number of cancers. CA efficiently suppressed UVB-irradiation-mediated COX-2 and prostaglandin E2 in JB6 cells and repressed UVB-irradiation-mediated skin carcinogenesis via preventing the Fyn kinase action (178, 183).

The combination therapy is the prevention and treatment strategy with two or more drugs with the target of accomplishing the comparable effectiveness levels with negligible toxicities at doses lesser than normal, which induces better synergistic/additive effects (184, 185). Hence, successful combinations of promising therapeutic drugs/nanoparticles with products can achieve the needed conclusion but with a slighter toxicity outline (186, 187). CA and cisplatin illustrated potent antitumor action in the tumor. Furthermore, cisplatin-sensitive cells, while exposed to combination therapy of CA and cisplatin, which elucidated speedily, improve in the activity of apoptotic cascade by increased caspase action in contrast to only administrating 5 μM cisplatin. However, combining 5:50 μM (cisplatin/CA) enhances the caspase activity via 4:3 folds through 60% cell viability in A2780cisR cells (188). However, cisplatin combined with CA improved its therapeutic consequence that led to the inhibition of cell survival of HeLa and CaSki cells, which could be revealed by the synergistic effect. Therefore, this combination was correlated with increasing caspase-3, -7, and -9 (172).

Metformin (Met) and CA were recognized to have synergistic results, while combined with anticancer therapies, chiefly to HTB-34 cells (126). CA combined with Met and cytotoxicity mechanism moved toward apoptosis without distressing healthy human fibroblasts. Studies continue to examine the mechanism of the anticancer role of the combination of Met and CA (189). The cytotoxicity of CA-coated iron oxide nanoparticles (CAMNPs) enhanced twofold in tumor cells. The proficient features of CAMNPs may be integrated into appliances, therefore enhancing the efficiency of clinical tumor treatment (190). Antitumor action of nanoparticles has been evaluated with DOX-resistant CT26 cells. Hence, DOX-loaded nanoparticles of ChitoCFA/CMD are a potent vehicle for antitumor drug targeting (191). The CA-SLN formulation might be potent as an alternative nanosize-based drug delivery system for tumor treatment (192).

Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder distinguished via deterioration of cognition and memory, progressively interfering with daily living actions attended through neuropsychiatric symptoms and behavioral disorders (121, 218). However, AD is the most general form of dementia (219). The disease is distinguished by general behavioral symptoms such as apraxia, agnosia, aphasia, erratic emotion, sleep disorders, and interpersonal or social worsening (220, 221). One of the well-identified pathological characteristics of AD is the deposition of amyloid-beta (Aβ), which contributes to neuronal cell death by several mechanisms, such as the disorder of cellular oxidant–antioxidant equilibrium. However, the agent can modify the Aβ creation that increases the antioxidant in neuronal cells, which increases cell viability and might offer therapeutic opportunities for AD (222). CA administration affected a considerable reduction in AChE action and nitrite production in rats with AD compared with the AD model (223). CA repressed inflammation, oxidative stress, NF−κB−p65 protein, and caspase−3 action and regulated the p53 protein expression and p-p38-MAPK expression in rats with AD. However, the useful effects of CA on learning deficits in the AD model were because of the repression of inflammation and oxidative stress by the p38-MAPK pathway (223). CA inhibited AlCl₃-mediated dementia in rats (206). It blocked memory deficits mediated through the focal cerebral ischemia (224). The expression of p-tau protein reduced in the rat’s hippocampus administered with CA in contrast to the HF group (225). The antidementia action of CA against AlCl₃-mediated dementia in rats (206). Hence, the conclusion of this study suggests a wider extent for screening CA against neurodegeneration-linked disorders.

The combined result of CA and ChA against AD has been performed to find its synergistic/additive result in the biological scheme. The approach targeting the inhibition of AChE and BChE has an excellent effect against AD (226). The combination therapy of ChA and CA demonstrated a synergistic action. However, the mechanism by which the combination therapy exerts its neuroprotective functions is to prevent AChE and BChE actions and inhibit oxidative stress-mediated neurodegeneration (227). The detected synergistic result of combination for these enzymes may improve efficiency and protect these ingredients against neurological states, including AD and PD ( Figure 2). CA and CAF combination treatment on a specific ratio might be an enhanced option for further assessment against AD. However, the food ingredients are found in combination and hence promising for exerting a superior neuroprotective effect (229).

Parkinson’s disease (PD) is a progressive and degenerative disease that affects more than 6 million public (230). Motor, as well as nonmotor, symptoms manifest it. Hence, the motor symptoms include resting tremor, bradykinesia, rigidity, and postural instability. Spontaneous movement is drastically reduced, with the failure of facial expression, decreased blink rate, and damaged spontaneous swallowing, which affects sialorrhea. However, patients with PD can experience retropulsion and festination (231, 232). The nonmotor symptoms include anxiety, dysautonomia, cognitive decline, anosmia, depression, urinary complaints, disturbances, sleep, and orthostatic hypotension (233, 234). CA’s inhibitory action against α-synuclein fibrillation could lead us to plan novel therapeutic agents for PD (235). CA pre-intake has sustained TH action, protein-making, and dopamine synthesis. It is a promising neuroprotective drug for the development of PD (236). CA possesses neurotrophic results exerted by the modulation of Akt and ERK1/2 pathways, hence representing potential agents for finding neurotrophic compounds for the treatment of neurodegenerative disorders (237). However, the anti-inflammatory action of CA emphasized its neuroprotective action against rotenone-mediated neurodegeneration in mice (238).